array(3) { [0]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(2) "21" ["~IBLOCK_SECTION_ID"]=> string(2) "21" ["ID"]=> string(3) "685" ["~ID"]=> string(3) "685" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(252) "Генная терапия лентивирусными векторами в гемо- поэтических стволовых клетках при врожденных дефицитах иммунитета и лизосомных энзимов" ["~NAME"]=> string(252) "Генная терапия лентивирусными векторами в гемо- поэтических стволовых клетках при врожденных дефицитах иммунитета и лизосомных энзимов" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(19) "30.03.2017 19:32:49" ["~TIMESTAMP_X"]=> string(19) "30.03.2017 19:32:49" ["DETAIL_PAGE_URL"]=> string(161) "/ru/archive/vypusk-5-nomer-4/eksperimentalnye-issledovaniya/gennaya-terapiya-lentivirusnymi-vektorami-v-gemo-poeticheskikh-stvolovykh-kletkakh-pri-vrozhdennykh-/" ["~DETAIL_PAGE_URL"]=> string(161) "/ru/archive/vypusk-5-nomer-4/eksperimentalnye-issledovaniya/gennaya-terapiya-lentivirusnymi-vektorami-v-gemo-poeticheskikh-stvolovykh-kletkakh-pri-vrozhdennykh-/" ["LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["~LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["DETAIL_TEXT"]=> string(28175) "

Introduction

Rare diseases, of which 80% are inherited disorders, affect some 6% of the human population, amounting in Europe to around 30 million people. Since many result in chronic disability and cost-intensive care, the impact is disproportional and may well be over 20% of health care costs, although the current lack of registration, contrary to cancer, makes exact estimates difficult. Most of the approximately 7500 known inherited diseases lack a curative intervention, are managed by symptomatic treatment and, in case of a family history, by prenatal diagnosis. A small minority is included in newborn screening programs. At the state of the art, gene therapy is within reach for diseases in which (i) the genetic defect is identified, (ii) the diagnosis is made sufficiently early for a meaningful therapeutic intervention, (iii) a specific animal model is available for efficacy and safety evaluation, (iv) strict regulation of transgene product levels is not required, (v) the transgene produces levels sufficient for sustained alleviation of symptoms or cure, and (vi) adverse immune responses to the transgene product are not expected, do not interfere with efficacy, or can be successfully counteracted or circumvented. Many of the more than 100 primary immune deficiencies and around 40 lysosomal storage disorders meet those criteria.

This brief review covers development and prospect of gene therapy for inherited immune deficiencies and lysosomal storage disorders, extending an earlier review [45].

Initial development of hematopoietic stem cell gene therapy

Hematopoietic stem cell gene therapy has been developed over more than 20 years. The pioneering trials for X-linked severe combined immune deficiency (SCID) using gammaretroviral gene transfer vectors resulted in successful restoration of T cell immunity [17, 22] in 18 patients and in long-term survival for 17 patients out of 20, a survival rate similar to HLA-identical BM transplantation [35]. Unfortunately, in 5 patients autonomous T cell clones developed into leukemia, among which 1 patient did not survive. In the context of European collaborative projects, the pathogenesis was rapidly elucidated, resulting in a series of publications on mechanisms involved in gammaretroviral mutagenesis and oncogenesis [3,12,13,28,31,32,37]. Briefly, gammaretroviral vectors generally integrate near the transcription start sites of expressed genes with a preference for proto-oncogenes, which results in aberrant expression driven by the promoter/ enhancer of the therapeutic transgene and may result in a preleukemic state. It is not excluded that the phenotypes of the treated diseases co-predispose to leukemia development [38], given the absence of leukemia in the ADA-SCID trial [1, 4], a 25% incidence in the X-linked SCID trials and an over 75% incidence in a gammaretroviral Wiskott-Aldrich trial [6].

Development of lentiviral vector gene therapy in inherited storage disorders

The gammaretroviral vectors have been replaced by HIV-1 derived lentiviral vectors [29,36,48], which lack the propensity for integration near proto-oncogenes and have the added advantage of integrating into quiescent cells, such as longterm repopulating stem cells. In addition, third generation lentiviral vectors made self-inactivating (SIN) by deletion of enhancer regions from the long terminal repeat sequences reduce the risk of influencing nearby genes, resulting in favorable safety profiles [8]. Systematic disease specific efficacy and safety evaluations, including codon optimization and careful promoter selection have enabled initial clinical trials using these vectors for selected metabolic storage disorders (Table 1), which include adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD), and Hurler (MPS I), Pompe (GSD II) and Fabry diseases. We have focused on Pompe disease, the only disorder so far developed for stem cell gene therapy [42] in which allogeneic stem cell transplantation has not been applied due to lack of enzyme expression in the hematopoietic system [25] and in addition studied stem cell gene therapy for Hurler syndrome.

Hurler Syndrome and Pompe disease

Hurler Syndrome (Mucopolysaccharidosis type I, OMIM # 252800) is a lethal autosomal recessive storage disorder caused by a deficiency of the lysosomal enzyme α-L-iduronidase (IDUA; EC 3.2.1.76). The deficiency leads to insufficient degradation of glycoaminoglycans (GAG’s’) that interferes with normal cellular function and causes a multisystem disorder affecting the CNS, liver, skeleton, lungs and sensory organs (corneal clouding and deafness), average expected life-span approximately 5-10 years. Treatment consists of alloSCT, currently the only therapeutic option to establish long-term survival and protection of the CNS. Enzyme replacement has a systemic effect but does not reach the brain or the skeletal bones. AlloSCT does not improve the skeleton pathology either. Although clinical outcome of SCT has improved by the use of umbilical cord stem cells, progressive bone disease persists, leading to severe handicaps. An international long term clinical follow-up cohort of Hurler patients treated with alloSCT including >80% of the patients successfully transplanted worldwide [2] showed that certain genotypes, age at HSCT, and poor performance at HSCT are predictors for poor skeletal and neurodevelopmental outcome. These findings warrant the development of a single curative gene therapy approach.

Pompe disease (glycogen storage disease type II, acid maltase deficiency, OMIM # 232300) is a rare autosomal recessive lysosomal storage disorder caused by mutations in the gene-encoding acid α-glucosidase (EC 3.2.1.20) [40]. Severe mutations cause complete enzyme deficiency, resulting in the classic infantile form of Pompe disease, which was first

described by the Dutch pathologist J.C.Pompe [33]. Symptoms are caused by glycogen accumulation, mainly in skeletal, cardiac and smooth muscle, but also in other tissues, including the central and peripheral nervous system. In the first months of life, patients present with progressive muscle weakness, hypertrophic cardiomyopathy, respiratory problems and feeding difficulties. If untreated, this leads to death before the age of one year [39]. Older children and adults may have up to 20-30% residual enzyme activity and show a more slowly progressive phenotype. The symptoms generally result from weakness of the (proximal) skeletal muscles. These patients eventually become wheelchair bound and ventilator dependent in late childhood or adulthood.

Enzyme replacement therapy (ERT) by administration of recombinant acid α-glucosidase [16,40] (Myozyme®) is currently the only effective treatment, requiring high dose biweekly administration. Although of considerable benefit to many patients, ERT is not curative, requires life-long administration, may result in immune responses to the recombinant enzyme [41] and, partly due to the high doses required for clinical efficacy, the costs are extremely high. Therefore, a corrective intervention with curative intent represents an unmet medical need.

Efficacy and safety evaluation of lentiviral vector gene therapy in the Hurler and Pompe mouse models

The natural course of Hurler’s disease is invalidating and lethal, and the drawbacks of the current therapeutic modalities justify a gene therapy approach. An IDUA knock-out mouse model has been developed suitable to study gene therapeutic approaches and made available to our research. A gene therapy study with HSC in the IDUA KO mice showed improvement of disease pathology, including the brain, but bone remodeling was not reported [14]. Using a codon optimized IDUA gene driven by a cellular promoter in a lentiviral vector to transduce hematopoietic stem cells, we demonstrated long-term expression in the hematopoietic system resulting in full correction of the Hurler phenotype (unpublished) without any severe adverse effects. Similar results and a further safety analysis were obtained in a parallel study [43,44], completing the preclinical analysis enabling an initial clinical trial in selected patients.

In the initial evaluation of lentiviral stem cell gene therapy for Pompe disease using an efficient overnight transduction protocol [42], we demonstrated that approximately 30% successfully transduced cells present in the bone marrow after sublethal total body irradiation as conditioning for transplantation resulted in high levels of α-glucosidase. Restoration of α-glucosidase activity in target tissues by uptake through the mannose-6-phosphate receptor reduced glycogen storage proportional to the enzyme levels achieved, with full correction of glycogen storage in liver and spleen, correction of the life-threatening cardiomyopathy, significantly improved respiration and improved, but not fully normalized skeletal muscle function. Of particular interest was the demonstration of robust immune tolerance to the recombinant transgene product. In the follow-up study (manuscript in preparation), codon-optimization of the therapeutic transgene resulted in full correction of the phenotype including skeletal muscles. Remarkably, although Pompe disease does not result in mental retardation or other neuronal problems, also brain glycogen levels normalized entirely, with all astrocytes, which play a key role in glycogen storage and glycogenolysis in the brain, showing active acid α-glucosidase activity. Apparently the microglia descendants of hematopoietic stem cells, which are capable of passing the blood-brain-barrier, as we originally demonstrated in the mouse model of Krabbe disease [24], provide sufficient acid α-glucosidase to normalize glycogen levels also in neuronal tissue. Up till now, hematopoietic stem cell gene therapy is the only approach to achieve both robust immune tolerance to the transgene product and efficacy in bypassing the blood/ brain barrier, as has also been observed by others [43].

Clinical implementation of stem cell gene therapy in primary immune deficiencies

A summary of the current developments is provided in Table 2. Briefly, successful clinical trials are ongoing for X-linked SCID, ADA-SCID and Wiskott-Aldrich syndrome, while

clinical trials are being prepared for RAG2 deficiency, chronic granulomatous disease and Artemis. Gene therapy for ADA-SCID, which is difficult to treat with allogeneic stem cell transplantation, has recently been registered as an advanced therapy medicinal product and will soon be considered as the standard treatment for this disease.

Further developments

The future development of stem cell gene therapy efficacy and safety would obviously benefit considerably from non-cytoreductive preparation of the patients to enable engraftment of the gene-corrected cells, ex vivo stem cell expansion both to promote engraftment of transduced cells and to enable selection of stem cells for transplantation, lineage specific expression of the therapeutic transgene, targeted gene delivery, and eventually gene editing of the deficient mutant genes. Promoting engraftment by temporary mobilization of endogenous stem cells to open the stem cell niches in the bone marrow has been proposed [9] and applied successfully in the X-SCID mouse model [26]. An initial success has recently been reported in gene editing [20]. If the current clinical trials using lentiviral stem cell gene transfer prove efficacious and safe, its rapid clinical implementation in a variety of eligible inherited disorders will become within reach in the interest of the patients involved and thereby of health care and its costs.

Funding

Funding was provided by the European Commission’s 5th, 6th and 7th Framework Programs, Contracts QLK3-CT- 2001-00427-INHERINET, LSHB-CT-2004-005242-CONSERT, LSHB-CT-2006-19038-Magselectofection, Grant Agreement 222878-PERSIST and Grant agreement 261387 CELL-PID, and by the Netherlands Health Research and Development Organization ZonMW (Translational Gene Therapy program grants 43100016 and 43400010).

Author Disclosure Statement

The author declares no competing financial interest.

References

1. Aiuti A, Cassani B, Andolfi G, Mirolo M, Biasco L, Recchia A, Urbinati F, Valacca C, Scaramuzza S, Aker M, Slavin S, Cazzola M, Sartori D, Ambrosi A, Di Serio C, Roncarolo MG, Mavilio F, Bordignon C. Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy. J Clin Invest 2007; 117 (8): 2233-2240.
2. Aldenhoven M, Wynn RF, Orchard PJ, O’Meara A, Veys P, Fischer A,Valayannopoulos V, Neven B, Rovelli A, Prasad VK, Tolar J, Allewelt H, Jones SA, Parini R, Renard M, Bordon V, Wulffraat NM, de Koning TJ, Shapiro EG, Kurtzberg J, Boelens JJ. Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study. Blood 2015; 125 (13): 2164-2172.
3. Baum C, von Kalle C, Staal FJ, Li Z, Fehse B, Schmidt M, Weerkamp F, Karlsson S, Wagemaker G, Williams DA. Chance or necessity? Insertional mutagenesis in gene therapy and its consequences. Mol Ther 2004; 9 (1): 5-13.
4. Biasco L, Ambrosi A, Pellin D, Bartholomae C, Brigida I, Roncarolo MG, Di Serio C, von Kalle C, Schmidt M, Aiuti A. Integration profile of retroviralvector in gene therapy treated patients is cell-specific according to gene expression and chromatin conformation of target cell. EMBO Mol Med 2011; 3 (2): 89-101.
5. Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, Baldoli C, Martino S, Calabria A, Canale S, Benedicenti F, Vallanti G, Biasco L, Leo S, Kabbara N, Zanetti G, Rizzo WB, Mehta NA, Cicalese MP, Casiraghi M, Boelens JJ, Del Carro U, Dow DJ, Schmidt M, Assanelli A, Neduva V, Di Serio C, Stupka E, Gardner J, von Kalle C, Bordignon C, Ciceri F, Rovelli A, Roncarolo MG, Aiuti A, Sessa M, Naldini L. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 2013;341(6148):1233158.
6. Braun CJ, Boztug K, Paruzynski A, Witzel M, Schwarzer A, Rothe M, Modlich U, Beier R, Göhring G, Steinemann D, Fronza R, Ball CR, Haemmerle R, Naundorf S, Kühlcke K, Rose M, Fraser C, Mathias L, Ferrari R, Abboud MR, Al- Herz W, Kondratenko I, Maródi L, Glimm H, Schlegelberger B, Schambach A, Albert MH, Schmidt M, von Kalle C, Klein C. Gene therapy for Wiskott-Aldrichsyndrome-longterm efficacy and genotoxicity. Sci Transl Med 2014; 6 (227): 227ra33.
7. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy.Cartier N, Hacein- Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, Vidaud M, Abel U, Dal-Cortivo L, Caccavelli L, Mahlaoui N, Kiermer V, Mittelstaedt D, Bellesme C, Lahlou N, Lefrère F, Blanche S, Audit M, Payen E, Leboulch P, l’Homme B, Bougnères P, Von Kalle C, Fischer A, Cavazzana- Calvo M, Aubourg P. Science 2009; 326 (5954): 818-823.
8. Cesana D, Ranzani M, Volpin M, Bartholomae C, Duros C, Artus A, Merella S, Benedicenti F, Sergi Sergi L, Sanvito F, Brombin C, Nonis A, Serio CD, Doglioni C, von Kalle C, Schmidt M, Cohen-Haguenauer O, Naldini L, Montini E. Uncovering and dissecting the genotoxicity of self-inactivating lentiviral vectors in vivo. Mol Ther 2014; 22 (4): 774-785.
9. Chen J, Larochelle A, Fricker S, Bridger G, Dunbar CE, Abkowitz JL. Mobilization as a preparative regimen for hematopoietic stem cell transplantation. Blood 2006; 107 (9): 3764-3771.
10. Cicalese MP, Ferrua F, Castagnaro L, Pajno R, Barzaghi F, Giannelli S, Dionisio F, Brigida I, Bonopane M, Casiraghi M, Tabucchi A, Carlucci F, Grunebaum E, Adeli M, Bredius RG, Puck JM, Stepensky P, Tezcan I, Rolfe K, De Boever E, Reinhardt RR, Appleby J, Ciceri F, Roncarolo MG, Aiuti A. Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency. Blood 2016; 128 (1): 45-54.
11. De Ravin SS, Reik A, Liu PQ, Li L, Wu X, Su L, Raley C, Theobald N, Choi U, Song AH, Chan A, Pearl JR, Paschon DE, Lee J, Newcombe H, Koontz S, Sweeney C, Shivak DA, Zarember KA, Peshwa MV, Gregory PD, Urnov FD, Malech HL. Targeted gene addition in human CD34(+) hematopoietic cells for correction of X-linked chronic granulomatous disease. Nat Biotechnol 2016; 34 (4): 424-429.
12. Deichmann A, Brugman MH, Bartholomae CC, Schwarzwaelder K, Verstegen MM, Howe SJ, Arens A, Ott MG, Hoelzer D, Seger R, Grez M, Hacein-Bey-Abina S, Cavazzana- Calvo M, Fischer A, Paruzynski A, Gabriel R, Glimm H, Abel U, Cattoglio C, Mavilio F, Cassani B, Aiuti A, Dunbar CE, Baum C, Gaspar HB, Thrasher AJ, von Kalle C, Schmidt M, Wagemaker G. Insertion sites in engrafted cells cluster within a limited repertoire of genomic areas after gammaretroviral vector gene therapy. Mol Ther 2011; 19 (11): 2031- 2039.
13. Deichmann A, Hacein-Bey-Abina S, Schmidt M, Garrigue A, Brugman MH, Hu J, Glimm H, Gyapay G, Prum B, Fraser CC, Fischer N, Schwarzwaelder K, Siegler ML, de Ridder D, Pike-Overzet K, Howe SJ, Thrasher AJ, Wagemaker G, Abel U, Staal FJ, Delabesse E, Villeval JL, Aronow B, Hue C, Prinz C, Wissler M, Klanke C, Weissenbach J, Alexander I, Fischer A, von Kalle C, Cavazzana-Calvo M. Vector integration is nonrandom and clustered and influences the fate of lymphopoiesis in SCID-X1 gene therapy. J Clin Invest 2007; 117 (8): 2225-2232.
14. Desmaris N, Verot L, Puech JP, Caillaud C, Vanier MT, Heard JM. Prevention of neuropathology in the mouse model of Hurler syndrome. Ann Neurol 2004; 56 (1): 68-76.
15. Enquist IB, Nilsson E, Ooka A, Månsson JE, Olsson K, Ehinger M, Brady RO, Richter J, Karlsson S. Effective cell and gene therapy in a murine model of Gaucher disease. Proc Natl Acad Sci USA 2006; 103 (37): 13819-13824.
16. Fuller M, Van der Ploeg A, Reuser AJ, Anson DS, Hopwood JJ. Isolation and characterization of a recombinant, precursor form of lysosomal acid alpha-glucosidase. Eur J Biochem 1995; 234 (3): 903-909.
17. Gaspar HB, Parsley KL, Howe S, King D, Gilmour KC, Sinclair J, Brouns G, Schmidt M, Von Kalle C, Barington T, Jakobsen MA, Christensen HO, Al Ghonaium A, White HN, Smith JL, Levinsky RJ, Ali RR, Kinnon C, Thrasher AJ. Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet 2004 ; 364 (9452): 2181-2187.
18. Gaspar HB, Cooray S, Gilmour KC, Parsley KL, Adams S, Howe SJ, Al Ghonaium A, Bayford J, Brown L, Davies EG, Kinnon C, Thrasher AJ. Long-term persistence of a polyclonal T cell repertoire after gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med 2011; 3 (97): 97ra79.
19. Gaspar HB, Cooray S, Gilmour KC, Parsley KL, Zhang F, Adams S, Bjorkegren E, Bayford J, Brown L, Davies EG, Veys P, Fairbanks L, Bordon V, Petropoulou T, Kinnon C, Thrasher AJ. Hematopoietic stem cell gene therapy for adenosine deaminase-deficient severe combined immunodeficiency leads to long-term immunological recovery and metabolic correction. Sci Transl Med 2011; 3 (97): 97ra80.
20. Genovese P, Schiroli G, Escobar G, Di Tomaso T, Firrito C, Calabria A, Moi D, Mazzieri R, Bonini C, Holmes MC, Gregory PD, van der Burg M, Gentner B, MontiniE, Lombardo A, Naldini L. Targeted genome editing in human repopulating haematopoietic stem cells. Nature 2014; 510 (7504): 235-240.
21. Gentner B, Visigalli I, Hiramatsu H, Lechman E, Ungari S, Giustacchini A, Schira G, Amendola M, Quattrini A, Martino S, Orlacchio A, Dick JE, Biffi A, Naldini L. Identification of hematopoietic stem cell-specific miRNAs enables gene therapy of globoid cell leukodystrophy. Sci Transl Med 2010; 2 (58): 58ra84.
22. Hacein-Bey-Abina S, Hauer J, Lim A, Picard C, Wang GP, Berry CC, Martinache C, Rieux-Laucat F, Latour S, Belohradsky BH, Leiva L, Sorensen R, Debré M, Casanova JL, Blanche S, Durandy A, Bushman FD, Fischer A, Cavazzana- Calvo M. Efficacy of gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2010; 363 (4): 355-364.
23. Hacein-Bey-Abina S, Pai SY, Gaspar HB, Armant M, Berry CC, Blanche S, Bleesing J, Blondeau J, de Boer H, Buckland KF, Caccavelli L, Cros G, De Oliveira S, Fernández KS, Guo D, Harris CE, Hopkins G, Lehmann LE, Lim A, London WB, van der Loo JC, Malani N, Male F, Malik P, Marinovic MA, McNicol AM, Moshous D, Neven B, Oleastro M, Picard C, Ritz J, Rivat C, Schambach A, Shaw KL, Sherman EA, Silberstein LE, Six E, Touzot F, Tsytsykova A, Xu-Bayford J, Baum C, Bushman FD, Fischer A, Kohn DB, Filipovich AH, Notarangelo LD, Cavazzana M, Williams DA, Thrasher AJ. A modified γ-retrovirus vector for X-linked severe combined immunodeficiency. N Engl J Med 2014; 371 (15): 1407-1417.
24. Hoogerbrugge PM, Suzuki K, Suzuki K, Poorthuis BJ, Kobayashi T, Wagemaker G, van Bekkum DW. Donor-derived cells in the central nervous system of twitcher mice after bone marrow transplantation. Science 1988; 239 (4843): 1035-1038.
25. Hoogerbrugge PM, Wagemaker G, van Bekkum DW, Reuser AJ, vd Ploeg AT. Bone marrow transplantation for Pompé’s disease. N Engl J Med 1986; 315 (1): 65-66.
26. Huston MW, Riegman AR, Yadak R, van Helsdingen Y, de Boer H, van Til NP, Wagemaker G. Pretransplant mobilization with granulocyte colony-stimulating factor improves B-cell reconstitution by lentiviral vector gene therapy in SCID-X1 mice. Hum Gene Ther 2014; 25 (10): 905-914.
27. Kaufmann KB, Chiriaco M, Siler U, Finocchi A, Reichenbach J, Stein S, Grez M. Gene therapy for chronic granulomatous disease: current status and future perspectives. Curr Gene Ther 2014; 14 (6): 447-460.
28. Kustikova OS, Geiger H, Li Z, Brugman MH, Chambers SM, Shaw CA, Pike-Overzet K, de Ridder D, Staal FJ, von Keudell G, Cornils K, Nattamai KJ, Modlich U, Wagemaker G, Goodell MA, Fehse B, Baum C. Retroviral vector insertion sites associated with dominant hematopoietic clones mark “stemness” pathways. Blood 2007; 109 (5): 1897-1907.
29. Naldini L, Blömer U, Gallay P, Ory D, Mulligan R, Gage FH, Verma IM, Trono D. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 1996; 272 (5259): 263-267.
30. Pala F, Morbach H, Castiello MC, Schickel JN, Scaramuzza S, Chamberlain N, Cassani B, Glauzy S, Romberg N, Candotti F, Aiuti A, Bosticardo M, Villa A, Meffre E. Lentiviral- mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients. J Clin Invest 2015; 125 (10): 3941-3951.
31. Pike-Overzet K, de Ridder D, Weerkamp F, Baert MR, Verstegen MM, Brugman MH, Howe SJ, Reinders MJ, Thrasher AJ, Wagemaker G, van Dongen JJ, Staal FJ. Gene therapy: is IL2RG oncogenic in T-cell development? Nature 2006; 443 (7109): E5; discussion E6-7.
32. Pike-Overzet K, van der Burg M, Wagemaker G, van Dongen JJ, Staal FJ. New insights and unresolved issues regarding insertional mutagenesis in X-linked SCID gene therapy. Mol Ther 2007; 15 (11): 1910-1916.
33. Pompe JC. Over idiopathische hypertrophie van het hart. 1932; N. T. v. G. 76.I.3.
34. Rivera-Munoz P, Abramowski V, Jacquot S, André P, Charrier S, Lipson-Ruffert K, Fischer A, Galy A, Cavazzana M, de Villartay JP. Lymphopoiesis in transgenic mice over-expressing Artemis. Gene Ther 2016; 23 (2): 176-186.
35. Rocha V, Wagner JE Jr, Sobocinski KA, Klein JP, Zhang MJ, Horowitz MM, Gluckman E. Graft-versus-host disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources. N Engl J Med 2000; 342 (25): 1846-1854.
36. Schambach A, Bohne J, Baum C, Hermann FG, Egerer L, von Laer D, Giroglou T. Woodchuck hepatitis virus post-transcriptional regulatory element deleted from X protein and promoter sequences enhances retroviral vector titer and expression. Gene Ther 2006; 13 (7): 641-645.
37. Schwarzwaelder K, Howe SJ, Schmidt M, Brugman MH, Deichmann A, Glimm H, Schmidt S, Prinz C, Wissler M, King DJ, Zhang F, Parsley KL, Gilmour KC, Sinclair J, Bayford J, Peraj R, Pike-Overzet K, Staal FJ, de Ridder D, Kinnon C, Abel U, Wagemaker G, Gaspar HB, Thrasher AJ, von Kalle C. Gammaretrovirus-mediated correction of SCID-X1 is associated with skewed vector integration site distribution in vivo. J Clin Invest 2007; 117 (8): 2241-2249.
38. Shou Y, Ma Z, Lu T, Sorrentino BP. Unique risk factors for insertional mutagenesis in a mouse model of XSCID gene therapy. Proc Natl Acad Sci USA 2006; 103 (31): 11730-11735.
39. van den Hout HM, Hop W, van Diggelen OP, Smeitink JA, Smit GP, Poll-The BT, Bakker HD, Loonen MC, de Klerk JB, Reuser AJ, van der Ploeg AT. The natural course of infantile Pompe’s disease: 20 original cases compared with 133 cases from the literature. Pediatrics 2003; 112 (2): 332-340.
40. van der Ploeg AT, Reuser AJ. Pompe’s disease. Lancet 2008 Oct 11; 372 (9646): 1342-53.
41. van Gelder CM, Hoogeveen-Westerveld M, Kroos MA, Plug I, van der Ploeg AT, Reuser AJ. Enzyme therapy and immune response in relation to CRIM status: the Dutch experience in classic infantile Pompe disease. J Inherit Metab Dis. 2015; 38 (2): 305-314.
42. van Til NP, Wagemaker G. Lentiviral gene transduction of mouse and human hematopoietic stem cells. Methods Mol Biol 2014; 1185: 311-319.
43. Visigalli I, Delai S, Politi LS, Di Domenico C, Cerri F, Mrak E, D’Isa R, Ungaro D, Stok M, Sanvito F, Mariani E, Staszewsky L, Godi C, Russo I, Cecere F, Del Carro U, Rubinacci A, Brambilla R, Quattrini A, Di Natale P, Ponder K, Naldini L, Biffi A. Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model. Blood 2010; 116 (24): 5130-5139.
44. Visigalli I, Delai S, Ferro F, Cecere F, Vezzoli M, Sanvito F, Chanut F, Benedicenti F, Spinozzi G, Wynn R, Calabria A, Naldini L, Montini E, Cristofori P, Biffi A. Preclinical testing of the safety and tolerability of LV-mediated above normal alpha-L-iduronidase expression in murine and human hematopoietic cells using toxicology and biodistribution GLP studies. Hum Gene Ther 2016 Jul 18.
45. Wagemaker G. Lentiviral hematopoietic stem cell gene therapy in inherited metabolic disorders. Hum Gene Ther 2014; 25 (10): 862-865.
46. Walia JS, Neschadim A, Lopez-Perez O, Alayoubi A, Fan X, Carpentier S, Madden M, Lee CJ, Cheung F, Jaffray DA, Levade T, McCart JA, Medin JA. Autologous transplantation of lentivector/acid ceramidase-transduced hematopoietic cells in nonhuman primates. Hum Gene Ther 2011; 22 (6): 679-687.
47. Yoshimitsu M, Higuchi K, Ramsubir S, Nonaka T, Rasaiah VI, Siatskas C, Liang SB, Murray GJ, Brady RO, Medin JA. Efficient correction of Fabry mice and patient cells mediated by lentiviral transduction of hematopoietic stem/progenitor cells. Gene Ther 2007; 14 (3): 256-265.
48. Zhang F, Thornhill SI, Howe SJ, Ulaganathan M, Schambach A, Sinclair J, Kinnon C, Gaspar HB, Antoniou M, Thrasher AJ. Lentiviral vectors containing an enhancer-less ubiquitously acting chromatin opening element (UCOE) provide highly reproducible and stable transgene expression in hematopoietic cells. Blood. 2007; 110 (5): 1448-1457.

" ["~DETAIL_TEXT"]=> string(28175) "

Introduction

Rare diseases, of which 80% are inherited disorders, affect some 6% of the human population, amounting in Europe to around 30 million people. Since many result in chronic disability and cost-intensive care, the impact is disproportional and may well be over 20% of health care costs, although the current lack of registration, contrary to cancer, makes exact estimates difficult. Most of the approximately 7500 known inherited diseases lack a curative intervention, are managed by symptomatic treatment and, in case of a family history, by prenatal diagnosis. A small minority is included in newborn screening programs. At the state of the art, gene therapy is within reach for diseases in which (i) the genetic defect is identified, (ii) the diagnosis is made sufficiently early for a meaningful therapeutic intervention, (iii) a specific animal model is available for efficacy and safety evaluation, (iv) strict regulation of transgene product levels is not required, (v) the transgene produces levels sufficient for sustained alleviation of symptoms or cure, and (vi) adverse immune responses to the transgene product are not expected, do not interfere with efficacy, or can be successfully counteracted or circumvented. Many of the more than 100 primary immune deficiencies and around 40 lysosomal storage disorders meet those criteria.

This brief review covers development and prospect of gene therapy for inherited immune deficiencies and lysosomal storage disorders, extending an earlier review [45].

Initial development of hematopoietic stem cell gene therapy

Hematopoietic stem cell gene therapy has been developed over more than 20 years. The pioneering trials for X-linked severe combined immune deficiency (SCID) using gammaretroviral gene transfer vectors resulted in successful restoration of T cell immunity [17, 22] in 18 patients and in long-term survival for 17 patients out of 20, a survival rate similar to HLA-identical BM transplantation [35]. Unfortunately, in 5 patients autonomous T cell clones developed into leukemia, among which 1 patient did not survive. In the context of European collaborative projects, the pathogenesis was rapidly elucidated, resulting in a series of publications on mechanisms involved in gammaretroviral mutagenesis and oncogenesis [3,12,13,28,31,32,37]. Briefly, gammaretroviral vectors generally integrate near the transcription start sites of expressed genes with a preference for proto-oncogenes, which results in aberrant expression driven by the promoter/ enhancer of the therapeutic transgene and may result in a preleukemic state. It is not excluded that the phenotypes of the treated diseases co-predispose to leukemia development [38], given the absence of leukemia in the ADA-SCID trial [1, 4], a 25% incidence in the X-linked SCID trials and an over 75% incidence in a gammaretroviral Wiskott-Aldrich trial [6].

Development of lentiviral vector gene therapy in inherited storage disorders

The gammaretroviral vectors have been replaced by HIV-1 derived lentiviral vectors [29,36,48], which lack the propensity for integration near proto-oncogenes and have the added advantage of integrating into quiescent cells, such as longterm repopulating stem cells. In addition, third generation lentiviral vectors made self-inactivating (SIN) by deletion of enhancer regions from the long terminal repeat sequences reduce the risk of influencing nearby genes, resulting in favorable safety profiles [8]. Systematic disease specific efficacy and safety evaluations, including codon optimization and careful promoter selection have enabled initial clinical trials using these vectors for selected metabolic storage disorders (Table 1), which include adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD), and Hurler (MPS I), Pompe (GSD II) and Fabry diseases. We have focused on Pompe disease, the only disorder so far developed for stem cell gene therapy [42] in which allogeneic stem cell transplantation has not been applied due to lack of enzyme expression in the hematopoietic system [25] and in addition studied stem cell gene therapy for Hurler syndrome.

Hurler Syndrome and Pompe disease

Hurler Syndrome (Mucopolysaccharidosis type I, OMIM # 252800) is a lethal autosomal recessive storage disorder caused by a deficiency of the lysosomal enzyme α-L-iduronidase (IDUA; EC 3.2.1.76). The deficiency leads to insufficient degradation of glycoaminoglycans (GAG’s’) that interferes with normal cellular function and causes a multisystem disorder affecting the CNS, liver, skeleton, lungs and sensory organs (corneal clouding and deafness), average expected life-span approximately 5-10 years. Treatment consists of alloSCT, currently the only therapeutic option to establish long-term survival and protection of the CNS. Enzyme replacement has a systemic effect but does not reach the brain or the skeletal bones. AlloSCT does not improve the skeleton pathology either. Although clinical outcome of SCT has improved by the use of umbilical cord stem cells, progressive bone disease persists, leading to severe handicaps. An international long term clinical follow-up cohort of Hurler patients treated with alloSCT including >80% of the patients successfully transplanted worldwide [2] showed that certain genotypes, age at HSCT, and poor performance at HSCT are predictors for poor skeletal and neurodevelopmental outcome. These findings warrant the development of a single curative gene therapy approach.

Pompe disease (glycogen storage disease type II, acid maltase deficiency, OMIM # 232300) is a rare autosomal recessive lysosomal storage disorder caused by mutations in the gene-encoding acid α-glucosidase (EC 3.2.1.20) [40]. Severe mutations cause complete enzyme deficiency, resulting in the classic infantile form of Pompe disease, which was first

described by the Dutch pathologist J.C.Pompe [33]. Symptoms are caused by glycogen accumulation, mainly in skeletal, cardiac and smooth muscle, but also in other tissues, including the central and peripheral nervous system. In the first months of life, patients present with progressive muscle weakness, hypertrophic cardiomyopathy, respiratory problems and feeding difficulties. If untreated, this leads to death before the age of one year [39]. Older children and adults may have up to 20-30% residual enzyme activity and show a more slowly progressive phenotype. The symptoms generally result from weakness of the (proximal) skeletal muscles. These patients eventually become wheelchair bound and ventilator dependent in late childhood or adulthood.

Enzyme replacement therapy (ERT) by administration of recombinant acid α-glucosidase [16,40] (Myozyme®) is currently the only effective treatment, requiring high dose biweekly administration. Although of considerable benefit to many patients, ERT is not curative, requires life-long administration, may result in immune responses to the recombinant enzyme [41] and, partly due to the high doses required for clinical efficacy, the costs are extremely high. Therefore, a corrective intervention with curative intent represents an unmet medical need.

Efficacy and safety evaluation of lentiviral vector gene therapy in the Hurler and Pompe mouse models

The natural course of Hurler’s disease is invalidating and lethal, and the drawbacks of the current therapeutic modalities justify a gene therapy approach. An IDUA knock-out mouse model has been developed suitable to study gene therapeutic approaches and made available to our research. A gene therapy study with HSC in the IDUA KO mice showed improvement of disease pathology, including the brain, but bone remodeling was not reported [14]. Using a codon optimized IDUA gene driven by a cellular promoter in a lentiviral vector to transduce hematopoietic stem cells, we demonstrated long-term expression in the hematopoietic system resulting in full correction of the Hurler phenotype (unpublished) without any severe adverse effects. Similar results and a further safety analysis were obtained in a parallel study [43,44], completing the preclinical analysis enabling an initial clinical trial in selected patients.

In the initial evaluation of lentiviral stem cell gene therapy for Pompe disease using an efficient overnight transduction protocol [42], we demonstrated that approximately 30% successfully transduced cells present in the bone marrow after sublethal total body irradiation as conditioning for transplantation resulted in high levels of α-glucosidase. Restoration of α-glucosidase activity in target tissues by uptake through the mannose-6-phosphate receptor reduced glycogen storage proportional to the enzyme levels achieved, with full correction of glycogen storage in liver and spleen, correction of the life-threatening cardiomyopathy, significantly improved respiration and improved, but not fully normalized skeletal muscle function. Of particular interest was the demonstration of robust immune tolerance to the recombinant transgene product. In the follow-up study (manuscript in preparation), codon-optimization of the therapeutic transgene resulted in full correction of the phenotype including skeletal muscles. Remarkably, although Pompe disease does not result in mental retardation or other neuronal problems, also brain glycogen levels normalized entirely, with all astrocytes, which play a key role in glycogen storage and glycogenolysis in the brain, showing active acid α-glucosidase activity. Apparently the microglia descendants of hematopoietic stem cells, which are capable of passing the blood-brain-barrier, as we originally demonstrated in the mouse model of Krabbe disease [24], provide sufficient acid α-glucosidase to normalize glycogen levels also in neuronal tissue. Up till now, hematopoietic stem cell gene therapy is the only approach to achieve both robust immune tolerance to the transgene product and efficacy in bypassing the blood/ brain barrier, as has also been observed by others [43].

Clinical implementation of stem cell gene therapy in primary immune deficiencies

A summary of the current developments is provided in Table 2. Briefly, successful clinical trials are ongoing for X-linked SCID, ADA-SCID and Wiskott-Aldrich syndrome, while

clinical trials are being prepared for RAG2 deficiency, chronic granulomatous disease and Artemis. Gene therapy for ADA-SCID, which is difficult to treat with allogeneic stem cell transplantation, has recently been registered as an advanced therapy medicinal product and will soon be considered as the standard treatment for this disease.

Further developments

The future development of stem cell gene therapy efficacy and safety would obviously benefit considerably from non-cytoreductive preparation of the patients to enable engraftment of the gene-corrected cells, ex vivo stem cell expansion both to promote engraftment of transduced cells and to enable selection of stem cells for transplantation, lineage specific expression of the therapeutic transgene, targeted gene delivery, and eventually gene editing of the deficient mutant genes. Promoting engraftment by temporary mobilization of endogenous stem cells to open the stem cell niches in the bone marrow has been proposed [9] and applied successfully in the X-SCID mouse model [26]. An initial success has recently been reported in gene editing [20]. If the current clinical trials using lentiviral stem cell gene transfer prove efficacious and safe, its rapid clinical implementation in a variety of eligible inherited disorders will become within reach in the interest of the patients involved and thereby of health care and its costs.

Funding

Funding was provided by the European Commission’s 5th, 6th and 7th Framework Programs, Contracts QLK3-CT- 2001-00427-INHERINET, LSHB-CT-2004-005242-CONSERT, LSHB-CT-2006-19038-Magselectofection, Grant Agreement 222878-PERSIST and Grant agreement 261387 CELL-PID, and by the Netherlands Health Research and Development Organization ZonMW (Translational Gene Therapy program grants 43100016 and 43400010).

Author Disclosure Statement

The author declares no competing financial interest.

References

1. Aiuti A, Cassani B, Andolfi G, Mirolo M, Biasco L, Recchia A, Urbinati F, Valacca C, Scaramuzza S, Aker M, Slavin S, Cazzola M, Sartori D, Ambrosi A, Di Serio C, Roncarolo MG, Mavilio F, Bordignon C. Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy. J Clin Invest 2007; 117 (8): 2233-2240.
2. Aldenhoven M, Wynn RF, Orchard PJ, O’Meara A, Veys P, Fischer A,Valayannopoulos V, Neven B, Rovelli A, Prasad VK, Tolar J, Allewelt H, Jones SA, Parini R, Renard M, Bordon V, Wulffraat NM, de Koning TJ, Shapiro EG, Kurtzberg J, Boelens JJ. Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study. Blood 2015; 125 (13): 2164-2172.
3. Baum C, von Kalle C, Staal FJ, Li Z, Fehse B, Schmidt M, Weerkamp F, Karlsson S, Wagemaker G, Williams DA. Chance or necessity? Insertional mutagenesis in gene therapy and its consequences. Mol Ther 2004; 9 (1): 5-13.
4. Biasco L, Ambrosi A, Pellin D, Bartholomae C, Brigida I, Roncarolo MG, Di Serio C, von Kalle C, Schmidt M, Aiuti A. Integration profile of retroviralvector in gene therapy treated patients is cell-specific according to gene expression and chromatin conformation of target cell. EMBO Mol Med 2011; 3 (2): 89-101.
5. Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, Baldoli C, Martino S, Calabria A, Canale S, Benedicenti F, Vallanti G, Biasco L, Leo S, Kabbara N, Zanetti G, Rizzo WB, Mehta NA, Cicalese MP, Casiraghi M, Boelens JJ, Del Carro U, Dow DJ, Schmidt M, Assanelli A, Neduva V, Di Serio C, Stupka E, Gardner J, von Kalle C, Bordignon C, Ciceri F, Rovelli A, Roncarolo MG, Aiuti A, Sessa M, Naldini L. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 2013;341(6148):1233158.
6. Braun CJ, Boztug K, Paruzynski A, Witzel M, Schwarzer A, Rothe M, Modlich U, Beier R, Göhring G, Steinemann D, Fronza R, Ball CR, Haemmerle R, Naundorf S, Kühlcke K, Rose M, Fraser C, Mathias L, Ferrari R, Abboud MR, Al- Herz W, Kondratenko I, Maródi L, Glimm H, Schlegelberger B, Schambach A, Albert MH, Schmidt M, von Kalle C, Klein C. Gene therapy for Wiskott-Aldrichsyndrome-longterm efficacy and genotoxicity. Sci Transl Med 2014; 6 (227): 227ra33.
7. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy.Cartier N, Hacein- Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, Vidaud M, Abel U, Dal-Cortivo L, Caccavelli L, Mahlaoui N, Kiermer V, Mittelstaedt D, Bellesme C, Lahlou N, Lefrère F, Blanche S, Audit M, Payen E, Leboulch P, l’Homme B, Bougnères P, Von Kalle C, Fischer A, Cavazzana- Calvo M, Aubourg P. Science 2009; 326 (5954): 818-823.
8. Cesana D, Ranzani M, Volpin M, Bartholomae C, Duros C, Artus A, Merella S, Benedicenti F, Sergi Sergi L, Sanvito F, Brombin C, Nonis A, Serio CD, Doglioni C, von Kalle C, Schmidt M, Cohen-Haguenauer O, Naldini L, Montini E. Uncovering and dissecting the genotoxicity of self-inactivating lentiviral vectors in vivo. Mol Ther 2014; 22 (4): 774-785.
9. Chen J, Larochelle A, Fricker S, Bridger G, Dunbar CE, Abkowitz JL. Mobilization as a preparative regimen for hematopoietic stem cell transplantation. Blood 2006; 107 (9): 3764-3771.
10. Cicalese MP, Ferrua F, Castagnaro L, Pajno R, Barzaghi F, Giannelli S, Dionisio F, Brigida I, Bonopane M, Casiraghi M, Tabucchi A, Carlucci F, Grunebaum E, Adeli M, Bredius RG, Puck JM, Stepensky P, Tezcan I, Rolfe K, De Boever E, Reinhardt RR, Appleby J, Ciceri F, Roncarolo MG, Aiuti A. Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency. Blood 2016; 128 (1): 45-54.
11. De Ravin SS, Reik A, Liu PQ, Li L, Wu X, Su L, Raley C, Theobald N, Choi U, Song AH, Chan A, Pearl JR, Paschon DE, Lee J, Newcombe H, Koontz S, Sweeney C, Shivak DA, Zarember KA, Peshwa MV, Gregory PD, Urnov FD, Malech HL. Targeted gene addition in human CD34(+) hematopoietic cells for correction of X-linked chronic granulomatous disease. Nat Biotechnol 2016; 34 (4): 424-429.
12. Deichmann A, Brugman MH, Bartholomae CC, Schwarzwaelder K, Verstegen MM, Howe SJ, Arens A, Ott MG, Hoelzer D, Seger R, Grez M, Hacein-Bey-Abina S, Cavazzana- Calvo M, Fischer A, Paruzynski A, Gabriel R, Glimm H, Abel U, Cattoglio C, Mavilio F, Cassani B, Aiuti A, Dunbar CE, Baum C, Gaspar HB, Thrasher AJ, von Kalle C, Schmidt M, Wagemaker G. Insertion sites in engrafted cells cluster within a limited repertoire of genomic areas after gammaretroviral vector gene therapy. Mol Ther 2011; 19 (11): 2031- 2039.
13. Deichmann A, Hacein-Bey-Abina S, Schmidt M, Garrigue A, Brugman MH, Hu J, Glimm H, Gyapay G, Prum B, Fraser CC, Fischer N, Schwarzwaelder K, Siegler ML, de Ridder D, Pike-Overzet K, Howe SJ, Thrasher AJ, Wagemaker G, Abel U, Staal FJ, Delabesse E, Villeval JL, Aronow B, Hue C, Prinz C, Wissler M, Klanke C, Weissenbach J, Alexander I, Fischer A, von Kalle C, Cavazzana-Calvo M. Vector integration is nonrandom and clustered and influences the fate of lymphopoiesis in SCID-X1 gene therapy. J Clin Invest 2007; 117 (8): 2225-2232.
14. Desmaris N, Verot L, Puech JP, Caillaud C, Vanier MT, Heard JM. Prevention of neuropathology in the mouse model of Hurler syndrome. Ann Neurol 2004; 56 (1): 68-76.
15. Enquist IB, Nilsson E, Ooka A, Månsson JE, Olsson K, Ehinger M, Brady RO, Richter J, Karlsson S. Effective cell and gene therapy in a murine model of Gaucher disease. Proc Natl Acad Sci USA 2006; 103 (37): 13819-13824.
16. Fuller M, Van der Ploeg A, Reuser AJ, Anson DS, Hopwood JJ. Isolation and characterization of a recombinant, precursor form of lysosomal acid alpha-glucosidase. Eur J Biochem 1995; 234 (3): 903-909.
17. Gaspar HB, Parsley KL, Howe S, King D, Gilmour KC, Sinclair J, Brouns G, Schmidt M, Von Kalle C, Barington T, Jakobsen MA, Christensen HO, Al Ghonaium A, White HN, Smith JL, Levinsky RJ, Ali RR, Kinnon C, Thrasher AJ. Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet 2004 ; 364 (9452): 2181-2187.
18. Gaspar HB, Cooray S, Gilmour KC, Parsley KL, Adams S, Howe SJ, Al Ghonaium A, Bayford J, Brown L, Davies EG, Kinnon C, Thrasher AJ. Long-term persistence of a polyclonal T cell repertoire after gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med 2011; 3 (97): 97ra79.
19. Gaspar HB, Cooray S, Gilmour KC, Parsley KL, Zhang F, Adams S, Bjorkegren E, Bayford J, Brown L, Davies EG, Veys P, Fairbanks L, Bordon V, Petropoulou T, Kinnon C, Thrasher AJ. Hematopoietic stem cell gene therapy for adenosine deaminase-deficient severe combined immunodeficiency leads to long-term immunological recovery and metabolic correction. Sci Transl Med 2011; 3 (97): 97ra80.
20. Genovese P, Schiroli G, Escobar G, Di Tomaso T, Firrito C, Calabria A, Moi D, Mazzieri R, Bonini C, Holmes MC, Gregory PD, van der Burg M, Gentner B, MontiniE, Lombardo A, Naldini L. Targeted genome editing in human repopulating haematopoietic stem cells. Nature 2014; 510 (7504): 235-240.
21. Gentner B, Visigalli I, Hiramatsu H, Lechman E, Ungari S, Giustacchini A, Schira G, Amendola M, Quattrini A, Martino S, Orlacchio A, Dick JE, Biffi A, Naldini L. Identification of hematopoietic stem cell-specific miRNAs enables gene therapy of globoid cell leukodystrophy. Sci Transl Med 2010; 2 (58): 58ra84.
22. Hacein-Bey-Abina S, Hauer J, Lim A, Picard C, Wang GP, Berry CC, Martinache C, Rieux-Laucat F, Latour S, Belohradsky BH, Leiva L, Sorensen R, Debré M, Casanova JL, Blanche S, Durandy A, Bushman FD, Fischer A, Cavazzana- Calvo M. Efficacy of gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2010; 363 (4): 355-364.
23. Hacein-Bey-Abina S, Pai SY, Gaspar HB, Armant M, Berry CC, Blanche S, Bleesing J, Blondeau J, de Boer H, Buckland KF, Caccavelli L, Cros G, De Oliveira S, Fernández KS, Guo D, Harris CE, Hopkins G, Lehmann LE, Lim A, London WB, van der Loo JC, Malani N, Male F, Malik P, Marinovic MA, McNicol AM, Moshous D, Neven B, Oleastro M, Picard C, Ritz J, Rivat C, Schambach A, Shaw KL, Sherman EA, Silberstein LE, Six E, Touzot F, Tsytsykova A, Xu-Bayford J, Baum C, Bushman FD, Fischer A, Kohn DB, Filipovich AH, Notarangelo LD, Cavazzana M, Williams DA, Thrasher AJ. A modified γ-retrovirus vector for X-linked severe combined immunodeficiency. N Engl J Med 2014; 371 (15): 1407-1417.
24. Hoogerbrugge PM, Suzuki K, Suzuki K, Poorthuis BJ, Kobayashi T, Wagemaker G, van Bekkum DW. Donor-derived cells in the central nervous system of twitcher mice after bone marrow transplantation. Science 1988; 239 (4843): 1035-1038.
25. Hoogerbrugge PM, Wagemaker G, van Bekkum DW, Reuser AJ, vd Ploeg AT. Bone marrow transplantation for Pompé’s disease. N Engl J Med 1986; 315 (1): 65-66.
26. Huston MW, Riegman AR, Yadak R, van Helsdingen Y, de Boer H, van Til NP, Wagemaker G. Pretransplant mobilization with granulocyte colony-stimulating factor improves B-cell reconstitution by lentiviral vector gene therapy in SCID-X1 mice. Hum Gene Ther 2014; 25 (10): 905-914.
27. Kaufmann KB, Chiriaco M, Siler U, Finocchi A, Reichenbach J, Stein S, Grez M. Gene therapy for chronic granulomatous disease: current status and future perspectives. Curr Gene Ther 2014; 14 (6): 447-460.
28. Kustikova OS, Geiger H, Li Z, Brugman MH, Chambers SM, Shaw CA, Pike-Overzet K, de Ridder D, Staal FJ, von Keudell G, Cornils K, Nattamai KJ, Modlich U, Wagemaker G, Goodell MA, Fehse B, Baum C. Retroviral vector insertion sites associated with dominant hematopoietic clones mark “stemness” pathways. Blood 2007; 109 (5): 1897-1907.
29. Naldini L, Blömer U, Gallay P, Ory D, Mulligan R, Gage FH, Verma IM, Trono D. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 1996; 272 (5259): 263-267.
30. Pala F, Morbach H, Castiello MC, Schickel JN, Scaramuzza S, Chamberlain N, Cassani B, Glauzy S, Romberg N, Candotti F, Aiuti A, Bosticardo M, Villa A, Meffre E. Lentiviral- mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients. J Clin Invest 2015; 125 (10): 3941-3951.
31. Pike-Overzet K, de Ridder D, Weerkamp F, Baert MR, Verstegen MM, Brugman MH, Howe SJ, Reinders MJ, Thrasher AJ, Wagemaker G, van Dongen JJ, Staal FJ. Gene therapy: is IL2RG oncogenic in T-cell development? Nature 2006; 443 (7109): E5; discussion E6-7.
32. Pike-Overzet K, van der Burg M, Wagemaker G, van Dongen JJ, Staal FJ. New insights and unresolved issues regarding insertional mutagenesis in X-linked SCID gene therapy. Mol Ther 2007; 15 (11): 1910-1916.
33. Pompe JC. Over idiopathische hypertrophie van het hart. 1932; N. T. v. G. 76.I.3.
34. Rivera-Munoz P, Abramowski V, Jacquot S, André P, Charrier S, Lipson-Ruffert K, Fischer A, Galy A, Cavazzana M, de Villartay JP. Lymphopoiesis in transgenic mice over-expressing Artemis. Gene Ther 2016; 23 (2): 176-186.
35. Rocha V, Wagner JE Jr, Sobocinski KA, Klein JP, Zhang MJ, Horowitz MM, Gluckman E. Graft-versus-host disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources. N Engl J Med 2000; 342 (25): 1846-1854.
36. Schambach A, Bohne J, Baum C, Hermann FG, Egerer L, von Laer D, Giroglou T. Woodchuck hepatitis virus post-transcriptional regulatory element deleted from X protein and promoter sequences enhances retroviral vector titer and expression. Gene Ther 2006; 13 (7): 641-645.
37. Schwarzwaelder K, Howe SJ, Schmidt M, Brugman MH, Deichmann A, Glimm H, Schmidt S, Prinz C, Wissler M, King DJ, Zhang F, Parsley KL, Gilmour KC, Sinclair J, Bayford J, Peraj R, Pike-Overzet K, Staal FJ, de Ridder D, Kinnon C, Abel U, Wagemaker G, Gaspar HB, Thrasher AJ, von Kalle C. Gammaretrovirus-mediated correction of SCID-X1 is associated with skewed vector integration site distribution in vivo. J Clin Invest 2007; 117 (8): 2241-2249.
38. Shou Y, Ma Z, Lu T, Sorrentino BP. Unique risk factors for insertional mutagenesis in a mouse model of XSCID gene therapy. Proc Natl Acad Sci USA 2006; 103 (31): 11730-11735.
39. van den Hout HM, Hop W, van Diggelen OP, Smeitink JA, Smit GP, Poll-The BT, Bakker HD, Loonen MC, de Klerk JB, Reuser AJ, van der Ploeg AT. The natural course of infantile Pompe’s disease: 20 original cases compared with 133 cases from the literature. Pediatrics 2003; 112 (2): 332-340.
40. van der Ploeg AT, Reuser AJ. Pompe’s disease. Lancet 2008 Oct 11; 372 (9646): 1342-53.
41. van Gelder CM, Hoogeveen-Westerveld M, Kroos MA, Plug I, van der Ploeg AT, Reuser AJ. Enzyme therapy and immune response in relation to CRIM status: the Dutch experience in classic infantile Pompe disease. J Inherit Metab Dis. 2015; 38 (2): 305-314.
42. van Til NP, Wagemaker G. Lentiviral gene transduction of mouse and human hematopoietic stem cells. Methods Mol Biol 2014; 1185: 311-319.
43. Visigalli I, Delai S, Politi LS, Di Domenico C, Cerri F, Mrak E, D’Isa R, Ungaro D, Stok M, Sanvito F, Mariani E, Staszewsky L, Godi C, Russo I, Cecere F, Del Carro U, Rubinacci A, Brambilla R, Quattrini A, Di Natale P, Ponder K, Naldini L, Biffi A. Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model. Blood 2010; 116 (24): 5130-5139.
44. Visigalli I, Delai S, Ferro F, Cecere F, Vezzoli M, Sanvito F, Chanut F, Benedicenti F, Spinozzi G, Wynn R, Calabria A, Naldini L, Montini E, Cristofori P, Biffi A. Preclinical testing of the safety and tolerability of LV-mediated above normal alpha-L-iduronidase expression in murine and human hematopoietic cells using toxicology and biodistribution GLP studies. Hum Gene Ther 2016 Jul 18.
45. Wagemaker G. Lentiviral hematopoietic stem cell gene therapy in inherited metabolic disorders. Hum Gene Ther 2014; 25 (10): 862-865.
46. Walia JS, Neschadim A, Lopez-Perez O, Alayoubi A, Fan X, Carpentier S, Madden M, Lee CJ, Cheung F, Jaffray DA, Levade T, McCart JA, Medin JA. Autologous transplantation of lentivector/acid ceramidase-transduced hematopoietic cells in nonhuman primates. Hum Gene Ther 2011; 22 (6): 679-687.
47. Yoshimitsu M, Higuchi K, Ramsubir S, Nonaka T, Rasaiah VI, Siatskas C, Liang SB, Murray GJ, Brady RO, Medin JA. Efficient correction of Fabry mice and patient cells mediated by lentiviral transduction of hematopoietic stem/progenitor cells. Gene Ther 2007; 14 (3): 256-265.
48. Zhang F, Thornhill SI, Howe SJ, Ulaganathan M, Schambach A, Sinclair J, Kinnon C, Gaspar HB, Antoniou M, Thrasher AJ. Lentiviral vectors containing an enhancer-less ubiquitously acting chromatin opening element (UCOE) provide highly reproducible and stable transgene expression in hematopoietic cells. Blood. 2007; 110 (5): 1448-1457.

" ["DETAIL_TEXT_TYPE"]=> string(4) "html" ["~DETAIL_TEXT_TYPE"]=> string(4) "html" ["PREVIEW_TEXT"]=> string(0) "" ["~PREVIEW_TEXT"]=> string(0) "" ["PREVIEW_TEXT_TYPE"]=> string(4) "text" ["~PREVIEW_TEXT_TYPE"]=> string(4) "text" ["PREVIEW_PICTURE"]=> NULL ["~PREVIEW_PICTURE"]=> NULL ["LANG_DIR"]=> string(4) "/ru/" ["~LANG_DIR"]=> string(4) "/ru/" ["SORT"]=> string(3) "500" ["~SORT"]=> string(3) "500" ["CODE"]=> string(100) "gennaya-terapiya-lentivirusnymi-vektorami-v-gemo-poeticheskikh-stvolovykh-kletkakh-pri-vrozhdennykh-" ["~CODE"]=> string(100) "gennaya-terapiya-lentivirusnymi-vektorami-v-gemo-poeticheskikh-stvolovykh-kletkakh-pri-vrozhdennykh-" ["EXTERNAL_ID"]=> string(3) "685" ["~EXTERNAL_ID"]=> string(3) "685" ["IBLOCK_TYPE_ID"]=> string(7) "journal" ["~IBLOCK_TYPE_ID"]=> string(7) "journal" ["IBLOCK_CODE"]=> string(7) "volumes" ["~IBLOCK_CODE"]=> string(7) "volumes" ["IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["~IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["LID"]=> string(2) "s2" ["~LID"]=> string(2) "s2" ["EDIT_LINK"]=> NULL ["DELETE_LINK"]=> NULL ["DISPLAY_ACTIVE_FROM"]=> string(0) "" ["IPROPERTY_VALUES"]=> array(18) { ["ELEMENT_META_TITLE"]=> string(252) "Генная терапия лентивирусными векторами в гемо- поэтических стволовых клетках при врожденных дефицитах иммунитета и лизосомных энзимов" ["ELEMENT_META_KEYWORDS"]=> string(216) "гемопоэтические стволовые клетки лентивирусный вектор генная терапия врожденные иммунодефициты лизосомные болезни" ["ELEMENT_META_DESCRIPTION"]=> string(353) "Генная терапия лентивирусными векторами в гемо- поэтических стволовых клетках при врожденных дефицитах иммунитета и лизосомных энзимовLentiviral Hematopoietic Stem Cell Gene Therapy in Inherited Immune and Lysosomal Enzyme Deficiencies" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(2620) "Редкие болезни поражают, в целом, миллионы людей во всем мире. Многие из этих являются наследственными заболеваниями, ведущими к инвалидности и требующими дорогостоящего ухода. Генная терапия гемопоэтическими стволовыми клетками (ГТГСК) разработана за последние 20 лет. На современном уровне генная терапия выполнима при заболеваниях, для которых (1) есть идентифицированный генетический дефект, (2) диагноз ставится достаточно рано для действенного терапевтического вмешательства, (3) имеется специфическая экспериментальная модель для оценки эффективности и безопасности лечения. Соответствующие терапевтические трансгены должны также отвечать определенным биологическим критериям. Лентивирусные векторы третьего поколения выполнены самоинактивирующимися (SIN), путем делеции энхансерных участков из LTR-последовательностей, тем самым снижая риск воздействия на соседние гены, что приводит к достаточным уровням безопасности. В настоящее время лентивирусная ГТГСК вступила в фазу начального клинического внедрения для лечения иммунодефицитов и лизосомных болезней накопления. Мы обсуждаем начальные клинические испытания с применением этих векторов для некоторых метаболических болезней накопления, которые включают адренолейкодистрофию, метахроматическую лейкодистрофию, синдром Гурлер (MPS I), Помпе (GSD II), и болезнь Фабри. Данный краткий обзор обобщает развитие и современное клиническое внедрение этих подходов." ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(252) "Генная терапия лентивирусными векторами в гемо- поэтических стволовых клетках при врожденных дефицитах иммунитета и лизосомных энзимов" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(252) "Генная терапия лентивирусными векторами в гемо- поэтических стволовых клетках при врожденных дефицитах иммунитета и лизосомных энзимов" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(252) "Генная терапия лентивирусными векторами в гемо- поэтических стволовых клетках при врожденных дефицитах иммунитета и лизосомных энзимов" ["SECTION_META_TITLE"]=> string(252) "Генная терапия лентивирусными векторами в гемо- поэтических стволовых клетках при врожденных дефицитах иммунитета и лизосомных энзимов" ["SECTION_META_KEYWORDS"]=> string(252) "Генная терапия лентивирусными векторами в гемо- поэтических стволовых клетках при врожденных дефицитах иммунитета и лизосомных энзимов" ["SECTION_META_DESCRIPTION"]=> string(252) "Генная терапия лентивирусными векторами в гемо- поэтических стволовых клетках при врожденных дефицитах иммунитета и лизосомных энзимов" ["SECTION_PICTURE_FILE_ALT"]=> string(252) "Генная терапия лентивирусными векторами в гемо- поэтических стволовых клетках при врожденных дефицитах иммунитета и лизосомных энзимов" ["SECTION_PICTURE_FILE_TITLE"]=> string(252) "Генная терапия лентивирусными векторами в гемо- поэтических стволовых клетках при врожденных дефицитах иммунитета и лизосомных энзимов" ["SECTION_PICTURE_FILE_NAME"]=> string(100) "gennaya-terapiya-lentivirusnymi-vektorami-v-gemo-poeticheskikh-stvolovykh-kletkakh-pri-vrozhdennykh-" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(252) "Генная терапия лентивирусными векторами в гемо- поэтических стволовых клетках при врожденных дефицитах иммунитета и лизосомных энзимов" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(252) "Генная терапия лентивирусными векторами в гемо- поэтических стволовых клетках при врожденных дефицитах иммунитета и лизосомных энзимов" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(100) "gennaya-terapiya-lentivirusnymi-vektorami-v-gemo-poeticheskikh-stvolovykh-kletkakh-pri-vrozhdennykh-" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(100) "gennaya-terapiya-lentivirusnymi-vektorami-v-gemo-poeticheskikh-stvolovykh-kletkakh-pri-vrozhdennykh-" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(100) "gennaya-terapiya-lentivirusnymi-vektorami-v-gemo-poeticheskikh-stvolovykh-kletkakh-pri-vrozhdennykh-" } ["FIELDS"]=> array(1) { ["IBLOCK_SECTION_ID"]=> string(2) "21" } ["PROPERTIES"]=> array(18) { ["KEYWORDS"]=> array(36) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые слова" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "KEYWORDS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "19" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(5) { [0]=> string(4) "8396" [1]=> string(4) "8397" [2]=> string(4) "8398" [3]=> string(4) "8399" [4]=> string(4) "8400" } ["VALUE"]=> array(5) { [0]=> string(3) "686" [1]=> string(3) "687" [2]=> string(3) "688" [3]=> string(3) "689" [4]=> string(3) "690" } ["DESCRIPTION"]=> array(5) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(5) { [0]=> string(3) "686" [1]=> string(3) "687" [2]=> string(3) "688" [3]=> string(3) "689" [4]=> string(3) "690" } ["~DESCRIPTION"]=> array(5) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" } ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" } ["SUBMITTED"]=> array(36) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8371" ["VALUE"]=> string(10) "28.11.2016" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "28.11.2016" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8372" ["VALUE"]=> string(10) "09.12.2016" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "09.12.2016" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL } ["PUBLISHED"]=> array(36) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Дата публикации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "PUBLISHED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "22" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Дата публикации" ["~DEFAULT_VALUE"]=> NULL } ["CONTACT"]=> array(36) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8373" ["VALUE"]=> string(3) "433" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(3) "433" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(1) { [0]=> string(4) "8401" } ["VALUE"]=> array(1) { [0]=> string(3) "433" } ["DESCRIPTION"]=> array(1) { [0]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(1) { [0]=> string(3) "433" } ["~DESCRIPTION"]=> array(1) { [0]=> string(0) "" } ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8388" ["VALUE"]=> array(2) { ["TEXT"]=> string(31) "Герард Вагемакер" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(31) "Герард Вагемакер" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8389" ["VALUE"]=> array(2) { ["TEXT"]=> string(617) "Университет Эразмус, Роттердам, Нидерланды; Центр исследования и разработки стволовых клеток, Университет<br> Хашеттепе, Анкара, Турция; НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый<br> Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(599) "Университет Эразмус, Роттердам, Нидерланды; Центр исследования и разработки стволовых клеток, Университет
Хашеттепе, Анкара, Турция; НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый
Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8390" ["VALUE"]=> array(2) { ["TEXT"]=> string(2620) "Редкие болезни поражают, в целом, миллионы людей во всем мире. Многие из этих являются наследственными заболеваниями, ведущими к инвалидности и требующими дорогостоящего ухода. Генная терапия гемопоэтическими стволовыми клетками (ГТГСК) разработана за последние 20 лет. На современном уровне генная терапия выполнима при заболеваниях, для которых (1) есть идентифицированный генетический дефект, (2) диагноз ставится достаточно рано для действенного терапевтического вмешательства, (3) имеется специфическая экспериментальная модель для оценки эффективности и безопасности лечения. Соответствующие терапевтические трансгены должны также отвечать определенным биологическим критериям. Лентивирусные векторы третьего поколения выполнены самоинактивирующимися (SIN), путем делеции энхансерных участков из LTR-последовательностей, тем самым снижая риск воздействия на соседние гены, что приводит к достаточным уровням безопасности. В настоящее время лентивирусная ГТГСК вступила в фазу начального клинического внедрения для лечения иммунодефицитов и лизосомных болезней накопления. Мы обсуждаем начальные клинические испытания с применением этих векторов для некоторых метаболических болезней накопления, которые включают адренолейкодистрофию, метахроматическую лейкодистрофию, синдром Гурлер (MPS I), Помпе (GSD II), и болезнь Фабри. Данный краткий обзор обобщает развитие и современное клиническое внедрение этих подходов." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2620) "Редкие болезни поражают, в целом, миллионы людей во всем мире. Многие из этих являются наследственными заболеваниями, ведущими к инвалидности и требующими дорогостоящего ухода. Генная терапия гемопоэтическими стволовыми клетками (ГТГСК) разработана за последние 20 лет. На современном уровне генная терапия выполнима при заболеваниях, для которых (1) есть идентифицированный генетический дефект, (2) диагноз ставится достаточно рано для действенного терапевтического вмешательства, (3) имеется специфическая экспериментальная модель для оценки эффективности и безопасности лечения. Соответствующие терапевтические трансгены должны также отвечать определенным биологическим критериям. Лентивирусные векторы третьего поколения выполнены самоинактивирующимися (SIN), путем делеции энхансерных участков из LTR-последовательностей, тем самым снижая риск воздействия на соседние гены, что приводит к достаточным уровням безопасности. В настоящее время лентивирусная ГТГСК вступила в фазу начального клинического внедрения для лечения иммунодефицитов и лизосомных болезней накопления. Мы обсуждаем начальные клинические испытания с применением этих векторов для некоторых метаболических болезней накопления, которые включают адренолейкодистрофию, метахроматическую лейкодистрофию, синдром Гурлер (MPS I), Помпе (GSD II), и болезнь Фабри. Данный краткий обзор обобщает развитие и современное клиническое внедрение этих подходов." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8375" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2016-5-4-56-62" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2016-5-4-56-62" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8391" ["VALUE"]=> array(2) { ["TEXT"]=> string(17) "Gerard Wagemaker*" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(17) "Gerard Wagemaker*" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8392" ["VALUE"]=> array(2) { ["TEXT"]=> string(599) "Erasmus University Rotterdam, The Netherlands; Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey;<br> Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, St. Petersburg, Russia<br> <br> Gerard Wagemaker, PhD, Professor, Erasmus University Rotterdam,<br> c/o PO Box 37048<br> 3005 LA Rotterdam, The Netherlands<br> <br>  Phone: +31-6-51619585<br> E-mail: <a href="mailto:g.wagemaker@genetherapy.nl">g.wagemaker@genetherapy.nl</a><br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(523) "Erasmus University Rotterdam, The Netherlands; Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey;
Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, St. Petersburg, Russia

Gerard Wagemaker, PhD, Professor, Erasmus University Rotterdam,
c/o PO Box 37048
3005 LA Rotterdam, The Netherlands

 Phone: +31-6-51619585
E-mail: g.wagemaker@genetherapy.nl
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8393" ["VALUE"]=> array(2) { ["TEXT"]=> string(1328) "Rare diseases affect millions of people worldwide. Many of those are inherited disorders resulting in chronic disability and requiring cost-intensive care. Hematopoietic stem cell gene therapy has been developed over more than 20 years. At the state of the art, gene therapy is within reach for diseases in which (i) the genetic defect is identified, (ii) the diagnosis is made sufficiently early for a meaningful therapeutic intervention, (iii) a specific animal model is available for efficacy and safety evaluation. Appropriate therapeutic transgenes should also comply with certain biological criteria. Third-generation lentiviral vectors have been made self-inactivating (SIN) by deletion of enhancer regions from the LTR sequences thus reducing the risk of influencing nearby genes, resulting in favorable safety profiles. At the present time, lentiviral hematopoietic stem cell gene therapy has entered the stage of initial clinical implementation for immune deficiencies and lysosomal storage disorders. We discuss initial clinical trials using these vectors for selected metabolic storage disorders, which include adrenoleukodystrophy, metachromatic leukodystrophy, Hurler (MPS I), Pompe (GSD II), and Fabry diseases. This brief review summarizes the development and current clinical implementation of these approaches." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1328) "Rare diseases affect millions of people worldwide. Many of those are inherited disorders resulting in chronic disability and requiring cost-intensive care. Hematopoietic stem cell gene therapy has been developed over more than 20 years. At the state of the art, gene therapy is within reach for diseases in which (i) the genetic defect is identified, (ii) the diagnosis is made sufficiently early for a meaningful therapeutic intervention, (iii) a specific animal model is available for efficacy and safety evaluation. Appropriate therapeutic transgenes should also comply with certain biological criteria. Third-generation lentiviral vectors have been made self-inactivating (SIN) by deletion of enhancer regions from the LTR sequences thus reducing the risk of influencing nearby genes, resulting in favorable safety profiles. At the present time, lentiviral hematopoietic stem cell gene therapy has entered the stage of initial clinical implementation for immune deficiencies and lysosomal storage disorders. We discuss initial clinical trials using these vectors for selected metabolic storage disorders, which include adrenoleukodystrophy, metachromatic leukodystrophy, Hurler (MPS I), Pompe (GSD II), and Fabry diseases. This brief review summarizes the development and current clinical implementation of these approaches." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["NAME_EN"]=> array(36) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8376" ["VALUE"]=> string(101) "Lentiviral Hematopoietic Stem Cell Gene Therapy in Inherited Immune and Lysosomal Enzyme Deficiencies" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(101) "Lentiviral Hematopoietic Stem Cell Gene Therapy in Inherited Immune and Lysosomal Enzyme Deficiencies" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" } ["FULL_TEXT_RU"]=> &array(36) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(23) "Полный текст" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["PDF_RU"]=> array(36) { ["ID"]=> string(2) "43" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF RUS" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_RU" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "43" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8394" ["VALUE"]=> string(3) "266" ["DESCRIPTION"]=> NULL ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(3) "266" ["~DESCRIPTION"]=> NULL ["~NAME"]=> string(7) "PDF RUS" ["~DEFAULT_VALUE"]=> string(0) "" } ["PDF_EN"]=> array(36) { ["ID"]=> string(2) "44" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF ENG" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "44" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8395" ["VALUE"]=> string(3) "267" ["DESCRIPTION"]=> NULL ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(3) "267" ["~DESCRIPTION"]=> NULL ["~NAME"]=> string(7) "PDF ENG" ["~DEFAULT_VALUE"]=> string(0) "" } ["NAME_LONG"]=> array(36) { ["ID"]=> string(2) "45" ["TIMESTAMP_X"]=> string(19) "2023-04-13 00:55:00" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(72) "Название (для очень длинных заголовков)" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "NAME_LONG" ["DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "45" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(80) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(72) "Название (для очень длинных заголовков)" ["~DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } } } ["DISPLAY_PROPERTIES"]=> array(13) { ["AUTHOR_EN"]=> array(37) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8391" ["VALUE"]=> array(2) { ["TEXT"]=> string(17) "Gerard Wagemaker*" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(17) "Gerard Wagemaker*" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(17) "Gerard Wagemaker*" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8393" ["VALUE"]=> array(2) { ["TEXT"]=> string(1328) "Rare diseases affect millions of people worldwide. Many of those are inherited disorders resulting in chronic disability and requiring cost-intensive care. Hematopoietic stem cell gene therapy has been developed over more than 20 years. At the state of the art, gene therapy is within reach for diseases in which (i) the genetic defect is identified, (ii) the diagnosis is made sufficiently early for a meaningful therapeutic intervention, (iii) a specific animal model is available for efficacy and safety evaluation. Appropriate therapeutic transgenes should also comply with certain biological criteria. Third-generation lentiviral vectors have been made self-inactivating (SIN) by deletion of enhancer regions from the LTR sequences thus reducing the risk of influencing nearby genes, resulting in favorable safety profiles. At the present time, lentiviral hematopoietic stem cell gene therapy has entered the stage of initial clinical implementation for immune deficiencies and lysosomal storage disorders. We discuss initial clinical trials using these vectors for selected metabolic storage disorders, which include adrenoleukodystrophy, metachromatic leukodystrophy, Hurler (MPS I), Pompe (GSD II), and Fabry diseases. This brief review summarizes the development and current clinical implementation of these approaches." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1328) "Rare diseases affect millions of people worldwide. Many of those are inherited disorders resulting in chronic disability and requiring cost-intensive care. Hematopoietic stem cell gene therapy has been developed over more than 20 years. At the state of the art, gene therapy is within reach for diseases in which (i) the genetic defect is identified, (ii) the diagnosis is made sufficiently early for a meaningful therapeutic intervention, (iii) a specific animal model is available for efficacy and safety evaluation. Appropriate therapeutic transgenes should also comply with certain biological criteria. Third-generation lentiviral vectors have been made self-inactivating (SIN) by deletion of enhancer regions from the LTR sequences thus reducing the risk of influencing nearby genes, resulting in favorable safety profiles. At the present time, lentiviral hematopoietic stem cell gene therapy has entered the stage of initial clinical implementation for immune deficiencies and lysosomal storage disorders. We discuss initial clinical trials using these vectors for selected metabolic storage disorders, which include adrenoleukodystrophy, metachromatic leukodystrophy, Hurler (MPS I), Pompe (GSD II), and Fabry diseases. This brief review summarizes the development and current clinical implementation of these approaches." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1328) "Rare diseases affect millions of people worldwide. Many of those are inherited disorders resulting in chronic disability and requiring cost-intensive care. Hematopoietic stem cell gene therapy has been developed over more than 20 years. At the state of the art, gene therapy is within reach for diseases in which (i) the genetic defect is identified, (ii) the diagnosis is made sufficiently early for a meaningful therapeutic intervention, (iii) a specific animal model is available for efficacy and safety evaluation. Appropriate therapeutic transgenes should also comply with certain biological criteria. Third-generation lentiviral vectors have been made self-inactivating (SIN) by deletion of enhancer regions from the LTR sequences thus reducing the risk of influencing nearby genes, resulting in favorable safety profiles. At the present time, lentiviral hematopoietic stem cell gene therapy has entered the stage of initial clinical implementation for immune deficiencies and lysosomal storage disorders. We discuss initial clinical trials using these vectors for selected metabolic storage disorders, which include adrenoleukodystrophy, metachromatic leukodystrophy, Hurler (MPS I), Pompe (GSD II), and Fabry diseases. This brief review summarizes the development and current clinical implementation of these approaches." } ["DOI"]=> array(37) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8375" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2016-5-4-56-62" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2016-5-4-56-62" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(37) "10.18620/ctt-1866-8836-2016-5-4-56-62" } ["NAME_EN"]=> array(37) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8376" ["VALUE"]=> string(101) "Lentiviral Hematopoietic Stem Cell Gene Therapy in Inherited Immune and Lysosomal Enzyme Deficiencies" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(101) "Lentiviral Hematopoietic Stem Cell Gene Therapy in Inherited Immune and Lysosomal Enzyme Deficiencies" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(101) "Lentiviral Hematopoietic Stem Cell Gene Therapy in Inherited Immune and Lysosomal Enzyme Deficiencies" } ["ORGANIZATION_EN"]=> array(37) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8392" ["VALUE"]=> array(2) { ["TEXT"]=> string(599) "Erasmus University Rotterdam, The Netherlands; Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey;<br> Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, St. Petersburg, Russia<br> <br> Gerard Wagemaker, PhD, Professor, Erasmus University Rotterdam,<br> c/o PO Box 37048<br> 3005 LA Rotterdam, The Netherlands<br> <br>  Phone: +31-6-51619585<br> E-mail: <a href="mailto:g.wagemaker@genetherapy.nl">g.wagemaker@genetherapy.nl</a><br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(523) "Erasmus University Rotterdam, The Netherlands; Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey;
Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, St. Petersburg, Russia

Gerard Wagemaker, PhD, Professor, Erasmus University Rotterdam,
c/o PO Box 37048
3005 LA Rotterdam, The Netherlands

 Phone: +31-6-51619585
E-mail: g.wagemaker@genetherapy.nl
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(523) "Erasmus University Rotterdam, The Netherlands; Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey;
Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, St. Petersburg, Russia

Gerard Wagemaker, PhD, Professor, Erasmus University Rotterdam,
c/o PO Box 37048
3005 LA Rotterdam, The Netherlands

 Phone: +31-6-51619585
E-mail: g.wagemaker@genetherapy.nl
" } ["AUTHORS"]=> array(38) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(1) { [0]=> string(4) "8401" } ["VALUE"]=> array(1) { [0]=> string(3) "433" } ["DESCRIPTION"]=> array(1) { [0]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(1) { [0]=> string(3) "433" } ["~DESCRIPTION"]=> array(1) { [0]=> string(0) "" } ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(59) "Gerard Wagemaker" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["AUTHOR_RU"]=> array(37) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8388" ["VALUE"]=> array(2) { ["TEXT"]=> string(31) "Герард Вагемакер" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(31) "Герард Вагемакер" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(31) "Герард Вагемакер" } ["SUBMITTED"]=> array(37) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8371" ["VALUE"]=> string(10) "28.11.2016" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "28.11.2016" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "28.11.2016" } ["ACCEPTED"]=> array(37) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8372" ["VALUE"]=> string(10) "09.12.2016" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "09.12.2016" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "09.12.2016" } ["KEYWORDS"]=> array(38) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые слова" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "KEYWORDS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "19" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(5) { [0]=> string(4) "8396" [1]=> string(4) "8397" [2]=> string(4) "8398" [3]=> string(4) "8399" [4]=> string(4) "8400" } ["VALUE"]=> array(5) { [0]=> string(3) "686" [1]=> string(3) "687" [2]=> string(3) "688" [3]=> string(3) "689" [4]=> string(3) "690" } ["DESCRIPTION"]=> array(5) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(5) { [0]=> string(3) "686" [1]=> string(3) "687" [2]=> string(3) "688" [3]=> string(3) "689" [4]=> string(3) "690" } ["~DESCRIPTION"]=> array(5) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" } ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> array(5) { [0]=> string(106) "гемопоэтические стволовые клетки" [1]=> string(83) "лентивирусный вектор" [2]=> string(71) "генная терапия" [3]=> string(93) "врожденные иммунодефициты" [4]=> string(79) "лизосомные болезни" } ["LINK_ELEMENT_VALUE"]=> bool(false) } ["CONTACT"]=> array(38) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8373" ["VALUE"]=> string(3) "433" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(3) "433" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(59) "Gerard Wagemaker" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8390" ["VALUE"]=> array(2) { ["TEXT"]=> string(2620) "Редкие болезни поражают, в целом, миллионы людей во всем мире. Многие из этих являются наследственными заболеваниями, ведущими к инвалидности и требующими дорогостоящего ухода. Генная терапия гемопоэтическими стволовыми клетками (ГТГСК) разработана за последние 20 лет. На современном уровне генная терапия выполнима при заболеваниях, для которых (1) есть идентифицированный генетический дефект, (2) диагноз ставится достаточно рано для действенного терапевтического вмешательства, (3) имеется специфическая экспериментальная модель для оценки эффективности и безопасности лечения. Соответствующие терапевтические трансгены должны также отвечать определенным биологическим критериям. Лентивирусные векторы третьего поколения выполнены самоинактивирующимися (SIN), путем делеции энхансерных участков из LTR-последовательностей, тем самым снижая риск воздействия на соседние гены, что приводит к достаточным уровням безопасности. В настоящее время лентивирусная ГТГСК вступила в фазу начального клинического внедрения для лечения иммунодефицитов и лизосомных болезней накопления. Мы обсуждаем начальные клинические испытания с применением этих векторов для некоторых метаболических болезней накопления, которые включают адренолейкодистрофию, метахроматическую лейкодистрофию, синдром Гурлер (MPS I), Помпе (GSD II), и болезнь Фабри. Данный краткий обзор обобщает развитие и современное клиническое внедрение этих подходов." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2620) "Редкие болезни поражают, в целом, миллионы людей во всем мире. Многие из этих являются наследственными заболеваниями, ведущими к инвалидности и требующими дорогостоящего ухода. Генная терапия гемопоэтическими стволовыми клетками (ГТГСК) разработана за последние 20 лет. На современном уровне генная терапия выполнима при заболеваниях, для которых (1) есть идентифицированный генетический дефект, (2) диагноз ставится достаточно рано для действенного терапевтического вмешательства, (3) имеется специфическая экспериментальная модель для оценки эффективности и безопасности лечения. Соответствующие терапевтические трансгены должны также отвечать определенным биологическим критериям. Лентивирусные векторы третьего поколения выполнены самоинактивирующимися (SIN), путем делеции энхансерных участков из LTR-последовательностей, тем самым снижая риск воздействия на соседние гены, что приводит к достаточным уровням безопасности. В настоящее время лентивирусная ГТГСК вступила в фазу начального клинического внедрения для лечения иммунодефицитов и лизосомных болезней накопления. Мы обсуждаем начальные клинические испытания с применением этих векторов для некоторых метаболических болезней накопления, которые включают адренолейкодистрофию, метахроматическую лейкодистрофию, синдром Гурлер (MPS I), Помпе (GSD II), и болезнь Фабри. Данный краткий обзор обобщает развитие и современное клиническое внедрение этих подходов." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2620) "Редкие болезни поражают, в целом, миллионы людей во всем мире. Многие из этих являются наследственными заболеваниями, ведущими к инвалидности и требующими дорогостоящего ухода. Генная терапия гемопоэтическими стволовыми клетками (ГТГСК) разработана за последние 20 лет. На современном уровне генная терапия выполнима при заболеваниях, для которых (1) есть идентифицированный генетический дефект, (2) диагноз ставится достаточно рано для действенного терапевтического вмешательства, (3) имеется специфическая экспериментальная модель для оценки эффективности и безопасности лечения. Соответствующие терапевтические трансгены должны также отвечать определенным биологическим критериям. Лентивирусные векторы третьего поколения выполнены самоинактивирующимися (SIN), путем делеции энхансерных участков из LTR-последовательностей, тем самым снижая риск воздействия на соседние гены, что приводит к достаточным уровням безопасности. В настоящее время лентивирусная ГТГСК вступила в фазу начального клинического внедрения для лечения иммунодефицитов и лизосомных болезней накопления. Мы обсуждаем начальные клинические испытания с применением этих векторов для некоторых метаболических болезней накопления, которые включают адренолейкодистрофию, метахроматическую лейкодистрофию, синдром Гурлер (MPS I), Помпе (GSD II), и болезнь Фабри. Данный краткий обзор обобщает развитие и современное клиническое внедрение этих подходов." } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8389" ["VALUE"]=> array(2) { ["TEXT"]=> string(617) "Университет Эразмус, Роттердам, Нидерланды; Центр исследования и разработки стволовых клеток, Университет<br> Хашеттепе, Анкара, Турция; НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый<br> Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(599) "Университет Эразмус, Роттердам, Нидерланды; Центр исследования и разработки стволовых клеток, Университет
Хашеттепе, Анкара, Турция; НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый
Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(599) "Университет Эразмус, Роттердам, Нидерланды; Центр исследования и разработки стволовых клеток, Университет
Хашеттепе, Анкара, Турция; НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый
Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
" } } } [1]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(2) "21" ["~IBLOCK_SECTION_ID"]=> string(2) "21" ["ID"]=> string(3) "694" ["~ID"]=> string(3) "694" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(185) "Современные методы и возможности секвенирования следующего поколения (NGS) для типирования системы HLA" ["~NAME"]=> string(185) "Современные методы и возможности секвенирования следующего поколения (NGS) для типирования системы HLA" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(19) "03.05.2017 09:37:32" ["~TIMESTAMP_X"]=> string(19) "03.05.2017 09:37:32" ["DETAIL_PAGE_URL"]=> string(161) "/ru/archive/vypusk-5-nomer-4/eksperimentalnye-issledovaniya/sovremennye-metody-i-vozmozhnosti-sekvenirovaniya-sleduyushchego-pokoleniya-ngs-dlya-tipirovaniya-si/" ["~DETAIL_PAGE_URL"]=> string(161) "/ru/archive/vypusk-5-nomer-4/eksperimentalnye-issledovaniya/sovremennye-metody-i-vozmozhnosti-sekvenirovaniya-sleduyushchego-pokoleniya-ngs-dlya-tipirovaniya-si/" ["LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["~LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["DETAIL_TEXT"]=> string(29128) "

Introduction

Allogeneic hematopoietic stem cell transplantation (allo- HSCT) is a proven option for treatment of hematological disorders, e.g., lymphoma, leukemia, and aplastic anemias. Among other factors, the HSCT outcomes strongly depend on aggressive reactions of donor lymphocytes against the patient’s cells. This complication is known as a graft-versushost disease (GVHD) and represents a serious threat to the patients, along with the risk of relapse and concomitant infections [1]. Over last decades, a progress in the donor-recipient matching lead to an imminent increase of patients’ survival post transplant, due to decreased rates of immune complications [3,20]. These advances are made, mostly, due to an improved technique of HLA gene typing [24]. E.g., sufficiently increased survival rates and better outcomes were shown for the patient-donor pairs typed by means of high-resolution allele typing for HLA-A, -B, -C and -DRB1 [27]. Analysis of HLA-DQB1 and -DPB1 loci is still under development [10].

Hence, implementation of high-resolution techniques for the classic HLA typing brings about higher clinical efficiency in allo-HSCT from relatives and unrelated donors. The aspects of optimal donor matching are connected with a sufficient allelic diversity (polymorphism) of the gene loci, mainly, due to gene recombination of the chromosome 6 regions, thus producing repeats at distinct HLA gene segments and causing some difficulties with HLA typing, even at four-digit resolution level. Therefore, novel technological achievements in immunogenetics are of special importance, and, first of all, new approaches to DNA typing [6].

Milestones of molecular HLA typing

Since the very beginning of molecular biology, individual HLA matching was oriented for gene polymorphism analysis. Forty years ago, Fred Sanger has proposed a method of DNA sequencing, by the generation of distinct DNA strands based on a complementary matrix, using DNA polymerase I Klenoff fragment, and then followed by analysis of radioactively labeled DNA fragments in polyacrylamide gel. A breakthrough in this technology and development of routine HLA typing methods occurred with the application of fluorescent dideoxynucleotides in the course of the cyclic process followed by microcapillary electrophoresis. Direct sequencing of heterozygous DNA samples has its limitations since, in the case of allelic polymorphism, the nucleic bases may be located at the same or homologous chromosome, thus precluding detection of subtle differences in the given HLA gene sequence.

Over the last 20 years, the automated Sanger technique is a prevalent approach to genome sequencing in humans, animals, bacteria, and viruses. However, a need for more rapid routine genome screening stimulated novel technologies of multiplex DNA sequencing. These modern methods are depicted as the second-generation approaches (Next-Generation Sequencing, NGS). These technological platforms are based on different strategies, with respect to unique preparations of DNA templates, their sequencing, registration, retrieval and evaluation of the nucleotide sequences by means of novel bioinformatic approaches [13]. A principal benefit of the new-generation sequencing is an opportunity of getting large databases of multiple defined gene sequences within a short time period and at relatively low cost.

A known polymorphism of HLA genes presents a special problem in search of optimal donors for hematopoietic stem cell transplantation (HSCT). E.g., as for September 2016, the International Nomenclature (HLA International ImMunoGeneTics (IMGT) [26, 29] included 15,813 HLA and related alleles, registered in the numerical nomenclature used worldwide (Fig. 1).

img

In addition to the unique allele number, there are additional optional suffixes that may be added to an allele to indicate its expression status. Alleles that have been shown not to be expressed – “Null” alleles – have been given the suffix ‘N’. Alleles that have been shown to be alternatively expressed may have the suffix “L”, “S”, “C”, “A” or “Q”. The suffix “L” is used to indicate an allele which has been shown to have “Low” cell surface expression when compared to normal levels. The “S” suffix is used to denote an allele specifying a protein which is expressed as a soluble, “Secreted” molecule but is not present on the cell surface. The “C” suffix is assigned to alleles that produce proteins that are present in the “Cytoplasm” and not on the cell surface. An “A” suffix indicates an “Aberrant” expression where there is some doubt as to whether a protein is actually expressed. A “Q” suffix is used when the expression of an allele is “Questionable”, given that the mutation seen in the allele has been shown to affect normal expression levels in other alleles.

No wonder that the general NGS approach adapted for HLA typing proved to be a breakthrough in molecular biology applications being quite promising to the transplantation clinics and bone marrow donor registries. However, to promote the NGS implementation, we need specialized typing strategies and digital program algorithms. The sequencing costs per single run are sharply decreased with NGS approach which may be quite accessible to the tissue typing laboratories in sooner time.

Multiple NGS technological platforms are offered on the market. At the present time, four types of NGS systems are implemented in research and clinics. E.g., the 454 Junior (Roche) was the first system equipped with commercial kits for HLA-typing. Illumina platform is most widely applied in fundamental and clinical research, however, not yet registered for HLA-typing. The Ion Torrent system was offered something later, being, however, a growing point in the field. Lately, the fourth generation of NGS appears – Single Molecule Sequencing. They can do long reads with very high throughput. Advantages: Low Cost, Simultaneous sequencing of several samples (barcoding). Currently manufactured by 2 companies, PacBio and Nanopore MiniON. They are amplicon-based and “true” single molecule sequencing. It has a very small footprint and even fits in the pocket.

At the present time, a four-digit resolution approach is used for optimal matching in the donor-recipient pairs, i.e., testing of HLA-A, -B, -C, (exons 2, 3); -DRB1 (exon 2), and – DQB1 (exons 2, 3) by means of conventional PCR technique.

Pitfalls in NGS-based HLA typing

To perform high-resolution typing, one should exclude non-coding alleles from HLA-A (exons 1, 4 and introns 2, 4), HLA-B (exons 1, 4 and intron 1), and HLA-C (exons 1, 4, 7).

Phase determination of the sequence motifs becomes an increasingly difficult task, due to new HLA polymorphisms reported, thus causing an exponential increase in genotyping ambiguity with every ongoing release of the HLA database release [10]. Therefore, novel typing strategies have been arranged, e.g., group-specific PCR [15], or allelic discrimination with distinct group-specific primers [18] before subsequent sequencing. These discrimination techniques are used at HLA laboratories for a long time. However, they are labor-consuming, and appropriate commercial kits are largely lacking.

The novel NGS-based HLA typing was developed over 2000’s, having been characterized by increased resolution ability and high throughput [22, 30]. In 2009, Gabriel et al. [11] and Erlich et al. [1] have independently shown an opportunity of HLA typing by means of a 454 technological platform. A double-blinded multicentric study based on exon amplification by primers’ annealing was performed and reported in 2011 [13]. This cooperative work has shown that HLA sequencing with 454 system allows reliable identification of the HLA genotypes. However, the analytic approaches proved to be quite diligent, labor-intensive and require automation. Moreover, a systemic algorithm for the Class I HLA typing was performed with different PCR-based barcoding methods [9]. Later on, Lank et al. [16, 19] proposed a DNA processing protocol for HLA typing with a less complicated DNA library preparation. Finally, it was shown that, as unlike with amplicon sequencing, the shotgun sequencing approach using long PCR products, fragmenting and ligation of the multiplex identifiers (MID) is a realistic way for the entire HLA gene sequencing. [20, 27, 32].

Meanwhile, the existing protocols provide additional proofs of NGS complexity. This technology is still difficult to introduce in laboratories working in the area of histocompatibility and immunogenetics. There were some unresolved technical issues concerning labor intensity of a gene library preparation, and too long time required for processing of the databases produced. Noteworthy, the bioinformatic tools in NGS rarely generated a readable report of HLA typing.

Taking this into account, an automated approach to the high-resolutionHLA typing was developed, being adapted for the 454 GS Junior, covering 17 exons of the following genes: HLA-A, -B, -C, -DQB1, -DPB1, -DRB1, -DRB3, -DRB4 и -DRB5 (DRB3 / 4/5). However, exact data on 5”- and 3”- untranslated sequences (UTR) are not available for all the alleles. Therefore, binding of primers in these regions cannot be definitely predicted, thus missing some alleles from analysis or nucleotide shifts due to suboptimal amplification primers. Another potential problem may be due to simultaneous amplification of pseudogenes since their sequences are quite similar to those of target HLA genes.

Despite these issues, NGS has a great future in the area. An opportunity of the whole-gene analysis should ultimately lead to better understanding of HLA role for HSCT outcomes and the course of the primary disease. Moreover, the zero alleles could be better defined. So far, we cannot exploit this benefit. However, some questions will be answered, e.g., assessing a “complete” HLA allele database and overcoming existing hurdles when assembling a single complete allelic sequence.

At the initial step, a maximal length of sequences readable with Myseq was limited of 2×150 bp. However, the manufacturer (Illumina) improves its software, as well as chemical equipment. Hence, their last version (version 3) allows sequencing of ca.300 bp, in order to cover one exon within each sequenced amplicon, thus diminishing potential error rates and simplifying the work process.

Main steps of the NGS as performed with Illumina platform

• Template generation: the complete sequences of HLA genes are amplified with complementary primers in a single reaction, using Long-Range DNA polymerase.
• Double-stranded DNA fragmentation by means of specific fragmentase optimized by its size for the given HLA locus
• Preparation of gene libraries: Appropriate reagents are used for the end repair, 5’ phosphorylation of poly-A and poly-T ends for subsequent adaptors’ ligation.
• Adapters’ ligation and their indexing.
• Mixing of the samples and their loading to the NGS sequencer.
• Analysis of results (Fig.1)

Following generation of a gene library, the DNA molecules are bound to the solid phase carrier, the s.c. flow well, by means of direct and reverse oligonucleotide adapters. During generation of the gene library, the complementary (adapter) sequences are fixed to the templates at the 5”- and 3”-ends, thus allowing them to bind the flow well surface covered with adapter molecules. To enhance the sequencing signal, molecular clusters are generated from one DNA molecule by means of solid-phase amplification bridge, resulting in up to 1000 tightly packed copies of the initial template in the flow well. Hence, each cluster corresponds to a single read by the end of sequencing. The adapter oligonucleotides are bound to the surface of flow well, both for the capture of sequenced templates molecules, and primers for bridge amplification. Sequencing is then carried out by means of chemical reaction “reversible terminator’” All 4 fluorescently labeled oligonucleotides are simultaneously driven through the flow well. Their labels are intended for termination of the chain synthesis. Therefore, only one nucleotide type is added for each polymerization cycle. The nonbound nucleotides are washed off. The labels and terminator are removed following CCD-assisted conversion of the pictures, in order to allow further elongation of the chain at the next sequencing cycle. To facilitate the multiplexing procedure, the adapter sequences are followed by the s.c. index sequences (DNA barcoding). These DNA barcodes are attached to the target fragments during the library design, with a unique code for given sample. Double indexing is possible by differential DNA barcoding from 5” to 3” end. In the course of four sequencing rounds, two indexing reads and two reads of target sequences are initiated. The data are accumulated for each single cluster and are used for generation of the output files in two directions of sequencing.

HLA data analysis with MiSeq platform

Miseq generates a working file in FASTQ format with two corresponding files (resp., direct and reverse reads). All the files contain equal numbers of the read sequences presented in the same order. Moreover, all the sequences read are of equal length according to the chosen specifications. Homogeneous structure of initial data provides some benefits for the pre-analytic data handling. Upon filtration and cutting, some algorithms are required here which are more applicable than with platforms generating variable reading length (e.g., Roche 454, or Ion Torrent systems). Data quality obtained with Miseq is high enough to perform HLA typing.

To assign the HLA alleles, software is required which allows communicating with updated HLA databases (IMGT last version, renewed 4 times a year). A number of such commercial packages are currently available. To date, the solutions with an open initial code are also offered, as follows:
HLAminer: http://genomemedicine.com/content/4/12/95
seq2HLA: http://genomemedicine.com/content/4/12/102
Athlates: http://nar.oxfordjournals.org/content/41/14/e142. long
HLAforest: http://www.plosone.org/article/info%3Adoi%2F10. 1371%2Fjournal.pone.0067885
PHLAT: http://www.biomedcentral.com/1471-2164/15/325

According to the guidelines of clinical trials and in order to observe acting regulations (European Federation for Immunogenetics (EFI), American Society for Histocompatibility and Immunogenetics (ASHI) standards), extensive studies of QC and QA are required for development of appropriate in-house reagents, and their testing for HLA typing bases on the Miseq platform. They should include both developments of the tests, and methods of automated data mining, and their presentation. Sufficient time is needed for design, feasibility evaluation, and implementation of NGS working protocols. The optimal choice of NGS platform and proper protocol is a difficult task for any individual setting in this rapidly developing technology [14].

Modern protocols of sequencing and data retrieval/handling differ, generally, in the aims of analysis, i.e., whole-genome evaluation (from 5’UTR to 3’UTR), or exome studies. So far, a limit of 400 bp exists for the length of sequencing, independently of the working protocol applied. This length of DNA fragment is sufficient to reading of whole exons and providing unequivocal clonal information for these exons. To sequence longer PCR products, a series of overlapping fragments is required, followed by their subsequent assembly (shotgun sequencing). The working processes under these two protocols significantly differ in labor intensity and complexity.

The output data are collected for each molecular cluster and used for generation of the output files containing results of direct and reverse reads as displayed on Fig. 2 [5]

img

The detailed information concerns HLA-A genotype assignment, as show in the master layer. Direct and reverse sequence reads are aligned to exons 2, 3, and 4, with partial coverage of intronic regions [33]. Read numbers and sequence direction are shown in white cells. For example, exon 4 is represented by two (alleles 1 and 2) direct and reverse sequences, with 90 coverages, and, respectively, 81 nucleotides read, and two reverse sequences with 82 and 86 nucleotides read. Low case: exon map, consensus sequence, and genotype assigned. Stepwise distribution of the sequences at exon2/intron 2 border is also shown, and an HLA-A * 01: 01: 01: 01, 24: 02: 01: 01 combination is proposed with zero mismatch conditions (MM master layer) as compared with the database. A non-expressed (А* 01: 01: 01: 02 N), and low-expressed (А * 24: 02: 01: 02 L) variants are discriminated by means of exclusion of intron 2 variants, as shown in the noncoding column (N-C). Discordances in phase layers 3 and 4 (ММ3, MM4) demonstrate potential ambiguities which could occur if the SNP phase in exons 3 and 2 could not be revealed (with conventional Sanger sequencing). Other detectable alleles, A * 24: 02: 01: 03 (change in intron 3), and A * 24: 02: 40 (synonymous substitution in exon 5) cannot be excluded, and therefore, are displayed in a similar way with zero mismatches. [5]

Factors to consider in cost analysis of in-depth sequencing

Reagents for the entire process include those used for conventional pre-analytic methods (e.g., DNA extraction, quality assessment, and initial low-resolution typing step. Additional expenditures are a subject to some ambiguities, due to different prices reagents and equipment offered by distinct manufacturers. Moreover, it should be stressed that all commercial NGS systems are of closed type, thus causing broad variations in prices for the entire NGS procedure per single DNA sample, and depending on the per year capacity of the given HLA typing laboratory.

However, even taking into account maintenance costs (estimated 10% equipment cost), usage of core facilities or shared equipment, the Sanger sequencing (220 K) proves to be twice more expensive than NGS (variable, all less than Sanger), as shown in Fig.3. I.e., the sample preparation costs remain the same however the sequencing cost decreases (Fig. 4).

img img img

Current progress and future directions

In 2005, Rochе produced the first NGS instrument, the Genome Sequencer 20. By means of this device, 100-bp reads are possible, and in future, up to 20 Mbp could be sequenced. Over last decade, rapid progress in NGS technologies has led to revolutionary changes in general genomics and its applications for clinical sequencing or medical exomics (RNA expression analysis). However, PCR-SSO and PCR-sequencing still remain the first-line methods in HLA typing. Meanhwile, commercial kits for NGS-assisted HLA typing have been recently appeared [8]. Hence, elucidation of the whole HLA gene sequence will bring a knowledge which will be of value for medical science in sooner time. However, this knowledge will be insufficient to the total understanding of MHS and HLA interactions. One should assess the sequences and haplotypes of other HLA segments, including regulatory (non-coding) regions [12]. Further analysis should determine transcriptional factors and events regulating the entire HLA unit, including HLA genes and relevant gene structures. They all should be carefully studied, in order to get complete HLA description, i.e., HLA-omics [4]. These efforts will bring real clinical benefits for the patients. Novel methods of HLA typing will be helpful to more accurate medical examination, assignment of biologically diverse clinical groups and individualized treatment of the patients.

Conclusions

A routine tissue-typing laboratory should be flexible, providing valid and reproducible HLA data within short time period. NGS-based HLA analysis is performed with 100% reliability, and well fits the tasks of HLA typing in unrelated donors, in concordance with EFI and ASHI policies. This work process well corresponds to the working schedules for medium- and high-capacity laboratories, thus being potentially attractive to the donor registries.

Recently introduced next-generation sequencing techniques have a facilitating potential for the high-resolution genotyping via decrease of general uncertainty, like as due to extended sequencing regions. The entire set of MHS genes could be sequenced by means of these technologies, in order to uncover the latent immune determinants relevant to autoaggresive reactions [7, 25]. In near future, the whole exome sequencing may be considered a method of decoding some genetic variants, influencing HSCT outcomes. The NGS approaches will be a quite effective and cost-effective technology when evaluating histocompatibility parameters and immunogenetic interactions.

Conflict of interests

No conflict of interests is declared.

References

1. Bentley G, Higuchi R, Hoglund B, Goodridge D, Sayer D, Trachtenberg EA, Erlich HA: High-resolution, high-throughput HLA genotyping by nextgeneration sequencing. Tissue Antigens 2009; 74: 393–403.
2. Blazar BR, Murphy WJ, Abedi M: Advances in graftversus- host disease biology and therapy. Nat Rev Immunol 2012; 12: 443–458.
3. Brunstein CG, Eapen M, Ahn KW, Appelbaum FR, Ballen KK, Champlin RE, Cutler C, Kan F, Laughlin MJ, Soiffer RJ, Weisdorf DJ, Woolfrey A, Wagner JE: Reduced-intensity conditioning transplantation in acute leukemia: the effect of source of unrelated donor stem cells on outcomes. Blood 2012; 119: 5591–5598.
4. Danzer M, Polin H, Proll J, Hofer K, Fae I, Fischer GF, Gabriel C: Highthroughput sequence-based typing strategy for HLA-DRB1 based on real-time polymerase chain reaction. Hum Immunol 2007; 68: 915–917.
5. Danzer M, Niklas N, Stabentheiner S, Hofer K, Pröll J, Stückler C, Raml E, Polinand H, Gabriel C. Rapid, scalable and highly automated HLA genotyping using next-generation sequencing: a transition from research to diagnostics. BMC Genomics 2013, 14: 221.
6. Dunn PP: Human leucocyte antigen typing: techniques and technology, a critical appraisal. Int J Immunogenet 2011; 38: 463–473.
7. Elsner HA, Blasczyk R: Immunogenetics of HLA null alleles: implications for blood stem cell transplantation. Tissue Antigens 2004; 64: 687–695.
8. Erlich H: HLA DNA typing: past, present, and future. Tissue Antigens 2012; 80: 1–11.
9. Erlich RL, Jia X, Anderson S, Banks E, Gao X, Carrington M, Gupta N, DePristo MA, Henn MR, Lennon NJ, de Bakker PI: Next-generation sequencing for HLA typing of class I loci. BMC Genomics 2011; 12: 42.
10. Fleischhauer K, Shaw BE, Gooley T, Malkki M, Bardy P, Bignon JD, Dubois V, Horowitz MM, Madrigal JA, Morishima Y, Oudshoorn M, Ringden O, Spellman S, Velardi A, Zino E, Petersdorf EW: Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoieticcell transplantation: a retrospective study. Lancet Oncol 2012; 13: 366–374.
11. Gabriel C, Danzer M, Hackl C, Kopal G, Hufnagl P, Hofer K, Polin H, Stabentheiner S, Proll J: Rapid high-throughput human leukocyte antigen typing by massively parallel pyrosequencing for high-resolution allele identification. Hum Immunol; 2009, 70: 960–964.
12. Harismendy O, Frazer K: Method for improving sequence coverage uniformity of targeted genomic intervals amplified by LR-PCR using Illumina GA sequencing-by-synthesis technology. Biotechniques 2009;46:229–231.
13. Holcomb CL, Hoglund B, Anderson MW, Blake LA, Bohme I, Egholm M, Ferriola D, Gabriel C, Gelber SE, Goodridge D, Hawbecker S, Klein R, Ladner M, Lind C, Monos D, Pando MJ, Proll J, Sayer DC, Schmitz-Agheguian G, Simen BB, Thiele B, Trachtenberg EA, Tyan DB, Wassmuth R, White S, Erlich HA: A multi-site study using high-resolution HLA genotyping by next generation sequencing. Tissue Antigens 2011, 77: 206–217.
14. Huse SM, Huber JA, Morrison HG, Sogin ML, Welch DM: Accuracy and quality of massively parallel DNA pyrosequencing. Genome Biol 2007; 8: R143.
15. Kotsch K, Wehling J, Blasczyk R: Sequencing of HLA class II genes based on the conserved diversity of the non-coding regions: sequencing based typing of HLA-DRB genes. Tissue Antigens 1999; 53: 486–497.
16. Lank SM, Golbach BA, Creager HM, Wiseman RW, Keskin DB, Reinherz EL, Brusic V, O’Connor DH: Ultra-high resolution HLA genotyping and allele discovery by highly multiplexed cDNA amplicon pyrosequencing. BMC Genomics 2012; 13: 378.
17. Lank SM, Wiseman RW, Dudley DM, O’Connor DH: A novel single cDNA amplicon pyrosequencing method for high-throughput, cost-effective sequence-based HLA class I genotyping. Hum Immunol 2010; 71: 1011–1017.
18. Lebedeva TV, Mastromarino SA, Lee E, Ohashi M, Alosco SM, Yu N: Resolution of HLA class I sequence-based typing ambiguities by groupspecific sequencing primers. Tissue Antigens 2011, 77: 247–250.
19. Baxter-Lowe LA. Tailoring NGS for smaller volume labs. 42nd ASHI Annual Meeting. St. Louis, MO, Poster report (Sept 28, 2016).
20. Li HW, Sykes M: Emerging concepts in haematopoietic cell transplantation. Nat Rev Immunol 2012; 12: 403–416.
21. Lind C, Ferriola D, Mackiewicz K, Heron S, Rogers M, Slavich L, Walker R, Hsiao T, McLaughlin L, D’Arcy M, Gai X, Goodridge D, Sayer D, Monos D: Next-generation sequencing: the solution for high-resolution, unambiguous human leukocyte antigen typing. Hum Immunol 2010; 71: 1033–1042.
22. McDevitt SL, Bredeson JV, Roy SW, Lane JA, Noble JA. HAPCAD: An open-source tool to detect PCR crossovers in next-generation sequencing generated HLA data. Hum Immunol. 2016; 77 (3): 257-63. doi: 10.1016/j.humimm. 2016.01.013.
23. Metzker ML: Sequencing technologies – the next generation. Nat Rev Genet 2010; 11: 31–46.
24. Petersdorf EW: Optimal HLA matching in hematopoietic cell transplantation. Curr Opin Immunol 2008; 20: 588–593.
25. Proll J, Danzer M, Stabentheiner S, Niklas N, Hackl C, Hofer K, Atzmuller S, Hufnagl P, Gully C, Hauser H, Krieger O, Gabriel C: Sequence capture and next generation resequencing of the MHC region highlights potential transplantation determinants in HLA identical haematopoietic stem cell transplantation. DNA Res 2011; 18: 201–210.
26. Robinson J, Halliwell JA, Hayhurst JD, Flicek P, Parham P, Marsh SG. The IPD and IMGT/HLA database: allele variant databases. Nucleic Acids Res 2015; 43(Database issue): D423-31. doi: 10.1093/nar/gku1161.
27. Shaw BE, Arguello R, Garcia-Sepulveda CA, Madrigal JA: The impact of HLA genotyping on survival following unrelated donor haematopoietic stem cell transplantation. Br J Haematol 2010; 150: 251–258.
28. Shiina T, Suzuki S, Ozaki Y, Taira H, Kikkawa E, Shigenari A, Oka A, UmemuraT, Joshita S, Takahashi O, Hayashi Y, Paumen M, Katsuyama Y, Mitsunaga S, Ota M, Kulski JK, Inoko H: Super high resolution for single molecule sequence-based typing of classical HLA loci at the 8-digit level using next generation sequencers. Tissue Antigens 2012; 80: 305–316.
29. Marsh SG, WHO Nomenclature Committee for Factors of the HLA System. Nomenclature for factors of the HLA system, update March 2016. Human Immunology 2016; 77 (8): 706-709.
30. Voorter CE, Mulkers E, Liebelt P, Sleyster E, van den Berg-Loonen EM: Reanalysis of sequence-based HLA-A, -B and -Cw typings: how ambiguous is today’s SBT typing tomorrow. Tissue Antigens 2007; 70: 383–389.
31. Voelkerding KV, Dames SA, Durtschi JD. Next-generation sequencing: from basic research to diagnostics. Clin Chem 2009; 55: 641–658.
32. Wang C, Krishnakumar S, Wilhelmy J, Babrzadeh F, Stepanyan L, Su LF, Levinson D, Fernandez-Vina MA, Davis RW, Davis MM, Mindrinos M: Highthroughput, high-fidelity HLA genotyping with deep sequencing. Proc Natl Acad Sci USA 2012; 109: 8676–8681.
33. Weimer ET, Montgomery M, Petraroia R, Crawford J, Schmitz JL. Performance characteristics and validation of next-generation sequencing for human leucocyte antigen typing. J Mol Diagnostics 2016; 18 (5): 668-675.

" ["~DETAIL_TEXT"]=> string(29128) "

Introduction

Allogeneic hematopoietic stem cell transplantation (allo- HSCT) is a proven option for treatment of hematological disorders, e.g., lymphoma, leukemia, and aplastic anemias. Among other factors, the HSCT outcomes strongly depend on aggressive reactions of donor lymphocytes against the patient’s cells. This complication is known as a graft-versushost disease (GVHD) and represents a serious threat to the patients, along with the risk of relapse and concomitant infections [1]. Over last decades, a progress in the donor-recipient matching lead to an imminent increase of patients’ survival post transplant, due to decreased rates of immune complications [3,20]. These advances are made, mostly, due to an improved technique of HLA gene typing [24]. E.g., sufficiently increased survival rates and better outcomes were shown for the patient-donor pairs typed by means of high-resolution allele typing for HLA-A, -B, -C and -DRB1 [27]. Analysis of HLA-DQB1 and -DPB1 loci is still under development [10].

Hence, implementation of high-resolution techniques for the classic HLA typing brings about higher clinical efficiency in allo-HSCT from relatives and unrelated donors. The aspects of optimal donor matching are connected with a sufficient allelic diversity (polymorphism) of the gene loci, mainly, due to gene recombination of the chromosome 6 regions, thus producing repeats at distinct HLA gene segments and causing some difficulties with HLA typing, even at four-digit resolution level. Therefore, novel technological achievements in immunogenetics are of special importance, and, first of all, new approaches to DNA typing [6].

Milestones of molecular HLA typing

Since the very beginning of molecular biology, individual HLA matching was oriented for gene polymorphism analysis. Forty years ago, Fred Sanger has proposed a method of DNA sequencing, by the generation of distinct DNA strands based on a complementary matrix, using DNA polymerase I Klenoff fragment, and then followed by analysis of radioactively labeled DNA fragments in polyacrylamide gel. A breakthrough in this technology and development of routine HLA typing methods occurred with the application of fluorescent dideoxynucleotides in the course of the cyclic process followed by microcapillary electrophoresis. Direct sequencing of heterozygous DNA samples has its limitations since, in the case of allelic polymorphism, the nucleic bases may be located at the same or homologous chromosome, thus precluding detection of subtle differences in the given HLA gene sequence.

Over the last 20 years, the automated Sanger technique is a prevalent approach to genome sequencing in humans, animals, bacteria, and viruses. However, a need for more rapid routine genome screening stimulated novel technologies of multiplex DNA sequencing. These modern methods are depicted as the second-generation approaches (Next-Generation Sequencing, NGS). These technological platforms are based on different strategies, with respect to unique preparations of DNA templates, their sequencing, registration, retrieval and evaluation of the nucleotide sequences by means of novel bioinformatic approaches [13]. A principal benefit of the new-generation sequencing is an opportunity of getting large databases of multiple defined gene sequences within a short time period and at relatively low cost.

A known polymorphism of HLA genes presents a special problem in search of optimal donors for hematopoietic stem cell transplantation (HSCT). E.g., as for September 2016, the International Nomenclature (HLA International ImMunoGeneTics (IMGT) [26, 29] included 15,813 HLA and related alleles, registered in the numerical nomenclature used worldwide (Fig. 1).

img

In addition to the unique allele number, there are additional optional suffixes that may be added to an allele to indicate its expression status. Alleles that have been shown not to be expressed – “Null” alleles – have been given the suffix ‘N’. Alleles that have been shown to be alternatively expressed may have the suffix “L”, “S”, “C”, “A” or “Q”. The suffix “L” is used to indicate an allele which has been shown to have “Low” cell surface expression when compared to normal levels. The “S” suffix is used to denote an allele specifying a protein which is expressed as a soluble, “Secreted” molecule but is not present on the cell surface. The “C” suffix is assigned to alleles that produce proteins that are present in the “Cytoplasm” and not on the cell surface. An “A” suffix indicates an “Aberrant” expression where there is some doubt as to whether a protein is actually expressed. A “Q” suffix is used when the expression of an allele is “Questionable”, given that the mutation seen in the allele has been shown to affect normal expression levels in other alleles.

No wonder that the general NGS approach adapted for HLA typing proved to be a breakthrough in molecular biology applications being quite promising to the transplantation clinics and bone marrow donor registries. However, to promote the NGS implementation, we need specialized typing strategies and digital program algorithms. The sequencing costs per single run are sharply decreased with NGS approach which may be quite accessible to the tissue typing laboratories in sooner time.

Multiple NGS technological platforms are offered on the market. At the present time, four types of NGS systems are implemented in research and clinics. E.g., the 454 Junior (Roche) was the first system equipped with commercial kits for HLA-typing. Illumina platform is most widely applied in fundamental and clinical research, however, not yet registered for HLA-typing. The Ion Torrent system was offered something later, being, however, a growing point in the field. Lately, the fourth generation of NGS appears – Single Molecule Sequencing. They can do long reads with very high throughput. Advantages: Low Cost, Simultaneous sequencing of several samples (barcoding). Currently manufactured by 2 companies, PacBio and Nanopore MiniON. They are amplicon-based and “true” single molecule sequencing. It has a very small footprint and even fits in the pocket.

At the present time, a four-digit resolution approach is used for optimal matching in the donor-recipient pairs, i.e., testing of HLA-A, -B, -C, (exons 2, 3); -DRB1 (exon 2), and – DQB1 (exons 2, 3) by means of conventional PCR technique.

Pitfalls in NGS-based HLA typing

To perform high-resolution typing, one should exclude non-coding alleles from HLA-A (exons 1, 4 and introns 2, 4), HLA-B (exons 1, 4 and intron 1), and HLA-C (exons 1, 4, 7).

Phase determination of the sequence motifs becomes an increasingly difficult task, due to new HLA polymorphisms reported, thus causing an exponential increase in genotyping ambiguity with every ongoing release of the HLA database release [10]. Therefore, novel typing strategies have been arranged, e.g., group-specific PCR [15], or allelic discrimination with distinct group-specific primers [18] before subsequent sequencing. These discrimination techniques are used at HLA laboratories for a long time. However, they are labor-consuming, and appropriate commercial kits are largely lacking.

The novel NGS-based HLA typing was developed over 2000’s, having been characterized by increased resolution ability and high throughput [22, 30]. In 2009, Gabriel et al. [11] and Erlich et al. [1] have independently shown an opportunity of HLA typing by means of a 454 technological platform. A double-blinded multicentric study based on exon amplification by primers’ annealing was performed and reported in 2011 [13]. This cooperative work has shown that HLA sequencing with 454 system allows reliable identification of the HLA genotypes. However, the analytic approaches proved to be quite diligent, labor-intensive and require automation. Moreover, a systemic algorithm for the Class I HLA typing was performed with different PCR-based barcoding methods [9]. Later on, Lank et al. [16, 19] proposed a DNA processing protocol for HLA typing with a less complicated DNA library preparation. Finally, it was shown that, as unlike with amplicon sequencing, the shotgun sequencing approach using long PCR products, fragmenting and ligation of the multiplex identifiers (MID) is a realistic way for the entire HLA gene sequencing. [20, 27, 32].

Meanwhile, the existing protocols provide additional proofs of NGS complexity. This technology is still difficult to introduce in laboratories working in the area of histocompatibility and immunogenetics. There were some unresolved technical issues concerning labor intensity of a gene library preparation, and too long time required for processing of the databases produced. Noteworthy, the bioinformatic tools in NGS rarely generated a readable report of HLA typing.

Taking this into account, an automated approach to the high-resolutionHLA typing was developed, being adapted for the 454 GS Junior, covering 17 exons of the following genes: HLA-A, -B, -C, -DQB1, -DPB1, -DRB1, -DRB3, -DRB4 и -DRB5 (DRB3 / 4/5). However, exact data on 5”- and 3”- untranslated sequences (UTR) are not available for all the alleles. Therefore, binding of primers in these regions cannot be definitely predicted, thus missing some alleles from analysis or nucleotide shifts due to suboptimal amplification primers. Another potential problem may be due to simultaneous amplification of pseudogenes since their sequences are quite similar to those of target HLA genes.

Despite these issues, NGS has a great future in the area. An opportunity of the whole-gene analysis should ultimately lead to better understanding of HLA role for HSCT outcomes and the course of the primary disease. Moreover, the zero alleles could be better defined. So far, we cannot exploit this benefit. However, some questions will be answered, e.g., assessing a “complete” HLA allele database and overcoming existing hurdles when assembling a single complete allelic sequence.

At the initial step, a maximal length of sequences readable with Myseq was limited of 2×150 bp. However, the manufacturer (Illumina) improves its software, as well as chemical equipment. Hence, their last version (version 3) allows sequencing of ca.300 bp, in order to cover one exon within each sequenced amplicon, thus diminishing potential error rates and simplifying the work process.

Main steps of the NGS as performed with Illumina platform

• Template generation: the complete sequences of HLA genes are amplified with complementary primers in a single reaction, using Long-Range DNA polymerase.
• Double-stranded DNA fragmentation by means of specific fragmentase optimized by its size for the given HLA locus
• Preparation of gene libraries: Appropriate reagents are used for the end repair, 5’ phosphorylation of poly-A and poly-T ends for subsequent adaptors’ ligation.
• Adapters’ ligation and their indexing.
• Mixing of the samples and their loading to the NGS sequencer.
• Analysis of results (Fig.1)

Following generation of a gene library, the DNA molecules are bound to the solid phase carrier, the s.c. flow well, by means of direct and reverse oligonucleotide adapters. During generation of the gene library, the complementary (adapter) sequences are fixed to the templates at the 5”- and 3”-ends, thus allowing them to bind the flow well surface covered with adapter molecules. To enhance the sequencing signal, molecular clusters are generated from one DNA molecule by means of solid-phase amplification bridge, resulting in up to 1000 tightly packed copies of the initial template in the flow well. Hence, each cluster corresponds to a single read by the end of sequencing. The adapter oligonucleotides are bound to the surface of flow well, both for the capture of sequenced templates molecules, and primers for bridge amplification. Sequencing is then carried out by means of chemical reaction “reversible terminator’” All 4 fluorescently labeled oligonucleotides are simultaneously driven through the flow well. Their labels are intended for termination of the chain synthesis. Therefore, only one nucleotide type is added for each polymerization cycle. The nonbound nucleotides are washed off. The labels and terminator are removed following CCD-assisted conversion of the pictures, in order to allow further elongation of the chain at the next sequencing cycle. To facilitate the multiplexing procedure, the adapter sequences are followed by the s.c. index sequences (DNA barcoding). These DNA barcodes are attached to the target fragments during the library design, with a unique code for given sample. Double indexing is possible by differential DNA barcoding from 5” to 3” end. In the course of four sequencing rounds, two indexing reads and two reads of target sequences are initiated. The data are accumulated for each single cluster and are used for generation of the output files in two directions of sequencing.

HLA data analysis with MiSeq platform

Miseq generates a working file in FASTQ format with two corresponding files (resp., direct and reverse reads). All the files contain equal numbers of the read sequences presented in the same order. Moreover, all the sequences read are of equal length according to the chosen specifications. Homogeneous structure of initial data provides some benefits for the pre-analytic data handling. Upon filtration and cutting, some algorithms are required here which are more applicable than with platforms generating variable reading length (e.g., Roche 454, or Ion Torrent systems). Data quality obtained with Miseq is high enough to perform HLA typing.

To assign the HLA alleles, software is required which allows communicating with updated HLA databases (IMGT last version, renewed 4 times a year). A number of such commercial packages are currently available. To date, the solutions with an open initial code are also offered, as follows:
HLAminer: http://genomemedicine.com/content/4/12/95
seq2HLA: http://genomemedicine.com/content/4/12/102
Athlates: http://nar.oxfordjournals.org/content/41/14/e142. long
HLAforest: http://www.plosone.org/article/info%3Adoi%2F10. 1371%2Fjournal.pone.0067885
PHLAT: http://www.biomedcentral.com/1471-2164/15/325

According to the guidelines of clinical trials and in order to observe acting regulations (European Federation for Immunogenetics (EFI), American Society for Histocompatibility and Immunogenetics (ASHI) standards), extensive studies of QC and QA are required for development of appropriate in-house reagents, and their testing for HLA typing bases on the Miseq platform. They should include both developments of the tests, and methods of automated data mining, and their presentation. Sufficient time is needed for design, feasibility evaluation, and implementation of NGS working protocols. The optimal choice of NGS platform and proper protocol is a difficult task for any individual setting in this rapidly developing technology [14].

Modern protocols of sequencing and data retrieval/handling differ, generally, in the aims of analysis, i.e., whole-genome evaluation (from 5’UTR to 3’UTR), or exome studies. So far, a limit of 400 bp exists for the length of sequencing, independently of the working protocol applied. This length of DNA fragment is sufficient to reading of whole exons and providing unequivocal clonal information for these exons. To sequence longer PCR products, a series of overlapping fragments is required, followed by their subsequent assembly (shotgun sequencing). The working processes under these two protocols significantly differ in labor intensity and complexity.

The output data are collected for each molecular cluster and used for generation of the output files containing results of direct and reverse reads as displayed on Fig. 2 [5]

img

The detailed information concerns HLA-A genotype assignment, as show in the master layer. Direct and reverse sequence reads are aligned to exons 2, 3, and 4, with partial coverage of intronic regions [33]. Read numbers and sequence direction are shown in white cells. For example, exon 4 is represented by two (alleles 1 and 2) direct and reverse sequences, with 90 coverages, and, respectively, 81 nucleotides read, and two reverse sequences with 82 and 86 nucleotides read. Low case: exon map, consensus sequence, and genotype assigned. Stepwise distribution of the sequences at exon2/intron 2 border is also shown, and an HLA-A * 01: 01: 01: 01, 24: 02: 01: 01 combination is proposed with zero mismatch conditions (MM master layer) as compared with the database. A non-expressed (А* 01: 01: 01: 02 N), and low-expressed (А * 24: 02: 01: 02 L) variants are discriminated by means of exclusion of intron 2 variants, as shown in the noncoding column (N-C). Discordances in phase layers 3 and 4 (ММ3, MM4) demonstrate potential ambiguities which could occur if the SNP phase in exons 3 and 2 could not be revealed (with conventional Sanger sequencing). Other detectable alleles, A * 24: 02: 01: 03 (change in intron 3), and A * 24: 02: 40 (synonymous substitution in exon 5) cannot be excluded, and therefore, are displayed in a similar way with zero mismatches. [5]

Factors to consider in cost analysis of in-depth sequencing

Reagents for the entire process include those used for conventional pre-analytic methods (e.g., DNA extraction, quality assessment, and initial low-resolution typing step. Additional expenditures are a subject to some ambiguities, due to different prices reagents and equipment offered by distinct manufacturers. Moreover, it should be stressed that all commercial NGS systems are of closed type, thus causing broad variations in prices for the entire NGS procedure per single DNA sample, and depending on the per year capacity of the given HLA typing laboratory.

However, even taking into account maintenance costs (estimated 10% equipment cost), usage of core facilities or shared equipment, the Sanger sequencing (220 K) proves to be twice more expensive than NGS (variable, all less than Sanger), as shown in Fig.3. I.e., the sample preparation costs remain the same however the sequencing cost decreases (Fig. 4).

img img img

Current progress and future directions

In 2005, Rochе produced the first NGS instrument, the Genome Sequencer 20. By means of this device, 100-bp reads are possible, and in future, up to 20 Mbp could be sequenced. Over last decade, rapid progress in NGS technologies has led to revolutionary changes in general genomics and its applications for clinical sequencing or medical exomics (RNA expression analysis). However, PCR-SSO and PCR-sequencing still remain the first-line methods in HLA typing. Meanhwile, commercial kits for NGS-assisted HLA typing have been recently appeared [8]. Hence, elucidation of the whole HLA gene sequence will bring a knowledge which will be of value for medical science in sooner time. However, this knowledge will be insufficient to the total understanding of MHS and HLA interactions. One should assess the sequences and haplotypes of other HLA segments, including regulatory (non-coding) regions [12]. Further analysis should determine transcriptional factors and events regulating the entire HLA unit, including HLA genes and relevant gene structures. They all should be carefully studied, in order to get complete HLA description, i.e., HLA-omics [4]. These efforts will bring real clinical benefits for the patients. Novel methods of HLA typing will be helpful to more accurate medical examination, assignment of biologically diverse clinical groups and individualized treatment of the patients.

Conclusions

A routine tissue-typing laboratory should be flexible, providing valid and reproducible HLA data within short time period. NGS-based HLA analysis is performed with 100% reliability, and well fits the tasks of HLA typing in unrelated donors, in concordance with EFI and ASHI policies. This work process well corresponds to the working schedules for medium- and high-capacity laboratories, thus being potentially attractive to the donor registries.

Recently introduced next-generation sequencing techniques have a facilitating potential for the high-resolution genotyping via decrease of general uncertainty, like as due to extended sequencing regions. The entire set of MHS genes could be sequenced by means of these technologies, in order to uncover the latent immune determinants relevant to autoaggresive reactions [7, 25]. In near future, the whole exome sequencing may be considered a method of decoding some genetic variants, influencing HSCT outcomes. The NGS approaches will be a quite effective and cost-effective technology when evaluating histocompatibility parameters and immunogenetic interactions.

Conflict of interests

No conflict of interests is declared.

References

1. Bentley G, Higuchi R, Hoglund B, Goodridge D, Sayer D, Trachtenberg EA, Erlich HA: High-resolution, high-throughput HLA genotyping by nextgeneration sequencing. Tissue Antigens 2009; 74: 393–403.
2. Blazar BR, Murphy WJ, Abedi M: Advances in graftversus- host disease biology and therapy. Nat Rev Immunol 2012; 12: 443–458.
3. Brunstein CG, Eapen M, Ahn KW, Appelbaum FR, Ballen KK, Champlin RE, Cutler C, Kan F, Laughlin MJ, Soiffer RJ, Weisdorf DJ, Woolfrey A, Wagner JE: Reduced-intensity conditioning transplantation in acute leukemia: the effect of source of unrelated donor stem cells on outcomes. Blood 2012; 119: 5591–5598.
4. Danzer M, Polin H, Proll J, Hofer K, Fae I, Fischer GF, Gabriel C: Highthroughput sequence-based typing strategy for HLA-DRB1 based on real-time polymerase chain reaction. Hum Immunol 2007; 68: 915–917.
5. Danzer M, Niklas N, Stabentheiner S, Hofer K, Pröll J, Stückler C, Raml E, Polinand H, Gabriel C. Rapid, scalable and highly automated HLA genotyping using next-generation sequencing: a transition from research to diagnostics. BMC Genomics 2013, 14: 221.
6. Dunn PP: Human leucocyte antigen typing: techniques and technology, a critical appraisal. Int J Immunogenet 2011; 38: 463–473.
7. Elsner HA, Blasczyk R: Immunogenetics of HLA null alleles: implications for blood stem cell transplantation. Tissue Antigens 2004; 64: 687–695.
8. Erlich H: HLA DNA typing: past, present, and future. Tissue Antigens 2012; 80: 1–11.
9. Erlich RL, Jia X, Anderson S, Banks E, Gao X, Carrington M, Gupta N, DePristo MA, Henn MR, Lennon NJ, de Bakker PI: Next-generation sequencing for HLA typing of class I loci. BMC Genomics 2011; 12: 42.
10. Fleischhauer K, Shaw BE, Gooley T, Malkki M, Bardy P, Bignon JD, Dubois V, Horowitz MM, Madrigal JA, Morishima Y, Oudshoorn M, Ringden O, Spellman S, Velardi A, Zino E, Petersdorf EW: Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoieticcell transplantation: a retrospective study. Lancet Oncol 2012; 13: 366–374.
11. Gabriel C, Danzer M, Hackl C, Kopal G, Hufnagl P, Hofer K, Polin H, Stabentheiner S, Proll J: Rapid high-throughput human leukocyte antigen typing by massively parallel pyrosequencing for high-resolution allele identification. Hum Immunol; 2009, 70: 960–964.
12. Harismendy O, Frazer K: Method for improving sequence coverage uniformity of targeted genomic intervals amplified by LR-PCR using Illumina GA sequencing-by-synthesis technology. Biotechniques 2009;46:229–231.
13. Holcomb CL, Hoglund B, Anderson MW, Blake LA, Bohme I, Egholm M, Ferriola D, Gabriel C, Gelber SE, Goodridge D, Hawbecker S, Klein R, Ladner M, Lind C, Monos D, Pando MJ, Proll J, Sayer DC, Schmitz-Agheguian G, Simen BB, Thiele B, Trachtenberg EA, Tyan DB, Wassmuth R, White S, Erlich HA: A multi-site study using high-resolution HLA genotyping by next generation sequencing. Tissue Antigens 2011, 77: 206–217.
14. Huse SM, Huber JA, Morrison HG, Sogin ML, Welch DM: Accuracy and quality of massively parallel DNA pyrosequencing. Genome Biol 2007; 8: R143.
15. Kotsch K, Wehling J, Blasczyk R: Sequencing of HLA class II genes based on the conserved diversity of the non-coding regions: sequencing based typing of HLA-DRB genes. Tissue Antigens 1999; 53: 486–497.
16. Lank SM, Golbach BA, Creager HM, Wiseman RW, Keskin DB, Reinherz EL, Brusic V, O’Connor DH: Ultra-high resolution HLA genotyping and allele discovery by highly multiplexed cDNA amplicon pyrosequencing. BMC Genomics 2012; 13: 378.
17. Lank SM, Wiseman RW, Dudley DM, O’Connor DH: A novel single cDNA amplicon pyrosequencing method for high-throughput, cost-effective sequence-based HLA class I genotyping. Hum Immunol 2010; 71: 1011–1017.
18. Lebedeva TV, Mastromarino SA, Lee E, Ohashi M, Alosco SM, Yu N: Resolution of HLA class I sequence-based typing ambiguities by groupspecific sequencing primers. Tissue Antigens 2011, 77: 247–250.
19. Baxter-Lowe LA. Tailoring NGS for smaller volume labs. 42nd ASHI Annual Meeting. St. Louis, MO, Poster report (Sept 28, 2016).
20. Li HW, Sykes M: Emerging concepts in haematopoietic cell transplantation. Nat Rev Immunol 2012; 12: 403–416.
21. Lind C, Ferriola D, Mackiewicz K, Heron S, Rogers M, Slavich L, Walker R, Hsiao T, McLaughlin L, D’Arcy M, Gai X, Goodridge D, Sayer D, Monos D: Next-generation sequencing: the solution for high-resolution, unambiguous human leukocyte antigen typing. Hum Immunol 2010; 71: 1033–1042.
22. McDevitt SL, Bredeson JV, Roy SW, Lane JA, Noble JA. HAPCAD: An open-source tool to detect PCR crossovers in next-generation sequencing generated HLA data. Hum Immunol. 2016; 77 (3): 257-63. doi: 10.1016/j.humimm. 2016.01.013.
23. Metzker ML: Sequencing technologies – the next generation. Nat Rev Genet 2010; 11: 31–46.
24. Petersdorf EW: Optimal HLA matching in hematopoietic cell transplantation. Curr Opin Immunol 2008; 20: 588–593.
25. Proll J, Danzer M, Stabentheiner S, Niklas N, Hackl C, Hofer K, Atzmuller S, Hufnagl P, Gully C, Hauser H, Krieger O, Gabriel C: Sequence capture and next generation resequencing of the MHC region highlights potential transplantation determinants in HLA identical haematopoietic stem cell transplantation. DNA Res 2011; 18: 201–210.
26. Robinson J, Halliwell JA, Hayhurst JD, Flicek P, Parham P, Marsh SG. The IPD and IMGT/HLA database: allele variant databases. Nucleic Acids Res 2015; 43(Database issue): D423-31. doi: 10.1093/nar/gku1161.
27. Shaw BE, Arguello R, Garcia-Sepulveda CA, Madrigal JA: The impact of HLA genotyping on survival following unrelated donor haematopoietic stem cell transplantation. Br J Haematol 2010; 150: 251–258.
28. Shiina T, Suzuki S, Ozaki Y, Taira H, Kikkawa E, Shigenari A, Oka A, UmemuraT, Joshita S, Takahashi O, Hayashi Y, Paumen M, Katsuyama Y, Mitsunaga S, Ota M, Kulski JK, Inoko H: Super high resolution for single molecule sequence-based typing of classical HLA loci at the 8-digit level using next generation sequencers. Tissue Antigens 2012; 80: 305–316.
29. Marsh SG, WHO Nomenclature Committee for Factors of the HLA System. Nomenclature for factors of the HLA system, update March 2016. Human Immunology 2016; 77 (8): 706-709.
30. Voorter CE, Mulkers E, Liebelt P, Sleyster E, van den Berg-Loonen EM: Reanalysis of sequence-based HLA-A, -B and -Cw typings: how ambiguous is today’s SBT typing tomorrow. Tissue Antigens 2007; 70: 383–389.
31. Voelkerding KV, Dames SA, Durtschi JD. Next-generation sequencing: from basic research to diagnostics. Clin Chem 2009; 55: 641–658.
32. Wang C, Krishnakumar S, Wilhelmy J, Babrzadeh F, Stepanyan L, Su LF, Levinson D, Fernandez-Vina MA, Davis RW, Davis MM, Mindrinos M: Highthroughput, high-fidelity HLA genotyping with deep sequencing. Proc Natl Acad Sci USA 2012; 109: 8676–8681.
33. Weimer ET, Montgomery M, Petraroia R, Crawford J, Schmitz JL. Performance characteristics and validation of next-generation sequencing for human leucocyte antigen typing. J Mol Diagnostics 2016; 18 (5): 668-675.

" ["DETAIL_TEXT_TYPE"]=> string(4) "html" ["~DETAIL_TEXT_TYPE"]=> string(4) "html" ["PREVIEW_TEXT"]=> string(0) "" ["~PREVIEW_TEXT"]=> string(0) "" ["PREVIEW_TEXT_TYPE"]=> string(4) "text" ["~PREVIEW_TEXT_TYPE"]=> string(4) "text" ["PREVIEW_PICTURE"]=> NULL ["~PREVIEW_PICTURE"]=> NULL ["LANG_DIR"]=> string(4) "/ru/" ["~LANG_DIR"]=> string(4) "/ru/" ["SORT"]=> string(3) "500" ["~SORT"]=> string(3) "500" ["CODE"]=> string(100) "sovremennye-metody-i-vozmozhnosti-sekvenirovaniya-sleduyushchego-pokoleniya-ngs-dlya-tipirovaniya-si" ["~CODE"]=> string(100) "sovremennye-metody-i-vozmozhnosti-sekvenirovaniya-sleduyushchego-pokoleniya-ngs-dlya-tipirovaniya-si" ["EXTERNAL_ID"]=> string(3) "694" ["~EXTERNAL_ID"]=> string(3) "694" ["IBLOCK_TYPE_ID"]=> string(7) "journal" ["~IBLOCK_TYPE_ID"]=> string(7) "journal" ["IBLOCK_CODE"]=> string(7) "volumes" ["~IBLOCK_CODE"]=> string(7) "volumes" ["IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["~IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["LID"]=> string(2) "s2" ["~LID"]=> string(2) "s2" ["EDIT_LINK"]=> NULL ["DELETE_LINK"]=> NULL ["DISPLAY_ACTIVE_FROM"]=> string(0) "" ["IPROPERTY_VALUES"]=> array(18) { ["ELEMENT_META_TITLE"]=> string(185) "Современные методы и возможности секвенирования следующего поколения (NGS) для типирования системы HLA" ["ELEMENT_META_KEYWORDS"]=> string(260) "Секвенирование следуюшего поколения (NGS) технологические решения HLA-типирование аллогенная трансплантация гемопоэтических стволовых клеток" ["ELEMENT_META_DESCRIPTION"]=> string(269) "Современные методы и возможности секвенирования следующего поколения (NGS) для типирования системы HLACurrent methods and opportunities of next-generation sequencing (NGS) for HLA typing" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(3546) "Область генома, кодирующая лейкоциты антигенов человека (HLA) – это сегмент длиной 3,6 миллиона пар оснований на хромосоме 6(p21). Сложная по антигенному составу система HLA содержит важные молекулы, участвующие в трансплантационном иммунитете. Специфические генные последовательности генов HLA довольно сложно расшифровать с помощью классических методов прямого секвенирования в связи с их техническими ограничениями, сложным составом генов HLA, и возрастающим числом новых аллелей, что требует новых методов генотипирования. Секвенирование следуюшего поколения (NGS) является методом, который может обеспечить полное решение проблемы HLA-типирования. За последнее десятилетие разработка NGS обеспечила более легкий способ полногеномного анализа у человека, в том числе для типирования генов HLA. Несколько вариантов высокопроизводительных методов оценки HLA, основанные на мультиплексных аналитических технологиях NGS были разработаны на основе различных технологических платформ. В этом обзоре мы обсуждаем возможные области применения и прогресс в оборудовании для NGS в плане глубокого типирования системы HLA, с особым вниманием к будущим аспектам его клинического использования. Общеизвестный полиморфизм генов HLA и минимальные межаллельные различия представляют собой особую проблему. Поэтому некоторые вопросы, связанные с биоинформатикой и углубленной обработкой данных для более эффективного анализа HLA в контексте оценки совместимости донора и реципиента. В этом плане различными производителями предложены специализированные компьютерные программы для анализа больших баз данных, получаемых посредством технологий NGS. Наконец, эти высокопроизводительные подходы позволяют минимизировать финансовые затраты на 1 образец, особенно в крупных HLA-лабораториях, где соответствующие расходы на NGS-исследования стали теперь значительно затрат, возникающих при использовании классических технологий секвенирования по Сэнгеру." ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(185) "Современные методы и возможности секвенирования следующего поколения (NGS) для типирования системы HLA" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(185) "Современные методы и возможности секвенирования следующего поколения (NGS) для типирования системы HLA" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(185) "Современные методы и возможности секвенирования следующего поколения (NGS) для типирования системы HLA" ["SECTION_META_TITLE"]=> string(185) "Современные методы и возможности секвенирования следующего поколения (NGS) для типирования системы HLA" ["SECTION_META_KEYWORDS"]=> string(185) "Современные методы и возможности секвенирования следующего поколения (NGS) для типирования системы HLA" ["SECTION_META_DESCRIPTION"]=> string(185) "Современные методы и возможности секвенирования следующего поколения (NGS) для типирования системы HLA" ["SECTION_PICTURE_FILE_ALT"]=> string(185) "Современные методы и возможности секвенирования следующего поколения (NGS) для типирования системы HLA" ["SECTION_PICTURE_FILE_TITLE"]=> string(185) "Современные методы и возможности секвенирования следующего поколения (NGS) для типирования системы HLA" ["SECTION_PICTURE_FILE_NAME"]=> string(100) "sovremennye-metody-i-vozmozhnosti-sekvenirovaniya-sleduyushchego-pokoleniya-ngs-dlya-tipirovaniya-si" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(185) "Современные методы и возможности секвенирования следующего поколения (NGS) для типирования системы HLA" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(185) "Современные методы и возможности секвенирования следующего поколения (NGS) для типирования системы HLA" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(100) "sovremennye-metody-i-vozmozhnosti-sekvenirovaniya-sleduyushchego-pokoleniya-ngs-dlya-tipirovaniya-si" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(100) "sovremennye-metody-i-vozmozhnosti-sekvenirovaniya-sleduyushchego-pokoleniya-ngs-dlya-tipirovaniya-si" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(100) "sovremennye-metody-i-vozmozhnosti-sekvenirovaniya-sleduyushchego-pokoleniya-ngs-dlya-tipirovaniya-si" } ["FIELDS"]=> array(1) { ["IBLOCK_SECTION_ID"]=> string(2) "21" } ["PROPERTIES"]=> array(18) { ["KEYWORDS"]=> array(36) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые слова" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "KEYWORDS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "19" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(4) { [0]=> string(4) "8467" [1]=> string(4) "8468" [2]=> string(4) "8469" [3]=> string(4) "8470" } ["VALUE"]=> array(4) { [0]=> string(3) "692" [1]=> string(3) "693" [2]=> string(3) "607" [3]=> string(3) "282" } ["DESCRIPTION"]=> array(4) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(4) { [0]=> string(3) "692" [1]=> string(3) "693" [2]=> string(3) "607" [3]=> string(3) "282" } ["~DESCRIPTION"]=> array(4) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" } ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" } ["SUBMITTED"]=> array(36) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8414" ["VALUE"]=> string(10) "14.09.2016" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "14.09.2016" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8415" ["VALUE"]=> string(10) "25.11.2016" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "25.11.2016" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL } ["PUBLISHED"]=> array(36) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Дата публикации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "PUBLISHED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "22" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Дата публикации" ["~DEFAULT_VALUE"]=> NULL } ["CONTACT"]=> array(36) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8416" ["VALUE"]=> string(3) "691" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(3) "691" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(1) { [0]=> string(4) "8471" } ["VALUE"]=> array(1) { [0]=> string(3) "691" } ["DESCRIPTION"]=> array(1) { [0]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(1) { [0]=> string(3) "691" } ["~DESCRIPTION"]=> array(1) { [0]=> string(0) "" } ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8418" ["VALUE"]=> array(2) { ["TEXT"]=> string(213) "¹Юрий А. Серов, ¹Ильдар M. Бархатов, ¹Антон С. Климов, ²Андрей С. Беркос" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(165) "¹Юрий А. Серов, ¹Ильдар M. Бархатов, ¹Антон С. Климов, ²Андрей С. Беркос" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8419" ["VALUE"]=> array(2) { ["TEXT"]=> string(545) "¹НИИ детской онкологии, гематологии и трансплантации им. Р. М. Горбачевой, Первый Санкт-Петербургский<br> государственный медицинский университет им. И. П. Павлова, Санкт-Петебург, Россия;<br> ²Российский НИИ гематологии и трансфузиологии, Санкт-Петербург, Россия<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(503) "¹НИИ детской онкологии, гематологии и трансплантации им. Р. М. Горбачевой, Первый Санкт-Петербургский
государственный медицинский университет им. И. П. Павлова, Санкт-Петебург, Россия;
²Российский НИИ гематологии и трансфузиологии, Санкт-Петербург, Россия
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8420" ["VALUE"]=> array(2) { ["TEXT"]=> string(3546) "Область генома, кодирующая лейкоциты антигенов человека (HLA) – это сегмент длиной 3,6 миллиона пар оснований на хромосоме 6(p21). Сложная по антигенному составу система HLA содержит важные молекулы, участвующие в трансплантационном иммунитете. Специфические генные последовательности генов HLA довольно сложно расшифровать с помощью классических методов прямого секвенирования в связи с их техническими ограничениями, сложным составом генов HLA, и возрастающим числом новых аллелей, что требует новых методов генотипирования. Секвенирование следуюшего поколения (NGS) является методом, который может обеспечить полное решение проблемы HLA-типирования. За последнее десятилетие разработка NGS обеспечила более легкий способ полногеномного анализа у человека, в том числе для типирования генов HLA. Несколько вариантов высокопроизводительных методов оценки HLA, основанные на мультиплексных аналитических технологиях NGS были разработаны на основе различных технологических платформ. В этом обзоре мы обсуждаем возможные области применения и прогресс в оборудовании для NGS в плане глубокого типирования системы HLA, с особым вниманием к будущим аспектам его клинического использования. Общеизвестный полиморфизм генов HLA и минимальные межаллельные различия представляют собой особую проблему. Поэтому некоторые вопросы, связанные с биоинформатикой и углубленной обработкой данных для более эффективного анализа HLA в контексте оценки совместимости донора и реципиента. В этом плане различными производителями предложены специализированные компьютерные программы для анализа больших баз данных, получаемых посредством технологий NGS. Наконец, эти высокопроизводительные подходы позволяют минимизировать финансовые затраты на 1 образец, особенно в крупных HLA-лабораториях, где соответствующие расходы на NGS-исследования стали теперь значительно затрат, возникающих при использовании классических технологий секвенирования по Сэнгеру." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3546) "Область генома, кодирующая лейкоциты антигенов человека (HLA) – это сегмент длиной 3,6 миллиона пар оснований на хромосоме 6(p21). Сложная по антигенному составу система HLA содержит важные молекулы, участвующие в трансплантационном иммунитете. Специфические генные последовательности генов HLA довольно сложно расшифровать с помощью классических методов прямого секвенирования в связи с их техническими ограничениями, сложным составом генов HLA, и возрастающим числом новых аллелей, что требует новых методов генотипирования. Секвенирование следуюшего поколения (NGS) является методом, который может обеспечить полное решение проблемы HLA-типирования. За последнее десятилетие разработка NGS обеспечила более легкий способ полногеномного анализа у человека, в том числе для типирования генов HLA. Несколько вариантов высокопроизводительных методов оценки HLA, основанные на мультиплексных аналитических технологиях NGS были разработаны на основе различных технологических платформ. В этом обзоре мы обсуждаем возможные области применения и прогресс в оборудовании для NGS в плане глубокого типирования системы HLA, с особым вниманием к будущим аспектам его клинического использования. Общеизвестный полиморфизм генов HLA и минимальные межаллельные различия представляют собой особую проблему. Поэтому некоторые вопросы, связанные с биоинформатикой и углубленной обработкой данных для более эффективного анализа HLA в контексте оценки совместимости донора и реципиента. В этом плане различными производителями предложены специализированные компьютерные программы для анализа больших баз данных, получаемых посредством технологий NGS. Наконец, эти высокопроизводительные подходы позволяют минимизировать финансовые затраты на 1 образец, особенно в крупных HLA-лабораториях, где соответствующие расходы на NGS-исследования стали теперь значительно затрат, возникающих при использовании классических технологий секвенирования по Сэнгеру." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8421" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2016-5-4-63-70" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2016-5-4-63-70" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8422" ["VALUE"]=> array(2) { ["TEXT"]=> string(165) "¹Youri A. Serov, ¹Ildar M. Barkhatov, ¹Anton S. Klimov, ²Andrey S. Berkos" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(117) "¹Youri A. Serov, ¹Ildar M. Barkhatov, ¹Anton S. Klimov, ²Andrey S. Berkos" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8423" ["VALUE"]=> array(2) { ["TEXT"]=> string(783) "¹Research Institute of Children Oncology, Hematology and Transplantation, The First State I. Pavlov Medical University,<br> St. Petersburg, Russia<br> ²Russian Research Institute of Hematology and Transfusiology, Federal Medical-Biological Agency, St. Petersburg, Russia<br> <br> Youri A. Serov, MD, Ph. D., CHS(ABHI), The Head of Biobank<br> Research Unit, Raisa Gorbacheva Memorial Institute of Children’s<br> Hematology, Oncology and Transplantation, The First<br> St. Petersburg I. P. Pavlov State Medical University, Leo Tolstoy<br> str. 6-8, 197022, St. Petersburg, Russia<br> <br> Phone: +7(812) 338-6260 (office); +7(981) 973-8041 (mob.)<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(693) "¹Research Institute of Children Oncology, Hematology and Transplantation, The First State I. Pavlov Medical University,
St. Petersburg, Russia
²Russian Research Institute of Hematology and Transfusiology, Federal Medical-Biological Agency, St. Petersburg, Russia

Youri A. Serov, MD, Ph. D., CHS(ABHI), The Head of Biobank
Research Unit, Raisa Gorbacheva Memorial Institute of Children’s
Hematology, Oncology and Transplantation, The First
St. Petersburg I. P. Pavlov State Medical University, Leo Tolstoy
str. 6-8, 197022, St. Petersburg, Russia

Phone: +7(812) 338-6260 (office); +7(981) 973-8041 (mob.)
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8424" ["VALUE"]=> array(2) { ["TEXT"]=> string(1211) "The region encoding human leukocyte antigens (HLA) is a 3.6-Mb segment at chromosome 6p21. A highly complex HLA system comprises important molecules involved in transplantation immunity, classical direct sequencing methods making it very complicating to resolve the genomic specificities of HLA genes, due of the complex nature of them. Current limitations of existing methods and the increasing rate of new alleles, strongly demanding for a new methodology approach for the HLA genotyping. Next-Generation Sequencing (NGS) is a method that can provide a complete solution to the HLA typing problem. Last decade, the development of (NGS) has shown the easy way for whole-genome analysis in individuals. HLA typing has also benefited from NGS technologies. Several high-throughput HLA- NGS-based typing methods were developed using different technological platforms. In this review, we summarize the possible applications and instrumentation developments of NGS in the in-depth HLA typing, with a focus on future clinical applications. However, some issues of bioinformatics and data mining remain an obstacle to more effective analysis of HLA analysis in the context of donor/recipient compatibility assessment." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1211) "The region encoding human leukocyte antigens (HLA) is a 3.6-Mb segment at chromosome 6p21. A highly complex HLA system comprises important molecules involved in transplantation immunity, classical direct sequencing methods making it very complicating to resolve the genomic specificities of HLA genes, due of the complex nature of them. Current limitations of existing methods and the increasing rate of new alleles, strongly demanding for a new methodology approach for the HLA genotyping. Next-Generation Sequencing (NGS) is a method that can provide a complete solution to the HLA typing problem. Last decade, the development of (NGS) has shown the easy way for whole-genome analysis in individuals. HLA typing has also benefited from NGS technologies. Several high-throughput HLA- NGS-based typing methods were developed using different technological platforms. In this review, we summarize the possible applications and instrumentation developments of NGS in the in-depth HLA typing, with a focus on future clinical applications. However, some issues of bioinformatics and data mining remain an obstacle to more effective analysis of HLA analysis in the context of donor/recipient compatibility assessment." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["NAME_EN"]=> array(36) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8425" ["VALUE"]=> string(84) "Current methods and opportunities of next-generation sequencing (NGS) for HLA typing" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(84) "Current methods and opportunities of next-generation sequencing (NGS) for HLA typing" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" } ["FULL_TEXT_RU"]=> array(36) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(23) "Полный текст" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["PDF_RU"]=> array(36) { ["ID"]=> string(2) "43" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF RUS" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_RU" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "43" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8472" ["VALUE"]=> string(3) "278" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(3) "278" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(7) "PDF RUS" ["~DEFAULT_VALUE"]=> string(0) "" } ["PDF_EN"]=> array(36) { ["ID"]=> string(2) "44" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF ENG" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "44" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8473" ["VALUE"]=> string(3) "279" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(3) "279" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(7) "PDF ENG" ["~DEFAULT_VALUE"]=> string(0) "" } ["NAME_LONG"]=> array(36) { ["ID"]=> string(2) "45" ["TIMESTAMP_X"]=> string(19) "2023-04-13 00:55:00" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(72) "Название (для очень длинных заголовков)" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "NAME_LONG" ["DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "45" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(80) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(72) "Название (для очень длинных заголовков)" ["~DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } } } ["DISPLAY_PROPERTIES"]=> array(13) { ["AUTHOR_EN"]=> array(37) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8422" ["VALUE"]=> array(2) { ["TEXT"]=> string(165) "¹Youri A. Serov, ¹Ildar M. Barkhatov, ¹Anton S. Klimov, ²Andrey S. Berkos" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(117) "¹Youri A. Serov, ¹Ildar M. Barkhatov, ¹Anton S. Klimov, ²Andrey S. Berkos" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(117) "¹Youri A. Serov, ¹Ildar M. Barkhatov, ¹Anton S. Klimov, ²Andrey S. Berkos" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8424" ["VALUE"]=> array(2) { ["TEXT"]=> string(1211) "The region encoding human leukocyte antigens (HLA) is a 3.6-Mb segment at chromosome 6p21. A highly complex HLA system comprises important molecules involved in transplantation immunity, classical direct sequencing methods making it very complicating to resolve the genomic specificities of HLA genes, due of the complex nature of them. Current limitations of existing methods and the increasing rate of new alleles, strongly demanding for a new methodology approach for the HLA genotyping. Next-Generation Sequencing (NGS) is a method that can provide a complete solution to the HLA typing problem. Last decade, the development of (NGS) has shown the easy way for whole-genome analysis in individuals. HLA typing has also benefited from NGS technologies. Several high-throughput HLA- NGS-based typing methods were developed using different technological platforms. In this review, we summarize the possible applications and instrumentation developments of NGS in the in-depth HLA typing, with a focus on future clinical applications. However, some issues of bioinformatics and data mining remain an obstacle to more effective analysis of HLA analysis in the context of donor/recipient compatibility assessment." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1211) "The region encoding human leukocyte antigens (HLA) is a 3.6-Mb segment at chromosome 6p21. A highly complex HLA system comprises important molecules involved in transplantation immunity, classical direct sequencing methods making it very complicating to resolve the genomic specificities of HLA genes, due of the complex nature of them. Current limitations of existing methods and the increasing rate of new alleles, strongly demanding for a new methodology approach for the HLA genotyping. Next-Generation Sequencing (NGS) is a method that can provide a complete solution to the HLA typing problem. Last decade, the development of (NGS) has shown the easy way for whole-genome analysis in individuals. HLA typing has also benefited from NGS technologies. Several high-throughput HLA- NGS-based typing methods were developed using different technological platforms. In this review, we summarize the possible applications and instrumentation developments of NGS in the in-depth HLA typing, with a focus on future clinical applications. However, some issues of bioinformatics and data mining remain an obstacle to more effective analysis of HLA analysis in the context of donor/recipient compatibility assessment." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1211) "The region encoding human leukocyte antigens (HLA) is a 3.6-Mb segment at chromosome 6p21. A highly complex HLA system comprises important molecules involved in transplantation immunity, classical direct sequencing methods making it very complicating to resolve the genomic specificities of HLA genes, due of the complex nature of them. Current limitations of existing methods and the increasing rate of new alleles, strongly demanding for a new methodology approach for the HLA genotyping. Next-Generation Sequencing (NGS) is a method that can provide a complete solution to the HLA typing problem. Last decade, the development of (NGS) has shown the easy way for whole-genome analysis in individuals. HLA typing has also benefited from NGS technologies. Several high-throughput HLA- NGS-based typing methods were developed using different technological platforms. In this review, we summarize the possible applications and instrumentation developments of NGS in the in-depth HLA typing, with a focus on future clinical applications. However, some issues of bioinformatics and data mining remain an obstacle to more effective analysis of HLA analysis in the context of donor/recipient compatibility assessment." } ["DOI"]=> array(37) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8421" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2016-5-4-63-70" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2016-5-4-63-70" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(37) "10.18620/ctt-1866-8836-2016-5-4-63-70" } ["NAME_EN"]=> array(37) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8425" ["VALUE"]=> string(84) "Current methods and opportunities of next-generation sequencing (NGS) for HLA typing" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(84) "Current methods and opportunities of next-generation sequencing (NGS) for HLA typing" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(84) "Current methods and opportunities of next-generation sequencing (NGS) for HLA typing" } ["ORGANIZATION_EN"]=> array(37) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8423" ["VALUE"]=> array(2) { ["TEXT"]=> string(783) "¹Research Institute of Children Oncology, Hematology and Transplantation, The First State I. Pavlov Medical University,<br> St. Petersburg, Russia<br> ²Russian Research Institute of Hematology and Transfusiology, Federal Medical-Biological Agency, St. Petersburg, Russia<br> <br> Youri A. Serov, MD, Ph. D., CHS(ABHI), The Head of Biobank<br> Research Unit, Raisa Gorbacheva Memorial Institute of Children’s<br> Hematology, Oncology and Transplantation, The First<br> St. Petersburg I. P. Pavlov State Medical University, Leo Tolstoy<br> str. 6-8, 197022, St. Petersburg, Russia<br> <br> Phone: +7(812) 338-6260 (office); +7(981) 973-8041 (mob.)<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(693) "¹Research Institute of Children Oncology, Hematology and Transplantation, The First State I. Pavlov Medical University,
St. Petersburg, Russia
²Russian Research Institute of Hematology and Transfusiology, Federal Medical-Biological Agency, St. Petersburg, Russia

Youri A. Serov, MD, Ph. D., CHS(ABHI), The Head of Biobank
Research Unit, Raisa Gorbacheva Memorial Institute of Children’s
Hematology, Oncology and Transplantation, The First
St. Petersburg I. P. Pavlov State Medical University, Leo Tolstoy
str. 6-8, 197022, St. Petersburg, Russia

Phone: +7(812) 338-6260 (office); +7(981) 973-8041 (mob.)
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(693) "¹Research Institute of Children Oncology, Hematology and Transplantation, The First State I. Pavlov Medical University,
St. Petersburg, Russia
²Russian Research Institute of Hematology and Transfusiology, Federal Medical-Biological Agency, St. Petersburg, Russia

Youri A. Serov, MD, Ph. D., CHS(ABHI), The Head of Biobank
Research Unit, Raisa Gorbacheva Memorial Institute of Children’s
Hematology, Oncology and Transplantation, The First
St. Petersburg I. P. Pavlov State Medical University, Leo Tolstoy
str. 6-8, 197022, St. Petersburg, Russia

Phone: +7(812) 338-6260 (office); +7(981) 973-8041 (mob.)
" } ["AUTHORS"]=> array(38) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(1) { [0]=> string(4) "8471" } ["VALUE"]=> array(1) { [0]=> string(3) "691" } ["DESCRIPTION"]=> array(1) { [0]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(1) { [0]=> string(3) "691" } ["~DESCRIPTION"]=> array(1) { [0]=> string(0) "" } ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(57) "Youri A. Serov" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["AUTHOR_RU"]=> array(37) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8418" ["VALUE"]=> array(2) { ["TEXT"]=> string(213) "¹Юрий А. Серов, ¹Ильдар M. Бархатов, ¹Антон С. Климов, ²Андрей С. Беркос" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(165) "¹Юрий А. Серов, ¹Ильдар M. Бархатов, ¹Антон С. Климов, ²Андрей С. Беркос" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(165) "¹Юрий А. Серов, ¹Ильдар M. Бархатов, ¹Антон С. Климов, ²Андрей С. Беркос" } ["SUBMITTED"]=> array(37) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8414" ["VALUE"]=> string(10) "14.09.2016" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "14.09.2016" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "14.09.2016" } ["ACCEPTED"]=> array(37) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8415" ["VALUE"]=> string(10) "25.11.2016" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "25.11.2016" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "25.11.2016" } ["KEYWORDS"]=> array(38) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые слова" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "KEYWORDS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "19" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(4) { [0]=> string(4) "8467" [1]=> string(4) "8468" [2]=> string(4) "8469" [3]=> string(4) "8470" } ["VALUE"]=> array(4) { [0]=> string(3) "692" [1]=> string(3) "693" [2]=> string(3) "607" [3]=> string(3) "282" } ["DESCRIPTION"]=> array(4) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(4) { [0]=> string(3) "692" [1]=> string(3) "693" [2]=> string(3) "607" [3]=> string(3) "282" } ["~DESCRIPTION"]=> array(4) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" } ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> array(4) { [0]=> string(118) "Секвенирование следуюшего поколения (NGS)" [1]=> string(89) "технологические решения" [2]=> string(70) "HLA-типирование" [3]=> string(156) "аллогенная трансплантация гемопоэтических стволовых клеток" } ["LINK_ELEMENT_VALUE"]=> bool(false) } ["CONTACT"]=> array(38) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8416" ["VALUE"]=> string(3) "691" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(3) "691" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(57) "Youri A. Serov" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8420" ["VALUE"]=> array(2) { ["TEXT"]=> string(3546) "Область генома, кодирующая лейкоциты антигенов человека (HLA) – это сегмент длиной 3,6 миллиона пар оснований на хромосоме 6(p21). Сложная по антигенному составу система HLA содержит важные молекулы, участвующие в трансплантационном иммунитете. Специфические генные последовательности генов HLA довольно сложно расшифровать с помощью классических методов прямого секвенирования в связи с их техническими ограничениями, сложным составом генов HLA, и возрастающим числом новых аллелей, что требует новых методов генотипирования. Секвенирование следуюшего поколения (NGS) является методом, который может обеспечить полное решение проблемы HLA-типирования. За последнее десятилетие разработка NGS обеспечила более легкий способ полногеномного анализа у человека, в том числе для типирования генов HLA. Несколько вариантов высокопроизводительных методов оценки HLA, основанные на мультиплексных аналитических технологиях NGS были разработаны на основе различных технологических платформ. В этом обзоре мы обсуждаем возможные области применения и прогресс в оборудовании для NGS в плане глубокого типирования системы HLA, с особым вниманием к будущим аспектам его клинического использования. Общеизвестный полиморфизм генов HLA и минимальные межаллельные различия представляют собой особую проблему. Поэтому некоторые вопросы, связанные с биоинформатикой и углубленной обработкой данных для более эффективного анализа HLA в контексте оценки совместимости донора и реципиента. В этом плане различными производителями предложены специализированные компьютерные программы для анализа больших баз данных, получаемых посредством технологий NGS. Наконец, эти высокопроизводительные подходы позволяют минимизировать финансовые затраты на 1 образец, особенно в крупных HLA-лабораториях, где соответствующие расходы на NGS-исследования стали теперь значительно затрат, возникающих при использовании классических технологий секвенирования по Сэнгеру." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3546) "Область генома, кодирующая лейкоциты антигенов человека (HLA) – это сегмент длиной 3,6 миллиона пар оснований на хромосоме 6(p21). Сложная по антигенному составу система HLA содержит важные молекулы, участвующие в трансплантационном иммунитете. Специфические генные последовательности генов HLA довольно сложно расшифровать с помощью классических методов прямого секвенирования в связи с их техническими ограничениями, сложным составом генов HLA, и возрастающим числом новых аллелей, что требует новых методов генотипирования. Секвенирование следуюшего поколения (NGS) является методом, который может обеспечить полное решение проблемы HLA-типирования. За последнее десятилетие разработка NGS обеспечила более легкий способ полногеномного анализа у человека, в том числе для типирования генов HLA. Несколько вариантов высокопроизводительных методов оценки HLA, основанные на мультиплексных аналитических технологиях NGS были разработаны на основе различных технологических платформ. В этом обзоре мы обсуждаем возможные области применения и прогресс в оборудовании для NGS в плане глубокого типирования системы HLA, с особым вниманием к будущим аспектам его клинического использования. Общеизвестный полиморфизм генов HLA и минимальные межаллельные различия представляют собой особую проблему. Поэтому некоторые вопросы, связанные с биоинформатикой и углубленной обработкой данных для более эффективного анализа HLA в контексте оценки совместимости донора и реципиента. В этом плане различными производителями предложены специализированные компьютерные программы для анализа больших баз данных, получаемых посредством технологий NGS. Наконец, эти высокопроизводительные подходы позволяют минимизировать финансовые затраты на 1 образец, особенно в крупных HLA-лабораториях, где соответствующие расходы на NGS-исследования стали теперь значительно затрат, возникающих при использовании классических технологий секвенирования по Сэнгеру." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(3546) "Область генома, кодирующая лейкоциты антигенов человека (HLA) – это сегмент длиной 3,6 миллиона пар оснований на хромосоме 6(p21). Сложная по антигенному составу система HLA содержит важные молекулы, участвующие в трансплантационном иммунитете. Специфические генные последовательности генов HLA довольно сложно расшифровать с помощью классических методов прямого секвенирования в связи с их техническими ограничениями, сложным составом генов HLA, и возрастающим числом новых аллелей, что требует новых методов генотипирования. Секвенирование следуюшего поколения (NGS) является методом, который может обеспечить полное решение проблемы HLA-типирования. За последнее десятилетие разработка NGS обеспечила более легкий способ полногеномного анализа у человека, в том числе для типирования генов HLA. Несколько вариантов высокопроизводительных методов оценки HLA, основанные на мультиплексных аналитических технологиях NGS были разработаны на основе различных технологических платформ. В этом обзоре мы обсуждаем возможные области применения и прогресс в оборудовании для NGS в плане глубокого типирования системы HLA, с особым вниманием к будущим аспектам его клинического использования. Общеизвестный полиморфизм генов HLA и минимальные межаллельные различия представляют собой особую проблему. Поэтому некоторые вопросы, связанные с биоинформатикой и углубленной обработкой данных для более эффективного анализа HLA в контексте оценки совместимости донора и реципиента. В этом плане различными производителями предложены специализированные компьютерные программы для анализа больших баз данных, получаемых посредством технологий NGS. Наконец, эти высокопроизводительные подходы позволяют минимизировать финансовые затраты на 1 образец, особенно в крупных HLA-лабораториях, где соответствующие расходы на NGS-исследования стали теперь значительно затрат, возникающих при использовании классических технологий секвенирования по Сэнгеру." } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8419" ["VALUE"]=> array(2) { ["TEXT"]=> string(545) "¹НИИ детской онкологии, гематологии и трансплантации им. Р. М. Горбачевой, Первый Санкт-Петербургский<br> государственный медицинский университет им. И. П. Павлова, Санкт-Петебург, Россия;<br> ²Российский НИИ гематологии и трансфузиологии, Санкт-Петербург, Россия<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(503) "¹НИИ детской онкологии, гематологии и трансплантации им. Р. М. Горбачевой, Первый Санкт-Петербургский
государственный медицинский университет им. И. П. Павлова, Санкт-Петебург, Россия;
²Российский НИИ гематологии и трансфузиологии, Санкт-Петербург, Россия
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(503) "¹НИИ детской онкологии, гематологии и трансплантации им. Р. М. Горбачевой, Первый Санкт-Петербургский
государственный медицинский университет им. И. П. Павлова, Санкт-Петебург, Россия;
²Российский НИИ гематологии и трансфузиологии, Санкт-Петербург, Россия
" } } } [2]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(2) "21" ["~IBLOCK_SECTION_ID"]=> string(2) "21" ["ID"]=> string(3) "700" ["~ID"]=> string(3) "700" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(212) "Влияние функциональных характеристик стромальных клеток костного мозга реципиента на приживление после алло-ТГСК" ["~NAME"]=> string(212) "Влияние функциональных характеристик стромальных клеток костного мозга реципиента на приживление после алло-ТГСК" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(19) "03.05.2017 09:38:32" ["~TIMESTAMP_X"]=> string(19) "03.05.2017 09:38:32" ["DETAIL_PAGE_URL"]=> string(161) "/ru/archive/vypusk-5-nomer-4/eksperimentalnye-issledovaniya/vliyanie-funktsionalnykh-kharakteristik-stromalnykh-kletok-kostnogo-mozga-retsipienta-na-prizhivleni/" ["~DETAIL_PAGE_URL"]=> string(161) "/ru/archive/vypusk-5-nomer-4/eksperimentalnye-issledovaniya/vliyanie-funktsionalnykh-kharakteristik-stromalnykh-kletok-kostnogo-mozga-retsipienta-na-prizhivleni/" ["LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["~LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["DETAIL_TEXT"]=> string(23125) "

Introduction

Morphological and functional patterns of malignant cells are largely determined by specific somatic gene aberrations, which represent the major factor in biology of oncohematological disorders. Meanwhile, some data suggest expression of tumor markers in non-hematopoietic bone marrow cells from the stromal microenvironment [2, 6]. Hence, potential mechanisms of leukemogenesis, like as specific gene mutations, may include certain effects of cellular environment which may promote proliferation and development of hematopoietic stem cells [7, 16]. The so-called bone marrow niches are represented by endothelium, stromal cells, macrophages etc. The role of bone marrow stromal cells (BMSC) in hematopoietic regulation was first described by A.Ya Friedenstein fifty years ago. There are several types of stromal cells, in particular, mesenchymal stem cells (MSC) which are best studied for their potential clinical applications. MSCs are shown to suppress immune conflicts in allogeneic transplantation [10]; to replace and restore functions of the damaged non-hematopoietic tissues [14], support hematopoiesis when co-transplanted with hematopoietic stem cells (HSCs) [11]. These effects are based on favorable actions upon proliferation and differentiation of different hematopoietic lineages, e.g., myeloid and lymphoid progenitors. Hence, studies of stromal cells seem to be quite rational in view of their possible involvement into pathogenesis of oncohematological disorders.

It is known that, despite successful engraftment of donor-derived hematopoietic stem cells after allogeneic stem cell transplantation (alloSCT), the mesenchymal stem cells, are, in general, of host origin, even years post-transplant [15]. Some patients after alloSCT do not recover their stem cells despite receiving large amounts of CD34+ blood progenitors. Possible basis for the graft failure may be due to affection of hematopoietic niche by conditioning chemotherapy which could disturb its supportive (nursing) capacity. A number of researchers have identified the cells of osteoblast lineage to be a key cellular component of the HSC niche. These cells are responsible for bone formation [4, 19]. In addition, some transplant-associated factors might affect the osteoblasts, along with direct driving of hematopoiesis. Thus, it may be assumed that a difference in morphology and functional activity of the bone marrow stromal populations before the transplant could sufficiently influence engraftment kinetics of the donor hematopoietic cells.

The aim of this study was to investigate changes in functional characteristics of bone marrow stromal cells (BMSC) in the patients with pre-treated hematological diseases and evaluate their significance in the post-transplant reconstitution of hematopoiesis.

Materials and Methods

We have studied bone marrow samples from thirty-eight patients with acute leukemia (0 to 47 years old). Twenty healthy donors (13 to 52 years old) served as control group. Bone marrow was obtained by sternal punctures. Separation of mononuclear cells was performed by Ficoll density gradient (1,077 g/l) followed by explantation to culture flasks containing alpha-MEM (Biolot, Russia) supplemented with 20% of fetal calf serum and antibiotics (Penicillin, 100 U/ml, and Streptomycin, 100 U/ml, Gibco). Cell cultures were maintained in sterile closed dishes at 37 °С, 100% humidity and 5% СО2. All the culture variants were studied in duplicate. To evaluate proliferative characteristics of BMSC, we have counted fibroblastic colony-forming units (CFU-F). After 10 days of culture, the cell colonies were fixed with 96% ethanol for 30 min, stained by Romanovsky-Giemsa (1:10 dilution) for another 30 min. The fibroblastic colonies were classified into large (>20 cells) and small ones (<20 cells).

To induce osteogenic and adipogenic differentiation of BMSCs, a standard conditioning medium was discarded at days 7 to 10 of primary cultures, and adherent cells were supplemented with fresh culture medium, or with the same medium supplied with differentiation-inducing agents. Osteogenic differentiation was achieved by addition of-glycerophosphate (7×10-3 М); dexamethasone (1×10-8 М); ascorbic acid (2×10-4 М) (Sigma, St Louis, MO, USA). Adipogenic differentiation of the BMSC was induced by dexamethasone (1×10-7 М); insulin (1×10-9 М). To detect osteocytic differentiation, the adherent cell layer was stained according to von Kossa method, or with Alizarin Red stain (Sigma, St Louis, MO, USA). Osteocytes were identified by typical calcium inclusions (black or red colour, respectively). To visualize adipocytic differentiation in cultured cell populations, the adherent fraction was fixed with formol vapor for 10 min., and incubated in the working Sudan Red O solution (Sigma- Aldrich, St Louis, MO, USA) for 1 hour at room temperature. Adipocytes were identified by orange lipid inclusions. In vitro hematopoietic support produced by BMSCs was evaluated in agar drop liquid culture system [1]. A monolayer of adherent marrow cells was used as a source of colony- stimulating factors. Bone marrow mononuclears from healthy donors were used as target cells. The cell colonies (CFU-GM) were counted at day 7 of culture. Colony-forming activity (CFA) and cluster-forming ability (ClFA) was assessed by colony numbers per culture and their sizes, i.e., small colonies, 20 to 40 cells; medium colonies, 41-100 cells; large colonies, >100 cells. Big cell clusters contained 10 to 19 cells; small clusters, 5-9 cells.

In parallel to the mentioned test system, hemostimulating activity of BMSC co-cultured with bone marrow mononuclears was tested in a liquid phase. The average term of coculture was 10-12 days. In order to analyze differentiation potential of hematopoietic progenitors, the colony-forming assays were performed in 100 μL Iscove’s modified Dulbecco’s medium (IMDM) plus 2% fetal bovine serum (Biolot, Russia), then added to 1 mL methylcellulose medium containing a cocktail of recombinant human stem cell factor, granulocyte-macrophage colony-stimulating factor, interleukin- 3, (MethoCult H4534, Stem Cell Technologies) before and after the co-culture initiation. The cells plated in 35-mm Petri dishes were cultured in a fully humidified environment with 5% CO2 at 37°C for 14 days.

Moreover, we measured expression of several genes responsible for cell adherence (SELECTIN, CXCR4, VCAM and PECAM). To this purpose, we performed reverse transcription of mRNAs from cell lysates. Real-time PCR with gene-specific primers was carried out in a standard reaction mix (Syntol, Russia). The post-PCR amplicon amounts were evaluated by means of a DNA-binding SYBR Green dye. The relative gene expression was normalized for a reference ABL gene.

Statistical evaluation was performed with STATISTICA software, version 6.0. In cases of statistically significant differences, we performed pairwise comparisons of the series using non-parametric Mann-Whitney criterion for two independent samples. The correlation quotients (r) were calculated using Spearman criterion. Statistical significance between experimental series was proven at confidence levels of p<0.05.

Results and Discussion

Comparison of BMSCs functional characteristics in patients and healthy donors A comparative assessment of fibroblast colony-forming units (CFU-F) CM in healthy donors and patients with acute leukemia shows a significant increase in big fibroblastic colonies of AML and ALL patients (p <0.05). (Fig. 1) These changes in proliferative ability of recipient stromal cells may occur due to the influence of malignant cell clones [18], or by previous rounds of chemotherapy [17]. One should discern between these potential causal factors.

Meanwhile, the number of CFU-F capable for adipogenic and osteogenic differentiation in acute leukemia was also significantly higher (p <0.05) (Fig. 2). A typical fibroblastic CFU is shown in Fig. 3. These results are in accordance with data presented by Borojevic et al., who showed similar changes of osteogenic marker expression and alkaline phosphatase activity in stromal cells from MDS patients [3]. Moreover, we find higher numbers of adipogenic progenitors in stroma from leukemia patients (AML and ALL), thus, probably, exerting a negative impact upon normal hematopoiesis. These data were recently described also by Le et al. [9].

When testing hemostimulating activity of stromal cells in soft agar, we observed a significant increase in hematopoiesis-supportive ability by stromal cells in acute myeloid leukemia (AML) (p <0.05), compared with healthy donors, whereas BMSC in patients with acute lymphoblastic leukemia, did not show similar properties (Fig. 4). This finding may suggest a possible role of stromal microenvironment in supporting malignant cell clones, as described elsewhere [13].

We have also revealed significant differences concerning expression of genes controlling adherence of hematopoietic cells to their substrates in bone marrow. We have found that stromal cells from AL patients exhibited higher expression of SELECTIN and VECAM genes in comparison to BMSC from healthy donors (p=0.008 and p=0.04, respectively, data not shown) in 17 patients with acute leukemia and healthy donors. Noteworthy, similar assays of PECAM and CXCR4 expression levels did not reveal such differences between stromal cells from AL patients and normal donors. However,

we have found a trend for decrease in CXCR4 gene expression among older leukemia patients (p=0.05). It should be noted that changed expression of adherence factors may be important over post-transplant period since they determine both engraftment kinetics of donor cells and graft functioning at later terms [5].

Role of BMSC supportive characteristics in hematopoietic engraftment kinetics

When analyzing a potentially predictive role of BMSC functional characteristics for the graft reconstitution, we have revealed a higher in vitro colony-forming ability of recipient BMSCs associated with longer terms of donor cell engraftment. A direct correlation was found between the large and small CFU-F colony numbers and leukocyte recovery terms (>1.0 peripheral leukocytes/μL), i.e., R = 0.34, p = 0.00006 and R = 0.23, p = 0.006, respectively. A similar trend was observed, when assessing connections with blood neutrophil recovery (R= 0.28, p = 0.001 and R = 0.21, p = 0.012, respectively, for large and small CFU-F colonies, data not shown).

Hence, when detecting in vitro hemostimulating activity of recipient stromal cells in comparison to in vivo hematopoietic recovery, we found a direct correlation be tween the number of CFU-GM colonies in soft agar cultures, and the recovery terms for leukocytes and platelets (> 20/L), R = 0.58 and R = 0.48, respectively. Meanwhile, analysis of colony formation in methylcellulose culture has shown an inverse correlation, i.e., shorter engraftment terms for blood leukocytes and platelets, with increasing support of colony-forming ability by stromal BMSCs derived from the recipient. Hence, it may indicate effects of short-distance factors promoting hematopoietic reconstitution after transplantation which may effectively support hematopoiesis in liquid culture but not in soft

agar. At the same time, while the higher hematopoietic progenitor colony formation in methylcellulose correlated with increased probability of post-transplant relapse (p <0.05). In the culture system “drop-agar liquid medium” such patterns have not been identified (Fig. 5), indicating that the contribution relapse in expectation of the same factors.

Moreover, we studied some relationships between quantitative parameters of osteogenic and adipogenic CFU-F, and the rates of hematopoietic engraftment. We have shown that the recovery time for leukocytes and platelets is reduced in the patients with higher in vitro osteogenic

potential of their CFU-F (p = 0,034), as well as a significantly reduced probability of graft hypofunction in cases of a higher number of adipogenic CFU-Fs in recipient stromal populations (p <0.05) (Fig. 6). A number of studies have shown that adipocytes act primarily as a negative regulator of hematopoiesis and are able to lengthen the periods of post-transplant reconstitution of hematopoiesis [12]. In turn, osteoblasts are seen as one of the key components of the hematopoietic microenvironment, regulating adhesion, homing and engraftment of HSCs during post-transplant period. There is the evidence of a leukemic clone inhibition by osteoblasts, thus creating favorable conditions for normal hematopoiesis [8].

When assessing a probability of acute graft-versus-host disease (aGvHD), we have shown that a higher risk of this common HSCT complication was associated with increased proliferative capacity characteristics of the recipient stromal cells, as expressed by CFU-F growth, and higher relative contents of large CFU-F colonies (>100 cells). Interestingly, despite our data, which point to hemostimulating ability of osteoblast progenitors and their role in faster post-transplant recovery, we have not received data which suggest higher risk of relapse in cases of increased osteogenic CFU-F numbers (p >0.05) There is also an association between increased numbers of osteogenic CFU-F and risk of aGvHD development (p >0.05) (Fig. 7).

Another evidence concerns mRNA expression of adhesion molecules (Selectin, Pecam, VCAM and CXCR4) in BMSCs. We have revealed shorter engraftment terms for leukocytes and platelets in the patients with increased mRNA expression of adhesion molecules in patient BMSC (p <0.05) (data not shown). However, the increase of these markers expression was associated with a higher probability of relapse and reduced post-transplant chimerism stability (p <0.05) (Fig. 8).

Conclusions

• Our findigs indicate the presence of higher proliferative activity and hemostimulating ability of BMSC in acute leukemia patients compared with healthy donors
• These biological effects of stroma may be ascribed to preceding chemotherapy and myelosuppression which affected stromal cells, or its interaction with the tumor clone.
• Functional characteristics of patients’ stromal cells may influence on posttransplant hematopoiesis recovery. Thus increase of the osteogenic differentiation is associated with a faster recovery of hematopoiesis, whereas adipogenic differentiation is associated with less probability of graft hypofunction. Some short-range haemostimulating factors may be responsible for such effect.
• Increased pre-transplant expression of some genes controlling HSC-homing molecules in recipient stroma is associated with sooner hematopoietic recovery, however, with higher occurence of post-transplant relapses.

Acknowledgement

The study was supported by The Russian Foundation for Basic Studies, Grant № 15-04-08679

References

1. Afanasyev BV, Kulibaba TG, Zabelina TS, Lukasheva TN, Smirnova GA. Agar cloning of hematopoietic cells from the patients with different forms of hematopoietic dysplasia (clinics vs culture). Ter Arkhiv. 1982; 8:97-103.
2. Blau O, Hofmann WK, Baldus CD, Thiel G, Serbent V, Schümann E, Thiel E, Blau IW.. Chromosomal aberrations in bone marrow mesenchymal stroma cells from patients with myelodysplastic syndrome and acute myeloblastic leukemia. Exp Hematol. 2007; 35 (2):221-229.
3. Borojevic R, Roela RA, Rodarte RS, Thiago LS, Pasini FS, Conti FM, Rossi MI, Reis LF, Lopes LF, Brentani MM. Bone marrow stroma in childhood myelodysplastic syndrome: Composition, ability to sustain hematopoiesis in vitro, and altered gene expression. Leuk Res. 2004; 28 (8):831-844.
4. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003; 425 (6960):841-846.
5. Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells. 2007; 25 (11):2739-2749.
6. Flores-Figueroa E, Arana-Trejo RM, Gutiérrez-Espíndola G, Pérez-Cabrera A, Mayani H. Mesenchymal stem cells in myelodysplastic syndromes: Phenotypic and cytogenetic characterization. Leuk Res. 2005; 29 (2):215-224.
7. Konopleva M, Tabe Y, Zeng Z, Andreeff M. Therapeutic targeting of microenvironmental interactions in leukemia: Mechanisms and approaches. Drug Resist Updat. 2009; 12 (4-5):103-113.
8. Krevvata M, Silva BC, Manavalan JS, Galan-Diez M, Kode A, Matthews BG, Park D, Zhang CA, Galili N, Nickolas TL, Dempster DW, Dougall WJ T-F. Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts. Blood. 2014; 124 (18):2834-2846.
9. Le Y, Fraineau S, Chandran P, Sabloff M, Brand M, Lavoie JR, Gagne R, Rosu-Myles M, Yauk CL, Richardson RB, Allan DS. Adipogenic mesenchymal stromal cells from bone marrow and their hematopoietic supportive role: towards understanding the permissive marrow microenvironment in acute myeloid leukemia. Stem Cell Rev Reports. 2016; 12 (2):235-244.
10. Le Blanc K. Mesenchymal stromal cells: Tissue repair and immune modulation. Cytotherapy. 2006; 8 (6):559-561.
11. Le Blanc K, Samuelsson H, Gustafsson B, Remberger M, Sundberg B, Arvidson J, Ljungman P, Lönnies H, Nava S, Ringdén O. Transplantation of mesenchymal stem cells to enhance engraftment of hematopoietic stem cells. Leukemia. 2007; 21 (8):1733-1738.
12. Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature. 2009; 460 (7252):259-263.
13. Podar K, Richardson PG, Hideshima T, Chauhan D, Anderson KC. The malignant clone and the bone-marrow environment. Best Pract Res Clin Haematol. 2007; 20 (4):597-612.
14. Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997;4;276(5309):71-74.
15. Rieger K, Marinets O, Fietz T, Körper S, Sommer D, Mücke C, Reufi B, Blau WI, Thiel E, Knauf WU. Mesenchymal stem cells remain of host origin even a long time after allogeneic peripheral blood stem cell or bone marrow transplantation. Exp Hematol. 2005; 33 (5):605-611.
16. Scadden DT. The stem cell niche in health and leukemic disease. Best Pr Res Clin Haematol. 2007; 20 (1):19-27.
17. Shipounova IN, Petinati NA, Bigildeev AE, Drize NJ, Sorokina TV, Kuzmina LA, Parovichnikova EN, Savchenko VG. Alterations of the bone marrow stromal microenvironment in adult patients with acute myeloid and lymphoblastic leukemias before and after allogeneic hematopoietic stem cell transplantation. Leuk Lymphoma. 2017; 58 (2):408-417.
18. Yang G-C, Xu Y-H, Chen H-X, Wang X-J. Acute Lymphoblastic Leukemia Cells Inhibit the Differentiation of Bone Mesenchymal Stem Cells into Osteoblasts In Vitro by Activating Notch Signaling. Stem Cells Int. 2015; 2015:1-11.
19. Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, Ross J, Haug J, Johnson T, Feng JQ, Harris S, Wiedemann LM, Mishina Y, Li L. Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003; 425:836-841.
    
    

" ["~DETAIL_TEXT"]=> string(23125) "

Introduction

Morphological and functional patterns of malignant cells are largely determined by specific somatic gene aberrations, which represent the major factor in biology of oncohematological disorders. Meanwhile, some data suggest expression of tumor markers in non-hematopoietic bone marrow cells from the stromal microenvironment [2, 6]. Hence, potential mechanisms of leukemogenesis, like as specific gene mutations, may include certain effects of cellular environment which may promote proliferation and development of hematopoietic stem cells [7, 16]. The so-called bone marrow niches are represented by endothelium, stromal cells, macrophages etc. The role of bone marrow stromal cells (BMSC) in hematopoietic regulation was first described by A.Ya Friedenstein fifty years ago. There are several types of stromal cells, in particular, mesenchymal stem cells (MSC) which are best studied for their potential clinical applications. MSCs are shown to suppress immune conflicts in allogeneic transplantation [10]; to replace and restore functions of the damaged non-hematopoietic tissues [14], support hematopoiesis when co-transplanted with hematopoietic stem cells (HSCs) [11]. These effects are based on favorable actions upon proliferation and differentiation of different hematopoietic lineages, e.g., myeloid and lymphoid progenitors. Hence, studies of stromal cells seem to be quite rational in view of their possible involvement into pathogenesis of oncohematological disorders.

It is known that, despite successful engraftment of donor-derived hematopoietic stem cells after allogeneic stem cell transplantation (alloSCT), the mesenchymal stem cells, are, in general, of host origin, even years post-transplant [15]. Some patients after alloSCT do not recover their stem cells despite receiving large amounts of CD34+ blood progenitors. Possible basis for the graft failure may be due to affection of hematopoietic niche by conditioning chemotherapy which could disturb its supportive (nursing) capacity. A number of researchers have identified the cells of osteoblast lineage to be a key cellular component of the HSC niche. These cells are responsible for bone formation [4, 19]. In addition, some transplant-associated factors might affect the osteoblasts, along with direct driving of hematopoiesis. Thus, it may be assumed that a difference in morphology and functional activity of the bone marrow stromal populations before the transplant could sufficiently influence engraftment kinetics of the donor hematopoietic cells.

The aim of this study was to investigate changes in functional characteristics of bone marrow stromal cells (BMSC) in the patients with pre-treated hematological diseases and evaluate their significance in the post-transplant reconstitution of hematopoiesis.

Materials and Methods

We have studied bone marrow samples from thirty-eight patients with acute leukemia (0 to 47 years old). Twenty healthy donors (13 to 52 years old) served as control group. Bone marrow was obtained by sternal punctures. Separation of mononuclear cells was performed by Ficoll density gradient (1,077 g/l) followed by explantation to culture flasks containing alpha-MEM (Biolot, Russia) supplemented with 20% of fetal calf serum and antibiotics (Penicillin, 100 U/ml, and Streptomycin, 100 U/ml, Gibco). Cell cultures were maintained in sterile closed dishes at 37 °С, 100% humidity and 5% СО2. All the culture variants were studied in duplicate. To evaluate proliferative characteristics of BMSC, we have counted fibroblastic colony-forming units (CFU-F). After 10 days of culture, the cell colonies were fixed with 96% ethanol for 30 min, stained by Romanovsky-Giemsa (1:10 dilution) for another 30 min. The fibroblastic colonies were classified into large (>20 cells) and small ones (<20 cells).

To induce osteogenic and adipogenic differentiation of BMSCs, a standard conditioning medium was discarded at days 7 to 10 of primary cultures, and adherent cells were supplemented with fresh culture medium, or with the same medium supplied with differentiation-inducing agents. Osteogenic differentiation was achieved by addition of-glycerophosphate (7×10-3 М); dexamethasone (1×10-8 М); ascorbic acid (2×10-4 М) (Sigma, St Louis, MO, USA). Adipogenic differentiation of the BMSC was induced by dexamethasone (1×10-7 М); insulin (1×10-9 М). To detect osteocytic differentiation, the adherent cell layer was stained according to von Kossa method, or with Alizarin Red stain (Sigma, St Louis, MO, USA). Osteocytes were identified by typical calcium inclusions (black or red colour, respectively). To visualize adipocytic differentiation in cultured cell populations, the adherent fraction was fixed with formol vapor for 10 min., and incubated in the working Sudan Red O solution (Sigma- Aldrich, St Louis, MO, USA) for 1 hour at room temperature. Adipocytes were identified by orange lipid inclusions. In vitro hematopoietic support produced by BMSCs was evaluated in agar drop liquid culture system [1]. A monolayer of adherent marrow cells was used as a source of colony- stimulating factors. Bone marrow mononuclears from healthy donors were used as target cells. The cell colonies (CFU-GM) were counted at day 7 of culture. Colony-forming activity (CFA) and cluster-forming ability (ClFA) was assessed by colony numbers per culture and their sizes, i.e., small colonies, 20 to 40 cells; medium colonies, 41-100 cells; large colonies, >100 cells. Big cell clusters contained 10 to 19 cells; small clusters, 5-9 cells.

In parallel to the mentioned test system, hemostimulating activity of BMSC co-cultured with bone marrow mononuclears was tested in a liquid phase. The average term of coculture was 10-12 days. In order to analyze differentiation potential of hematopoietic progenitors, the colony-forming assays were performed in 100 μL Iscove’s modified Dulbecco’s medium (IMDM) plus 2% fetal bovine serum (Biolot, Russia), then added to 1 mL methylcellulose medium containing a cocktail of recombinant human stem cell factor, granulocyte-macrophage colony-stimulating factor, interleukin- 3, (MethoCult H4534, Stem Cell Technologies) before and after the co-culture initiation. The cells plated in 35-mm Petri dishes were cultured in a fully humidified environment with 5% CO2 at 37°C for 14 days.

Moreover, we measured expression of several genes responsible for cell adherence (SELECTIN, CXCR4, VCAM and PECAM). To this purpose, we performed reverse transcription of mRNAs from cell lysates. Real-time PCR with gene-specific primers was carried out in a standard reaction mix (Syntol, Russia). The post-PCR amplicon amounts were evaluated by means of a DNA-binding SYBR Green dye. The relative gene expression was normalized for a reference ABL gene.

Statistical evaluation was performed with STATISTICA software, version 6.0. In cases of statistically significant differences, we performed pairwise comparisons of the series using non-parametric Mann-Whitney criterion for two independent samples. The correlation quotients (r) were calculated using Spearman criterion. Statistical significance between experimental series was proven at confidence levels of p<0.05.

Results and Discussion

Comparison of BMSCs functional characteristics in patients and healthy donors A comparative assessment of fibroblast colony-forming units (CFU-F) CM in healthy donors and patients with acute leukemia shows a significant increase in big fibroblastic colonies of AML and ALL patients (p <0.05). (Fig. 1) These changes in proliferative ability of recipient stromal cells may occur due to the influence of malignant cell clones [18], or by previous rounds of chemotherapy [17]. One should discern between these potential causal factors.

Meanwhile, the number of CFU-F capable for adipogenic and osteogenic differentiation in acute leukemia was also significantly higher (p <0.05) (Fig. 2). A typical fibroblastic CFU is shown in Fig. 3. These results are in accordance with data presented by Borojevic et al., who showed similar changes of osteogenic marker expression and alkaline phosphatase activity in stromal cells from MDS patients [3]. Moreover, we find higher numbers of adipogenic progenitors in stroma from leukemia patients (AML and ALL), thus, probably, exerting a negative impact upon normal hematopoiesis. These data were recently described also by Le et al. [9].

When testing hemostimulating activity of stromal cells in soft agar, we observed a significant increase in hematopoiesis-supportive ability by stromal cells in acute myeloid leukemia (AML) (p <0.05), compared with healthy donors, whereas BMSC in patients with acute lymphoblastic leukemia, did not show similar properties (Fig. 4). This finding may suggest a possible role of stromal microenvironment in supporting malignant cell clones, as described elsewhere [13].

We have also revealed significant differences concerning expression of genes controlling adherence of hematopoietic cells to their substrates in bone marrow. We have found that stromal cells from AL patients exhibited higher expression of SELECTIN and VECAM genes in comparison to BMSC from healthy donors (p=0.008 and p=0.04, respectively, data not shown) in 17 patients with acute leukemia and healthy donors. Noteworthy, similar assays of PECAM and CXCR4 expression levels did not reveal such differences between stromal cells from AL patients and normal donors. However,

we have found a trend for decrease in CXCR4 gene expression among older leukemia patients (p=0.05). It should be noted that changed expression of adherence factors may be important over post-transplant period since they determine both engraftment kinetics of donor cells and graft functioning at later terms [5].

Role of BMSC supportive characteristics in hematopoietic engraftment kinetics

When analyzing a potentially predictive role of BMSC functional characteristics for the graft reconstitution, we have revealed a higher in vitro colony-forming ability of recipient BMSCs associated with longer terms of donor cell engraftment. A direct correlation was found between the large and small CFU-F colony numbers and leukocyte recovery terms (>1.0 peripheral leukocytes/μL), i.e., R = 0.34, p = 0.00006 and R = 0.23, p = 0.006, respectively. A similar trend was observed, when assessing connections with blood neutrophil recovery (R= 0.28, p = 0.001 and R = 0.21, p = 0.012, respectively, for large and small CFU-F colonies, data not shown).

Hence, when detecting in vitro hemostimulating activity of recipient stromal cells in comparison to in vivo hematopoietic recovery, we found a direct correlation be tween the number of CFU-GM colonies in soft agar cultures, and the recovery terms for leukocytes and platelets (> 20/L), R = 0.58 and R = 0.48, respectively. Meanwhile, analysis of colony formation in methylcellulose culture has shown an inverse correlation, i.e., shorter engraftment terms for blood leukocytes and platelets, with increasing support of colony-forming ability by stromal BMSCs derived from the recipient. Hence, it may indicate effects of short-distance factors promoting hematopoietic reconstitution after transplantation which may effectively support hematopoiesis in liquid culture but not in soft

agar. At the same time, while the higher hematopoietic progenitor colony formation in methylcellulose correlated with increased probability of post-transplant relapse (p <0.05). In the culture system “drop-agar liquid medium” such patterns have not been identified (Fig. 5), indicating that the contribution relapse in expectation of the same factors.

Moreover, we studied some relationships between quantitative parameters of osteogenic and adipogenic CFU-F, and the rates of hematopoietic engraftment. We have shown that the recovery time for leukocytes and platelets is reduced in the patients with higher in vitro osteogenic

potential of their CFU-F (p = 0,034), as well as a significantly reduced probability of graft hypofunction in cases of a higher number of adipogenic CFU-Fs in recipient stromal populations (p <0.05) (Fig. 6). A number of studies have shown that adipocytes act primarily as a negative regulator of hematopoiesis and are able to lengthen the periods of post-transplant reconstitution of hematopoiesis [12]. In turn, osteoblasts are seen as one of the key components of the hematopoietic microenvironment, regulating adhesion, homing and engraftment of HSCs during post-transplant period. There is the evidence of a leukemic clone inhibition by osteoblasts, thus creating favorable conditions for normal hematopoiesis [8].

When assessing a probability of acute graft-versus-host disease (aGvHD), we have shown that a higher risk of this common HSCT complication was associated with increased proliferative capacity characteristics of the recipient stromal cells, as expressed by CFU-F growth, and higher relative contents of large CFU-F colonies (>100 cells). Interestingly, despite our data, which point to hemostimulating ability of osteoblast progenitors and their role in faster post-transplant recovery, we have not received data which suggest higher risk of relapse in cases of increased osteogenic CFU-F numbers (p >0.05) There is also an association between increased numbers of osteogenic CFU-F and risk of aGvHD development (p >0.05) (Fig. 7).

Another evidence concerns mRNA expression of adhesion molecules (Selectin, Pecam, VCAM and CXCR4) in BMSCs. We have revealed shorter engraftment terms for leukocytes and platelets in the patients with increased mRNA expression of adhesion molecules in patient BMSC (p <0.05) (data not shown). However, the increase of these markers expression was associated with a higher probability of relapse and reduced post-transplant chimerism stability (p <0.05) (Fig. 8).

Conclusions

• Our findigs indicate the presence of higher proliferative activity and hemostimulating ability of BMSC in acute leukemia patients compared with healthy donors
• These biological effects of stroma may be ascribed to preceding chemotherapy and myelosuppression which affected stromal cells, or its interaction with the tumor clone.
• Functional characteristics of patients’ stromal cells may influence on posttransplant hematopoiesis recovery. Thus increase of the osteogenic differentiation is associated with a faster recovery of hematopoiesis, whereas adipogenic differentiation is associated with less probability of graft hypofunction. Some short-range haemostimulating factors may be responsible for such effect.
• Increased pre-transplant expression of some genes controlling HSC-homing molecules in recipient stroma is associated with sooner hematopoietic recovery, however, with higher occurence of post-transplant relapses.

Acknowledgement

The study was supported by The Russian Foundation for Basic Studies, Grant № 15-04-08679

References

1. Afanasyev BV, Kulibaba TG, Zabelina TS, Lukasheva TN, Smirnova GA. Agar cloning of hematopoietic cells from the patients with different forms of hematopoietic dysplasia (clinics vs culture). Ter Arkhiv. 1982; 8:97-103.
2. Blau O, Hofmann WK, Baldus CD, Thiel G, Serbent V, Schümann E, Thiel E, Blau IW.. Chromosomal aberrations in bone marrow mesenchymal stroma cells from patients with myelodysplastic syndrome and acute myeloblastic leukemia. Exp Hematol. 2007; 35 (2):221-229.
3. Borojevic R, Roela RA, Rodarte RS, Thiago LS, Pasini FS, Conti FM, Rossi MI, Reis LF, Lopes LF, Brentani MM. Bone marrow stroma in childhood myelodysplastic syndrome: Composition, ability to sustain hematopoiesis in vitro, and altered gene expression. Leuk Res. 2004; 28 (8):831-844.
4. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003; 425 (6960):841-846.
5. Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells. 2007; 25 (11):2739-2749.
6. Flores-Figueroa E, Arana-Trejo RM, Gutiérrez-Espíndola G, Pérez-Cabrera A, Mayani H. Mesenchymal stem cells in myelodysplastic syndromes: Phenotypic and cytogenetic characterization. Leuk Res. 2005; 29 (2):215-224.
7. Konopleva M, Tabe Y, Zeng Z, Andreeff M. Therapeutic targeting of microenvironmental interactions in leukemia: Mechanisms and approaches. Drug Resist Updat. 2009; 12 (4-5):103-113.
8. Krevvata M, Silva BC, Manavalan JS, Galan-Diez M, Kode A, Matthews BG, Park D, Zhang CA, Galili N, Nickolas TL, Dempster DW, Dougall WJ T-F. Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts. Blood. 2014; 124 (18):2834-2846.
9. Le Y, Fraineau S, Chandran P, Sabloff M, Brand M, Lavoie JR, Gagne R, Rosu-Myles M, Yauk CL, Richardson RB, Allan DS. Adipogenic mesenchymal stromal cells from bone marrow and their hematopoietic supportive role: towards understanding the permissive marrow microenvironment in acute myeloid leukemia. Stem Cell Rev Reports. 2016; 12 (2):235-244.
10. Le Blanc K. Mesenchymal stromal cells: Tissue repair and immune modulation. Cytotherapy. 2006; 8 (6):559-561.
11. Le Blanc K, Samuelsson H, Gustafsson B, Remberger M, Sundberg B, Arvidson J, Ljungman P, Lönnies H, Nava S, Ringdén O. Transplantation of mesenchymal stem cells to enhance engraftment of hematopoietic stem cells. Leukemia. 2007; 21 (8):1733-1738.
12. Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature. 2009; 460 (7252):259-263.
13. Podar K, Richardson PG, Hideshima T, Chauhan D, Anderson KC. The malignant clone and the bone-marrow environment. Best Pract Res Clin Haematol. 2007; 20 (4):597-612.
14. Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997;4;276(5309):71-74.
15. Rieger K, Marinets O, Fietz T, Körper S, Sommer D, Mücke C, Reufi B, Blau WI, Thiel E, Knauf WU. Mesenchymal stem cells remain of host origin even a long time after allogeneic peripheral blood stem cell or bone marrow transplantation. Exp Hematol. 2005; 33 (5):605-611.
16. Scadden DT. The stem cell niche in health and leukemic disease. Best Pr Res Clin Haematol. 2007; 20 (1):19-27.
17. Shipounova IN, Petinati NA, Bigildeev AE, Drize NJ, Sorokina TV, Kuzmina LA, Parovichnikova EN, Savchenko VG. Alterations of the bone marrow stromal microenvironment in adult patients with acute myeloid and lymphoblastic leukemias before and after allogeneic hematopoietic stem cell transplantation. Leuk Lymphoma. 2017; 58 (2):408-417.
18. Yang G-C, Xu Y-H, Chen H-X, Wang X-J. Acute Lymphoblastic Leukemia Cells Inhibit the Differentiation of Bone Mesenchymal Stem Cells into Osteoblasts In Vitro by Activating Notch Signaling. Stem Cells Int. 2015; 2015:1-11.
19. Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, Ross J, Haug J, Johnson T, Feng JQ, Harris S, Wiedemann LM, Mishina Y, Li L. Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003; 425:836-841.
    
    

" ["DETAIL_TEXT_TYPE"]=> string(4) "html" ["~DETAIL_TEXT_TYPE"]=> string(4) "html" ["PREVIEW_TEXT"]=> string(0) "" ["~PREVIEW_TEXT"]=> string(0) "" ["PREVIEW_TEXT_TYPE"]=> string(4) "text" ["~PREVIEW_TEXT_TYPE"]=> string(4) "text" ["PREVIEW_PICTURE"]=> NULL ["~PREVIEW_PICTURE"]=> NULL ["LANG_DIR"]=> string(4) "/ru/" ["~LANG_DIR"]=> string(4) "/ru/" ["SORT"]=> string(3) "500" ["~SORT"]=> string(3) "500" ["CODE"]=> string(100) "vliyanie-funktsionalnykh-kharakteristik-stromalnykh-kletok-kostnogo-mozga-retsipienta-na-prizhivleni" ["~CODE"]=> string(100) "vliyanie-funktsionalnykh-kharakteristik-stromalnykh-kletok-kostnogo-mozga-retsipienta-na-prizhivleni" ["EXTERNAL_ID"]=> string(3) "700" ["~EXTERNAL_ID"]=> string(3) "700" ["IBLOCK_TYPE_ID"]=> string(7) "journal" ["~IBLOCK_TYPE_ID"]=> string(7) "journal" ["IBLOCK_CODE"]=> string(7) "volumes" ["~IBLOCK_CODE"]=> string(7) "volumes" ["IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["~IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["LID"]=> string(2) "s2" ["~LID"]=> string(2) "s2" ["EDIT_LINK"]=> NULL ["DELETE_LINK"]=> NULL ["DISPLAY_ACTIVE_FROM"]=> string(0) "" ["IPROPERTY_VALUES"]=> array(18) { ["ELEMENT_META_TITLE"]=> string(212) "Влияние функциональных характеристик стромальных клеток костного мозга реципиента на приживление после алло-ТГСК" ["ELEMENT_META_KEYWORDS"]=> string(189) "Стромальные клетки костного мозга острые лейкозы функциональные характеристики типы дифференцировки" ["ELEMENT_META_DESCRIPTION"]=> string(310) "Влияние функциональных характеристик стромальных клеток костного мозга реципиента на приживление после алло-ТГСКImpact of recipient marrow stromal cells functional characteristics on engraftment after allo-HSCT" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(2500) "Наблюдаемая в ряде случаев гипофункция транс- плантата является нередкой и обусловливает не- обходимость разработки функциональных тестов исследования клеток стромы с целью обоснования показаний к совместной трансплантации гемопоэ- тических и стромальных клеток костного мозга. Це- лью данного исследования являлось изучение роли стромальных клеток костного мозга в процессе при- живления донорского костного мозга и их значения в развитии осложнений после ТГСК. При анализе функциональных характеристик стромальных кле- ток у 38 реципиентов аллогенного трансплантата ге- мопоэтических стволовых клеток было показано уве- личение активности остеогенной дифференцировки на фоне укорочения сроков восстановления кро- ветворения. Вместе с тем, наличие более выражен- ной способности к адипогенной дифференцировке ассоциировано с меньшей вероятностью развития гипофункции трансплантата. При исследовании ге- мостимулирующей активности стромальных клеток реципиента были отмечены факты, указывающие на преимущественное влияние короткодистантных ростовых факторов на посттрансплантационную реконституцию гемопоэза. При этом более выра- женная экспрессия молекул, опосредующих хоу- минг ГСК в стромальных клетках реципиента перед трансплантацией ассоциировано с более быстрым восстановлением гемопоэза у трансплантированных больных." ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(212) "Влияние функциональных характеристик стромальных клеток костного мозга реципиента на приживление после алло-ТГСК" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(212) "Влияние функциональных характеристик стромальных клеток костного мозга реципиента на приживление после алло-ТГСК" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(212) "Влияние функциональных характеристик стромальных клеток костного мозга реципиента на приживление после алло-ТГСК" ["SECTION_META_TITLE"]=> string(212) "Влияние функциональных характеристик стромальных клеток костного мозга реципиента на приживление после алло-ТГСК" ["SECTION_META_KEYWORDS"]=> string(212) "Влияние функциональных характеристик стромальных клеток костного мозга реципиента на приживление после алло-ТГСК" ["SECTION_META_DESCRIPTION"]=> string(212) "Влияние функциональных характеристик стромальных клеток костного мозга реципиента на приживление после алло-ТГСК" ["SECTION_PICTURE_FILE_ALT"]=> string(212) "Влияние функциональных характеристик стромальных клеток костного мозга реципиента на приживление после алло-ТГСК" ["SECTION_PICTURE_FILE_TITLE"]=> string(212) "Влияние функциональных характеристик стромальных клеток костного мозга реципиента на приживление после алло-ТГСК" ["SECTION_PICTURE_FILE_NAME"]=> string(100) "vliyanie-funktsionalnykh-kharakteristik-stromalnykh-kletok-kostnogo-mozga-retsipienta-na-prizhivleni" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(212) "Влияние функциональных характеристик стромальных клеток костного мозга реципиента на приживление после алло-ТГСК" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(212) "Влияние функциональных характеристик стромальных клеток костного мозга реципиента на приживление после алло-ТГСК" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(100) "vliyanie-funktsionalnykh-kharakteristik-stromalnykh-kletok-kostnogo-mozga-retsipienta-na-prizhivleni" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(100) "vliyanie-funktsionalnykh-kharakteristik-stromalnykh-kletok-kostnogo-mozga-retsipienta-na-prizhivleni" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(100) "vliyanie-funktsionalnykh-kharakteristik-stromalnykh-kletok-kostnogo-mozga-retsipienta-na-prizhivleni" } ["FIELDS"]=> array(1) { ["IBLOCK_SECTION_ID"]=> string(2) "21" } ["PROPERTIES"]=> array(18) { ["KEYWORDS"]=> array(36) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые слова" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "KEYWORDS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "19" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(4) { [0]=> string(4) "8474" [1]=> string(4) "8475" [2]=> string(4) "8476" [3]=> string(4) "8477" } ["VALUE"]=> array(4) { [0]=> string(3) "696" [1]=> string(3) "697" [2]=> string(3) "698" [3]=> string(3) "699" } ["DESCRIPTION"]=> array(4) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(4) { [0]=> string(3) "696" [1]=> string(3) "697" [2]=> string(3) "698" [3]=> string(3) "699" } ["~DESCRIPTION"]=> array(4) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" } ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" } ["SUBMITTED"]=> array(36) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8445" ["VALUE"]=> string(10) "10.10.2016" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "10.10.2016" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8446" ["VALUE"]=> string(10) "25.11.2016" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "25.11.2016" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL } ["PUBLISHED"]=> array(36) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Дата публикации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "PUBLISHED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "22" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Дата публикации" ["~DEFAULT_VALUE"]=> NULL } ["CONTACT"]=> array(36) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8447" ["VALUE"]=> string(3) "695" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(3) "695" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(1) { [0]=> string(4) "8478" } ["VALUE"]=> array(1) { [0]=> string(3) "695" } ["DESCRIPTION"]=> array(1) { [0]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(1) { [0]=> string(3) "695" } ["~DESCRIPTION"]=> array(1) { [0]=> string(0) "" } ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8449" ["VALUE"]=> array(2) { ["TEXT"]=> string(327) "Ильдар М. Бархатов, Николай Ю. Цветков, Даниил Е. Ершов, Марина Ю. Лаврухина, Алена И. Шакирова, Алиса Я.<br> Поттер, Анна Г. Смирнова, Людмила С. Зубаровская, Борис В. Афанасьев<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(315) "Ильдар М. Бархатов, Николай Ю. Цветков, Даниил Е. Ершов, Марина Ю. Лаврухина, Алена И. Шакирова, Алиса Я.
Поттер, Анна Г. Смирнова, Людмила С. Зубаровская, Борис В. Афанасьев
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8450" ["VALUE"]=> array(2) { ["TEXT"]=> string(294) "Первый Санкт-Петербургский государственный медицинский Университет им. акад. И. П. Павлова Министерства<br> Здравоохранения РФ, Санкт-Петербург, Россия<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(282) "Первый Санкт-Петербургский государственный медицинский Университет им. акад. И. П. Павлова Министерства
Здравоохранения РФ, Санкт-Петербург, Россия
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8451" ["VALUE"]=> array(2) { ["TEXT"]=> string(2500) "Наблюдаемая в ряде случаев гипофункция транс- плантата является нередкой и обусловливает не- обходимость разработки функциональных тестов исследования клеток стромы с целью обоснования показаний к совместной трансплантации гемопоэ- тических и стромальных клеток костного мозга. Це- лью данного исследования являлось изучение роли стромальных клеток костного мозга в процессе при- живления донорского костного мозга и их значения в развитии осложнений после ТГСК. При анализе функциональных характеристик стромальных кле- ток у 38 реципиентов аллогенного трансплантата ге- мопоэтических стволовых клеток было показано уве- личение активности остеогенной дифференцировки на фоне укорочения сроков восстановления кро- ветворения. Вместе с тем, наличие более выражен- ной способности к адипогенной дифференцировке ассоциировано с меньшей вероятностью развития гипофункции трансплантата. При исследовании ге- мостимулирующей активности стромальных клеток реципиента были отмечены факты, указывающие на преимущественное влияние короткодистантных ростовых факторов на посттрансплантационную реконституцию гемопоэза. При этом более выра- женная экспрессия молекул, опосредующих хоу- минг ГСК в стромальных клетках реципиента перед трансплантацией ассоциировано с более быстрым восстановлением гемопоэза у трансплантированных больных." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2500) "Наблюдаемая в ряде случаев гипофункция транс- плантата является нередкой и обусловливает не- обходимость разработки функциональных тестов исследования клеток стромы с целью обоснования показаний к совместной трансплантации гемопоэ- тических и стромальных клеток костного мозга. Це- лью данного исследования являлось изучение роли стромальных клеток костного мозга в процессе при- живления донорского костного мозга и их значения в развитии осложнений после ТГСК. При анализе функциональных характеристик стромальных кле- ток у 38 реципиентов аллогенного трансплантата ге- мопоэтических стволовых клеток было показано уве- личение активности остеогенной дифференцировки на фоне укорочения сроков восстановления кро- ветворения. Вместе с тем, наличие более выражен- ной способности к адипогенной дифференцировке ассоциировано с меньшей вероятностью развития гипофункции трансплантата. При исследовании ге- мостимулирующей активности стромальных клеток реципиента были отмечены факты, указывающие на преимущественное влияние короткодистантных ростовых факторов на посттрансплантационную реконституцию гемопоэза. При этом более выра- женная экспрессия молекул, опосредующих хоу- минг ГСК в стромальных клетках реципиента перед трансплантацией ассоциировано с более быстрым восстановлением гемопоэза у трансплантированных больных." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8452" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2016-5-4-71-77" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2016-5-4-71-77" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8453" ["VALUE"]=> array(2) { ["TEXT"]=> string(202) "Ildar M. Barkhatov, Nikolay Yu Tsvetkov, Daniil E. Ershov, Marina Y. Lavrukhina, Alena I. Shakirova, Alisa Ya. Potter,<br> Anna G. Smirnova, Ludmila S. Zubarovskaya, Boris V. Afanasyev<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(190) "Ildar M. Barkhatov, Nikolay Yu Tsvetkov, Daniil E. Ershov, Marina Y. Lavrukhina, Alena I. Shakirova, Alisa Ya. Potter,
Anna G. Smirnova, Ludmila S. Zubarovskaya, Boris V. Afanasyev
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8454" ["VALUE"]=> array(2) { ["TEXT"]=> string(785) "R. M. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, and Chair of Hematology,<br> Transfusiology and Transplantation, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russian<br> Federation<br> <br> Dr. Ildar M.Barkhatov, PhD, Laboratory Head, R. M. Gorbacheva<br> Memorial Research Institute of Children Oncology,<br> Hematology and Transplantation, The First St. Petersburg<br> State I. Pavlov Medical University, L.Tolstoy St. 6/8, 197022,<br> St. Petersburg, Russian Federation<br> <br> Phone: +7(911) 778 2785<br> E-mail: <a href="mailto:i.barkhatov@gmail.com">i.barkhatov@gmail.com</a><br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(691) "R. M. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, and Chair of Hematology,
Transfusiology and Transplantation, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russian
Federation

Dr. Ildar M.Barkhatov, PhD, Laboratory Head, R. M. Gorbacheva
Memorial Research Institute of Children Oncology,
Hematology and Transplantation, The First St. Petersburg
State I. Pavlov Medical University, L.Tolstoy St. 6/8, 197022,
St. Petersburg, Russian Federation

Phone: +7(911) 778 2785
E-mail: i.barkhatov@gmail.com
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8455" ["VALUE"]=> array(2) { ["TEXT"]=> string(1295) "Functional insufficiency of stem cell grafts is not rare in hematopoietic stem cell transplantation (HSCT), thus requiring further development of functional tests for recipient’s stromal cells, in order to substantiate clinical indications for co-transplantation of hematopoietic and stromal bone marrow cells. The aim of this study was to investigate a role of bone marrow stromal cells (BMSC) in the donor bone marrow engraftment, and their importance for development of complications after HSCT. Functional analysis of BMSC cultures from thirty-eight recipients of allogeneic hematopoietic stem cells has been shown that induced osteogenic differentiation correlated with faster hematopoiesis recovery in transplanted patients. Moreover, a pronounced ability for adipogenic differentiation proved to be associated with lower probability of the graft hypofunction. A pronounced hemostimulatory activity of stromal cells was observed in our study, thus suggesting effects of short-range hematopoietic growth factors from BMSC upon hematopoietic reconstitution. At the same time, a more pronounced pre-transplant expression of molecules which promote donor HSC homing by the recipient stromal cells was associated with faster hematopoietic recovery after transplantation." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1295) "Functional insufficiency of stem cell grafts is not rare in hematopoietic stem cell transplantation (HSCT), thus requiring further development of functional tests for recipient’s stromal cells, in order to substantiate clinical indications for co-transplantation of hematopoietic and stromal bone marrow cells. The aim of this study was to investigate a role of bone marrow stromal cells (BMSC) in the donor bone marrow engraftment, and their importance for development of complications after HSCT. Functional analysis of BMSC cultures from thirty-eight recipients of allogeneic hematopoietic stem cells has been shown that induced osteogenic differentiation correlated with faster hematopoiesis recovery in transplanted patients. Moreover, a pronounced ability for adipogenic differentiation proved to be associated with lower probability of the graft hypofunction. A pronounced hemostimulatory activity of stromal cells was observed in our study, thus suggesting effects of short-range hematopoietic growth factors from BMSC upon hematopoietic reconstitution. At the same time, a more pronounced pre-transplant expression of molecules which promote donor HSC homing by the recipient stromal cells was associated with faster hematopoietic recovery after transplantation." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["NAME_EN"]=> array(36) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8456" ["VALUE"]=> string(98) "Impact of recipient marrow stromal cells functional characteristics on engraftment after allo-HSCT" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(98) "Impact of recipient marrow stromal cells functional characteristics on engraftment after allo-HSCT" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" } ["FULL_TEXT_RU"]=> array(36) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(23) "Полный текст" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["PDF_RU"]=> array(36) { ["ID"]=> string(2) "43" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF RUS" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_RU" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "43" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8479" ["VALUE"]=> string(3) "280" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(3) "280" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(7) "PDF RUS" ["~DEFAULT_VALUE"]=> string(0) "" } ["PDF_EN"]=> array(36) { ["ID"]=> string(2) "44" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF ENG" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "44" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8480" ["VALUE"]=> string(3) "281" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(3) "281" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(7) "PDF ENG" ["~DEFAULT_VALUE"]=> string(0) "" } ["NAME_LONG"]=> array(36) { ["ID"]=> string(2) "45" ["TIMESTAMP_X"]=> string(19) "2023-04-13 00:55:00" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(72) "Название (для очень длинных заголовков)" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "NAME_LONG" ["DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "45" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(80) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(72) "Название (для очень длинных заголовков)" ["~DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } } } ["DISPLAY_PROPERTIES"]=> array(13) { ["AUTHOR_EN"]=> array(37) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8453" ["VALUE"]=> array(2) { ["TEXT"]=> string(202) "Ildar M. Barkhatov, Nikolay Yu Tsvetkov, Daniil E. Ershov, Marina Y. Lavrukhina, Alena I. Shakirova, Alisa Ya. Potter,<br> Anna G. Smirnova, Ludmila S. Zubarovskaya, Boris V. Afanasyev<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(190) "Ildar M. Barkhatov, Nikolay Yu Tsvetkov, Daniil E. Ershov, Marina Y. Lavrukhina, Alena I. Shakirova, Alisa Ya. Potter,
Anna G. Smirnova, Ludmila S. Zubarovskaya, Boris V. Afanasyev
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(190) "Ildar M. Barkhatov, Nikolay Yu Tsvetkov, Daniil E. Ershov, Marina Y. Lavrukhina, Alena I. Shakirova, Alisa Ya. Potter,
Anna G. Smirnova, Ludmila S. Zubarovskaya, Boris V. Afanasyev
" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8455" ["VALUE"]=> array(2) { ["TEXT"]=> string(1295) "Functional insufficiency of stem cell grafts is not rare in hematopoietic stem cell transplantation (HSCT), thus requiring further development of functional tests for recipient’s stromal cells, in order to substantiate clinical indications for co-transplantation of hematopoietic and stromal bone marrow cells. The aim of this study was to investigate a role of bone marrow stromal cells (BMSC) in the donor bone marrow engraftment, and their importance for development of complications after HSCT. Functional analysis of BMSC cultures from thirty-eight recipients of allogeneic hematopoietic stem cells has been shown that induced osteogenic differentiation correlated with faster hematopoiesis recovery in transplanted patients. Moreover, a pronounced ability for adipogenic differentiation proved to be associated with lower probability of the graft hypofunction. A pronounced hemostimulatory activity of stromal cells was observed in our study, thus suggesting effects of short-range hematopoietic growth factors from BMSC upon hematopoietic reconstitution. At the same time, a more pronounced pre-transplant expression of molecules which promote donor HSC homing by the recipient stromal cells was associated with faster hematopoietic recovery after transplantation." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1295) "Functional insufficiency of stem cell grafts is not rare in hematopoietic stem cell transplantation (HSCT), thus requiring further development of functional tests for recipient’s stromal cells, in order to substantiate clinical indications for co-transplantation of hematopoietic and stromal bone marrow cells. The aim of this study was to investigate a role of bone marrow stromal cells (BMSC) in the donor bone marrow engraftment, and their importance for development of complications after HSCT. Functional analysis of BMSC cultures from thirty-eight recipients of allogeneic hematopoietic stem cells has been shown that induced osteogenic differentiation correlated with faster hematopoiesis recovery in transplanted patients. Moreover, a pronounced ability for adipogenic differentiation proved to be associated with lower probability of the graft hypofunction. A pronounced hemostimulatory activity of stromal cells was observed in our study, thus suggesting effects of short-range hematopoietic growth factors from BMSC upon hematopoietic reconstitution. At the same time, a more pronounced pre-transplant expression of molecules which promote donor HSC homing by the recipient stromal cells was associated with faster hematopoietic recovery after transplantation." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1295) "Functional insufficiency of stem cell grafts is not rare in hematopoietic stem cell transplantation (HSCT), thus requiring further development of functional tests for recipient’s stromal cells, in order to substantiate clinical indications for co-transplantation of hematopoietic and stromal bone marrow cells. The aim of this study was to investigate a role of bone marrow stromal cells (BMSC) in the donor bone marrow engraftment, and their importance for development of complications after HSCT. Functional analysis of BMSC cultures from thirty-eight recipients of allogeneic hematopoietic stem cells has been shown that induced osteogenic differentiation correlated with faster hematopoiesis recovery in transplanted patients. Moreover, a pronounced ability for adipogenic differentiation proved to be associated with lower probability of the graft hypofunction. A pronounced hemostimulatory activity of stromal cells was observed in our study, thus suggesting effects of short-range hematopoietic growth factors from BMSC upon hematopoietic reconstitution. At the same time, a more pronounced pre-transplant expression of molecules which promote donor HSC homing by the recipient stromal cells was associated with faster hematopoietic recovery after transplantation." } ["DOI"]=> array(37) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8452" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2016-5-4-71-77" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2016-5-4-71-77" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(37) "10.18620/ctt-1866-8836-2016-5-4-71-77" } ["NAME_EN"]=> array(37) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8456" ["VALUE"]=> string(98) "Impact of recipient marrow stromal cells functional characteristics on engraftment after allo-HSCT" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(98) "Impact of recipient marrow stromal cells functional characteristics on engraftment after allo-HSCT" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(98) "Impact of recipient marrow stromal cells functional characteristics on engraftment after allo-HSCT" } ["ORGANIZATION_EN"]=> array(37) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8454" ["VALUE"]=> array(2) { ["TEXT"]=> string(785) "R. M. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, and Chair of Hematology,<br> Transfusiology and Transplantation, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russian<br> Federation<br> <br> Dr. Ildar M.Barkhatov, PhD, Laboratory Head, R. M. Gorbacheva<br> Memorial Research Institute of Children Oncology,<br> Hematology and Transplantation, The First St. Petersburg<br> State I. Pavlov Medical University, L.Tolstoy St. 6/8, 197022,<br> St. Petersburg, Russian Federation<br> <br> Phone: +7(911) 778 2785<br> E-mail: <a href="mailto:i.barkhatov@gmail.com">i.barkhatov@gmail.com</a><br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(691) "R. M. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, and Chair of Hematology,
Transfusiology and Transplantation, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russian
Federation

Dr. Ildar M.Barkhatov, PhD, Laboratory Head, R. M. Gorbacheva
Memorial Research Institute of Children Oncology,
Hematology and Transplantation, The First St. Petersburg
State I. Pavlov Medical University, L.Tolstoy St. 6/8, 197022,
St. Petersburg, Russian Federation

Phone: +7(911) 778 2785
E-mail: i.barkhatov@gmail.com
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(691) "R. M. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, and Chair of Hematology,
Transfusiology and Transplantation, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russian
Federation

Dr. Ildar M.Barkhatov, PhD, Laboratory Head, R. M. Gorbacheva
Memorial Research Institute of Children Oncology,
Hematology and Transplantation, The First St. Petersburg
State I. Pavlov Medical University, L.Tolstoy St. 6/8, 197022,
St. Petersburg, Russian Federation

Phone: +7(911) 778 2785
E-mail: i.barkhatov@gmail.com
" } ["AUTHORS"]=> array(38) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(1) { [0]=> string(4) "8478" } ["VALUE"]=> array(1) { [0]=> string(3) "695" } ["DESCRIPTION"]=> array(1) { [0]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(1) { [0]=> string(3) "695" } ["~DESCRIPTION"]=> array(1) { [0]=> string(0) "" } ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(61) "Ildar M. Barkhatov" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["AUTHOR_RU"]=> array(37) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8449" ["VALUE"]=> array(2) { ["TEXT"]=> string(327) "Ильдар М. Бархатов, Николай Ю. Цветков, Даниил Е. Ершов, Марина Ю. Лаврухина, Алена И. Шакирова, Алиса Я.<br> Поттер, Анна Г. Смирнова, Людмила С. Зубаровская, Борис В. Афанасьев<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(315) "Ильдар М. Бархатов, Николай Ю. Цветков, Даниил Е. Ершов, Марина Ю. Лаврухина, Алена И. Шакирова, Алиса Я.
Поттер, Анна Г. Смирнова, Людмила С. Зубаровская, Борис В. Афанасьев
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(315) "Ильдар М. Бархатов, Николай Ю. Цветков, Даниил Е. Ершов, Марина Ю. Лаврухина, Алена И. Шакирова, Алиса Я.
Поттер, Анна Г. Смирнова, Людмила С. Зубаровская, Борис В. Афанасьев
" } ["SUBMITTED"]=> array(37) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8445" ["VALUE"]=> string(10) "10.10.2016" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "10.10.2016" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "10.10.2016" } ["ACCEPTED"]=> array(37) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8446" ["VALUE"]=> string(10) "25.11.2016" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "25.11.2016" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "25.11.2016" } ["KEYWORDS"]=> array(38) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые слова" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "KEYWORDS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "19" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(4) { [0]=> string(4) "8474" [1]=> string(4) "8475" [2]=> string(4) "8476" [3]=> string(4) "8477" } ["VALUE"]=> array(4) { [0]=> string(3) "696" [1]=> string(3) "697" [2]=> string(3) "698" [3]=> string(3) "699" } ["DESCRIPTION"]=> array(4) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(4) { [0]=> string(3) "696" [1]=> string(3) "697" [2]=> string(3) "698" [3]=> string(3) "699" } ["~DESCRIPTION"]=> array(4) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" } ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> array(4) { [0]=> string(107) "Стромальные клетки костного мозга" [1]=> string(71) "острые лейкозы" [2]=> string(101) "функциональные характеристики" [3]=> string(83) "типы дифференцировки" } ["LINK_ELEMENT_VALUE"]=> bool(false) } ["CONTACT"]=> array(38) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8447" ["VALUE"]=> string(3) "695" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(3) "695" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(61) "Ildar M. Barkhatov" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8451" ["VALUE"]=> array(2) { ["TEXT"]=> string(2500) "Наблюдаемая в ряде случаев гипофункция транс- плантата является нередкой и обусловливает не- обходимость разработки функциональных тестов исследования клеток стромы с целью обоснования показаний к совместной трансплантации гемопоэ- тических и стромальных клеток костного мозга. Це- лью данного исследования являлось изучение роли стромальных клеток костного мозга в процессе при- живления донорского костного мозга и их значения в развитии осложнений после ТГСК. При анализе функциональных характеристик стромальных кле- ток у 38 реципиентов аллогенного трансплантата ге- мопоэтических стволовых клеток было показано уве- личение активности остеогенной дифференцировки на фоне укорочения сроков восстановления кро- ветворения. Вместе с тем, наличие более выражен- ной способности к адипогенной дифференцировке ассоциировано с меньшей вероятностью развития гипофункции трансплантата. При исследовании ге- мостимулирующей активности стромальных клеток реципиента были отмечены факты, указывающие на преимущественное влияние короткодистантных ростовых факторов на посттрансплантационную реконституцию гемопоэза. При этом более выра- женная экспрессия молекул, опосредующих хоу- минг ГСК в стромальных клетках реципиента перед трансплантацией ассоциировано с более быстрым восстановлением гемопоэза у трансплантированных больных." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2500) "Наблюдаемая в ряде случаев гипофункция транс- плантата является нередкой и обусловливает не- обходимость разработки функциональных тестов исследования клеток стромы с целью обоснования показаний к совместной трансплантации гемопоэ- тических и стромальных клеток костного мозга. Це- лью данного исследования являлось изучение роли стромальных клеток костного мозга в процессе при- живления донорского костного мозга и их значения в развитии осложнений после ТГСК. При анализе функциональных характеристик стромальных кле- ток у 38 реципиентов аллогенного трансплантата ге- мопоэтических стволовых клеток было показано уве- личение активности остеогенной дифференцировки на фоне укорочения сроков восстановления кро- ветворения. Вместе с тем, наличие более выражен- ной способности к адипогенной дифференцировке ассоциировано с меньшей вероятностью развития гипофункции трансплантата. При исследовании ге- мостимулирующей активности стромальных клеток реципиента были отмечены факты, указывающие на преимущественное влияние короткодистантных ростовых факторов на посттрансплантационную реконституцию гемопоэза. При этом более выра- женная экспрессия молекул, опосредующих хоу- минг ГСК в стромальных клетках реципиента перед трансплантацией ассоциировано с более быстрым восстановлением гемопоэза у трансплантированных больных." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2500) "Наблюдаемая в ряде случаев гипофункция транс- плантата является нередкой и обусловливает не- обходимость разработки функциональных тестов исследования клеток стромы с целью обоснования показаний к совместной трансплантации гемопоэ- тических и стромальных клеток костного мозга. Це- лью данного исследования являлось изучение роли стромальных клеток костного мозга в процессе при- живления донорского костного мозга и их значения в развитии осложнений после ТГСК. При анализе функциональных характеристик стромальных кле- ток у 38 реципиентов аллогенного трансплантата ге- мопоэтических стволовых клеток было показано уве- личение активности остеогенной дифференцировки на фоне укорочения сроков восстановления кро- ветворения. Вместе с тем, наличие более выражен- ной способности к адипогенной дифференцировке ассоциировано с меньшей вероятностью развития гипофункции трансплантата. При исследовании ге- мостимулирующей активности стромальных клеток реципиента были отмечены факты, указывающие на преимущественное влияние короткодистантных ростовых факторов на посттрансплантационную реконституцию гемопоэза. При этом более выра- женная экспрессия молекул, опосредующих хоу- минг ГСК в стромальных клетках реципиента перед трансплантацией ассоциировано с более быстрым восстановлением гемопоэза у трансплантированных больных." } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "8450" ["VALUE"]=> array(2) { ["TEXT"]=> string(294) "Первый Санкт-Петербургский государственный медицинский Университет им. акад. И. П. Павлова Министерства<br> Здравоохранения РФ, Санкт-Петербург, Россия<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(282) "Первый Санкт-Петербургский государственный медицинский Университет им. акад. И. П. Павлова Министерства
Здравоохранения РФ, Санкт-Петербург, Россия
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(282) "Первый Санкт-Петербургский государственный медицинский Университет им. акад. И. П. Павлова Министерства
Здравоохранения РФ, Санкт-Петербург, Россия
" } } } }

						Array
(
    [KEYWORDS] => Array
        (
            [ID] => 19
            [TIMESTAMP_X] => 2015-09-03 10:46:01
            [IBLOCK_ID] => 2
            [NAME] => Ключевые слова
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => KEYWORDS
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => E
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => Y
            [XML_ID] => 19
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 4
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => Y
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => EAutocomplete
            [USER_TYPE_SETTINGS] => Array
                (
                    [VIEW] => E
                    [SHOW_ADD] => Y
                    [MAX_WIDTH] => 0
                    [MIN_HEIGHT] => 24
                    [MAX_HEIGHT] => 1000
                    [BAN_SYM] => ,;
                    [REP_SYM] =>  
                    [OTHER_REP_SYM] => 
                    [IBLOCK_MESS] => Y
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => Array
                (
                    [0] => 8396
                    [1] => 8397
                    [2] => 8398
                    [3] => 8399
                    [4] => 8400
                )

            [VALUE] => Array
                (
                    [0] => 686
                    [1] => 687
                    [2] => 688
                    [3] => 689
                    [4] => 690
                )

            [DESCRIPTION] => Array
                (
                    [0] => 
                    [1] => 
                    [2] => 
                    [3] => 
                    [4] => 
                )

            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [0] => 686
                    [1] => 687
                    [2] => 688
                    [3] => 689
                    [4] => 690
                )

            [~DESCRIPTION] => Array
                (
                    [0] => 
                    [1] => 
                    [2] => 
                    [3] => 
                    [4] => 
                )

            [~NAME] => Ключевые слова
            [~DEFAULT_VALUE] => 
        )

    [SUBMITTED] => Array
        (
            [ID] => 20
            [TIMESTAMP_X] => 2015-09-02 17:21:42
            [IBLOCK_ID] => 2
            [NAME] => Дата подачи
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => SUBMITTED
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 20
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => DateTime
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 8371
            [VALUE] => 28.11.2016
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 28.11.2016
            [~DESCRIPTION] => 
            [~NAME] => Дата подачи
            [~DEFAULT_VALUE] => 
        )

    [ACCEPTED] => Array
        (
            [ID] => 21
            [TIMESTAMP_X] => 2015-09-02 17:21:42
            [IBLOCK_ID] => 2
            [NAME] => Дата принятия
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => ACCEPTED
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 21
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => DateTime
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 8372
            [VALUE] => 09.12.2016
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 09.12.2016
            [~DESCRIPTION] => 
            [~NAME] => Дата принятия
            [~DEFAULT_VALUE] => 
        )

    [PUBLISHED] => Array
        (
            [ID] => 22
            [TIMESTAMP_X] => 2015-09-02 17:21:42
            [IBLOCK_ID] => 2
            [NAME] => Дата публикации
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => PUBLISHED
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 22
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => DateTime
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 
            [VALUE] => 
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 
            [~DESCRIPTION] => 
            [~NAME] => Дата публикации
            [~DEFAULT_VALUE] => 
        )

    [CONTACT] => Array
        (
            [ID] => 23
            [TIMESTAMP_X] => 2015-09-03 14:43:05
            [IBLOCK_ID] => 2
            [NAME] => Контакт
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => CONTACT
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => E
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 23
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 3
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => Y
            [VERSION] => 1
            [USER_TYPE] => EAutocomplete
            [USER_TYPE_SETTINGS] => Array
                (
                    [VIEW] => E
                    [SHOW_ADD] => Y
                    [MAX_WIDTH] => 0
                    [MIN_HEIGHT] => 24
                    [MAX_HEIGHT] => 1000
                    [BAN_SYM] => ,;
                    [REP_SYM] =>  
                    [OTHER_REP_SYM] => 
                    [IBLOCK_MESS] => N
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8373
            [VALUE] => 433
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 433
            [~DESCRIPTION] => 
            [~NAME] => Контакт
            [~DEFAULT_VALUE] => 
        )

    [AUTHORS] => Array
        (
            [ID] => 24
            [TIMESTAMP_X] => 2015-09-03 10:45:07
            [IBLOCK_ID] => 2
            [NAME] => Авторы
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => AUTHORS
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => E
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => Y
            [XML_ID] => 24
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 3
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => Y
            [VERSION] => 1
            [USER_TYPE] => EAutocomplete
            [USER_TYPE_SETTINGS] => Array
                (
                    [VIEW] => E
                    [SHOW_ADD] => Y
                    [MAX_WIDTH] => 0
                    [MIN_HEIGHT] => 24
                    [MAX_HEIGHT] => 1000
                    [BAN_SYM] => ,;
                    [REP_SYM] =>  
                    [OTHER_REP_SYM] => 
                    [IBLOCK_MESS] => N
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => Array
                (
                    [0] => 8401
                )

            [VALUE] => Array
                (
                    [0] => 433
                )

            [DESCRIPTION] => Array
                (
                    [0] => 
                )

            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [0] => 433
                )

            [~DESCRIPTION] => Array
                (
                    [0] => 
                )

            [~NAME] => Авторы
            [~DEFAULT_VALUE] => 
        )

    [AUTHOR_RU] => Array
        (
            [ID] => 25
            [TIMESTAMP_X] => 2015-09-02 18:01:20
            [IBLOCK_ID] => 2
            [NAME] => Авторы
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => AUTHOR_RU
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 25
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8388
            [VALUE] => Array
                (
                    [TEXT] => Герард Вагемакер
                    [TYPE] => HTML
                )

            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [TEXT] => Герард Вагемакер
                    [TYPE] => HTML
                )

            [~DESCRIPTION] => 
            [~NAME] => Авторы
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [ORGANIZATION_RU] => Array
        (
            [ID] => 26
            [TIMESTAMP_X] => 2015-09-02 18:01:20
            [IBLOCK_ID] => 2
            [NAME] => Организации
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => ORGANIZATION_RU
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 26
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8389
            [VALUE] => Array
                (
                    [TEXT] => Университет Эразмус, Роттердам, Нидерланды; Центр исследования и разработки стволовых клеток, Университет<br>
 Хашеттепе, Анкара, Турция; НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый<br>
 Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия<br>
                    [TYPE] => HTML
                )

            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [TEXT] => Университет Эразмус, Роттердам, Нидерланды; Центр исследования и разработки стволовых клеток, Университет

 Хашеттепе, Анкара, Турция; НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый

 Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия

                    [TYPE] => HTML
                )

            [~DESCRIPTION] => 
            [~NAME] => Организации
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [SUMMARY_RU] => Array
        (
            [ID] => 27
            [TIMESTAMP_X] => 2015-09-02 18:01:20
            [IBLOCK_ID] => 2
            [NAME] => Описание/Резюме
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => SUMMARY_RU
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 27
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8390
            [VALUE] => Array
                (
                    [TEXT] => Редкие болезни поражают, в целом, миллионы людей во всем мире. Многие из этих являются наследственными заболеваниями, ведущими к инвалидности и требующими дорогостоящего ухода. Генная терапия гемопоэтическими стволовыми клетками (ГТГСК) разработана за последние 20 лет. На современном уровне генная терапия выполнима при заболеваниях, для которых (1) есть идентифицированный генетический дефект, (2) диагноз ставится достаточно рано для действенного терапевтического вмешательства, (3) имеется специфическая экспериментальная модель для оценки эффективности и безопасности лечения. Соответствующие терапевтические трансгены должны также отвечать определенным биологическим критериям. Лентивирусные векторы третьего поколения выполнены самоинактивирующимися (SIN), путем делеции энхансерных участков из LTR-последовательностей, тем самым снижая риск воздействия на соседние гены, что приводит к достаточным уровням безопасности. В настоящее время лентивирусная ГТГСК вступила в фазу начального клинического внедрения для лечения иммунодефицитов и лизосомных болезней накопления. Мы обсуждаем начальные клинические испытания с применением этих векторов для некоторых метаболических болезней накопления, которые включают адренолейкодистрофию, метахроматическую лейкодистрофию, синдром Гурлер (MPS I), Помпе (GSD II), и болезнь Фабри. Данный краткий обзор обобщает развитие и современное клиническое внедрение этих подходов.
                    [TYPE] => HTML
                )

            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [TEXT] => Редкие болезни поражают, в целом, миллионы людей во всем мире. Многие из этих являются наследственными заболеваниями, ведущими к инвалидности и требующими дорогостоящего ухода. Генная терапия гемопоэтическими стволовыми клетками (ГТГСК) разработана за последние 20 лет. На современном уровне генная терапия выполнима при заболеваниях, для которых (1) есть идентифицированный генетический дефект, (2) диагноз ставится достаточно рано для действенного терапевтического вмешательства, (3) имеется специфическая экспериментальная модель для оценки эффективности и безопасности лечения. Соответствующие терапевтические трансгены должны также отвечать определенным биологическим критериям. Лентивирусные векторы третьего поколения выполнены самоинактивирующимися (SIN), путем делеции энхансерных участков из LTR-последовательностей, тем самым снижая риск воздействия на соседние гены, что приводит к достаточным уровням безопасности. В настоящее время лентивирусная ГТГСК вступила в фазу начального клинического внедрения для лечения иммунодефицитов и лизосомных болезней накопления. Мы обсуждаем начальные клинические испытания с применением этих векторов для некоторых метаболических болезней накопления, которые включают адренолейкодистрофию, метахроматическую лейкодистрофию, синдром Гурлер (MPS I), Помпе (GSD II), и болезнь Фабри. Данный краткий обзор обобщает развитие и современное клиническое внедрение этих подходов.
                    [TYPE] => HTML
                )

            [~DESCRIPTION] => 
            [~NAME] => Описание/Резюме
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [DOI] => Array
        (
            [ID] => 28
            [TIMESTAMP_X] => 2016-04-06 14:11:12
            [IBLOCK_ID] => 2
            [NAME] => DOI
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => DOI
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 80
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 28
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => 
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 8375
            [VALUE] => 10.18620/ctt-1866-8836-2016-5-4-56-62
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 10.18620/ctt-1866-8836-2016-5-4-56-62
            [~DESCRIPTION] => 
            [~NAME] => DOI
            [~DEFAULT_VALUE] => 
        )

    [AUTHOR_EN] => Array
        (
            [ID] => 37
            [TIMESTAMP_X] => 2015-09-02 18:02:59
            [IBLOCK_ID] => 2
            [NAME] => Author
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => AUTHOR_EN
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 37
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8391
            [VALUE] => Array
                (
                    [TEXT] => Gerard Wagemaker*
                    [TYPE] => HTML
                )

            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [TEXT] => Gerard Wagemaker*
                    [TYPE] => HTML
                )

            [~DESCRIPTION] => 
            [~NAME] => Author
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [ORGANIZATION_EN] => Array
        (
            [ID] => 38
            [TIMESTAMP_X] => 2015-09-02 18:02:59
            [IBLOCK_ID] => 2
            [NAME] => Organization
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => ORGANIZATION_EN
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 38
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8392
            [VALUE] => Array
                (
                    [TEXT] => Erasmus University Rotterdam, The Netherlands; Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey;<br>
 Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, St. Petersburg, Russia<br>
 <br>
 Gerard Wagemaker, PhD, Professor, Erasmus University Rotterdam,<br>
 c/o PO Box 37048<br>
 3005 LA Rotterdam, The Netherlands<br>
<br>
 Phone: +31-6-51619585<br>
 E-mail: <a href="mailto:g.wagemaker@genetherapy.nl">g.wagemaker@genetherapy.nl</a><br>
                    [TYPE] => HTML
                )

            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [TEXT] => Erasmus University Rotterdam, The Netherlands; Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey;

 Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, St. Petersburg, Russia

 

 Gerard Wagemaker, PhD, Professor, Erasmus University Rotterdam,

 c/o PO Box 37048

 3005 LA Rotterdam, The Netherlands



 Phone: +31-6-51619585

 E-mail: g.wagemaker@genetherapy.nl

                    [TYPE] => HTML
                )

            [~DESCRIPTION] => 
            [~NAME] => Organization
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [SUMMARY_EN] => Array
        (
            [ID] => 39
            [TIMESTAMP_X] => 2015-09-02 18:02:59
            [IBLOCK_ID] => 2
            [NAME] => Description / Summary
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => SUMMARY_EN
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 39
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8393
            [VALUE] => Array
                (
                    [TEXT] => Rare diseases affect millions of people worldwide. Many of those are inherited disorders resulting in chronic disability and requiring cost-intensive care. Hematopoietic stem cell gene therapy has been developed over more than 20 years. At the state of the art, gene therapy is within reach for diseases in which (i) the genetic defect is identified, (ii) the diagnosis is made sufficiently early for a meaningful therapeutic intervention, (iii) a specific animal model is available for efficacy and safety evaluation. Appropriate therapeutic transgenes should also comply with certain biological criteria. Third-generation lentiviral vectors have been made self-inactivating (SIN) by deletion of enhancer regions from the LTR sequences thus reducing the risk of influencing nearby genes, resulting in favorable safety profiles. At the present time, lentiviral hematopoietic stem cell gene therapy has entered the stage of initial clinical implementation for immune deficiencies and lysosomal storage disorders. We discuss initial clinical trials using these vectors for selected metabolic storage disorders, which include adrenoleukodystrophy, metachromatic leukodystrophy, Hurler (MPS I), Pompe (GSD II), and Fabry diseases. This brief review summarizes the development and current clinical implementation of these approaches.
                    [TYPE] => HTML
                )

            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [TEXT] => Rare diseases affect millions of people worldwide. Many of those are inherited disorders resulting in chronic disability and requiring cost-intensive care. Hematopoietic stem cell gene therapy has been developed over more than 20 years. At the state of the art, gene therapy is within reach for diseases in which (i) the genetic defect is identified, (ii) the diagnosis is made sufficiently early for a meaningful therapeutic intervention, (iii) a specific animal model is available for efficacy and safety evaluation. Appropriate therapeutic transgenes should also comply with certain biological criteria. Third-generation lentiviral vectors have been made self-inactivating (SIN) by deletion of enhancer regions from the LTR sequences thus reducing the risk of influencing nearby genes, resulting in favorable safety profiles. At the present time, lentiviral hematopoietic stem cell gene therapy has entered the stage of initial clinical implementation for immune deficiencies and lysosomal storage disorders. We discuss initial clinical trials using these vectors for selected metabolic storage disorders, which include adrenoleukodystrophy, metachromatic leukodystrophy, Hurler (MPS I), Pompe (GSD II), and Fabry diseases. This brief review summarizes the development and current clinical implementation of these approaches.
                    [TYPE] => HTML
                )

            [~DESCRIPTION] => 
            [~NAME] => Description / Summary
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [NAME_EN] => Array
        (
            [ID] => 40
            [TIMESTAMP_X] => 2015-09-03 10:49:47
            [IBLOCK_ID] => 2
            [NAME] => Name
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => NAME_EN
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 80
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 40
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => Y
            [VERSION] => 1
            [USER_TYPE] => 
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 8376
            [VALUE] => Lentiviral Hematopoietic Stem Cell Gene Therapy in Inherited Immune and Lysosomal Enzyme Deficiencies
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Lentiviral Hematopoietic Stem Cell Gene Therapy in Inherited Immune and Lysosomal Enzyme Deficiencies
            [~DESCRIPTION] => 
            [~NAME] => Name
            [~DEFAULT_VALUE] => 
        )

    [FULL_TEXT_RU] => Array
        (
            [ID] => 42
            [TIMESTAMP_X] => 2015-09-07 20:29:18
            [IBLOCK_ID] => 2
            [NAME] => Полный текст
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => FULL_TEXT_RU
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 42
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 
            [VALUE] => 
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 
            [~DESCRIPTION] => 
            [~NAME] => Полный текст
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [PDF_RU] => Array
        (
            [ID] => 43
            [TIMESTAMP_X] => 2015-09-09 16:05:20
            [IBLOCK_ID] => 2
            [NAME] => PDF RUS
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => PDF_RU
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => F
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 43
            [FILE_TYPE] => doc, txt, rtf, pdf
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => 
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 8394
            [VALUE] => 266
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 266
            [~DESCRIPTION] => 
            [~NAME] => PDF RUS
            [~DEFAULT_VALUE] => 
        )

    [PDF_EN] => Array
        (
            [ID] => 44
            [TIMESTAMP_X] => 2015-09-09 16:05:20
            [IBLOCK_ID] => 2
            [NAME] => PDF ENG
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => PDF_EN
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => F
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 44
            [FILE_TYPE] => doc, txt, rtf, pdf
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => 
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 8395
            [VALUE] => 267
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 267
            [~DESCRIPTION] => 
            [~NAME] => PDF ENG
            [~DEFAULT_VALUE] => 
        )

    [NAME_LONG] => Array
        (
            [ID] => 45
            [TIMESTAMP_X] => 2023-04-13 00:55:00
            [IBLOCK_ID] => 2
            [NAME] => Название (для очень длинных заголовков)
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => NAME_LONG
            [DEFAULT_VALUE] => Array
                (
                    [TYPE] => HTML
                    [TEXT] => 
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 45
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 80
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 
            [VALUE] => 
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 
            [~DESCRIPTION] => 
            [~NAME] => Название (для очень длинных заголовков)
            [~DEFAULT_VALUE] => Array
                (
                    [TYPE] => HTML
                    [TEXT] => 
                )

        )

)
					

						Array
(
    [KEYWORDS] => Array
        (
            [ID] => 19
            [TIMESTAMP_X] => 2015-09-03 10:46:01
            [IBLOCK_ID] => 2
            [NAME] => Ключевые слова
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => KEYWORDS
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => E
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => Y
            [XML_ID] => 19
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 4
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => Y
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => EAutocomplete
            [USER_TYPE_SETTINGS] => Array
                (
                    [VIEW] => E
                    [SHOW_ADD] => Y
                    [MAX_WIDTH] => 0
                    [MIN_HEIGHT] => 24
                    [MAX_HEIGHT] => 1000
                    [BAN_SYM] => ,;
                    [REP_SYM] =>  
                    [OTHER_REP_SYM] => 
                    [IBLOCK_MESS] => Y
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => Array
                (
                    [0] => 8467
                    [1] => 8468
                    [2] => 8469
                    [3] => 8470
                )

            [VALUE] => Array
                (
                    [0] => 692
                    [1] => 693
                    [2] => 607
                    [3] => 282
                )

            [DESCRIPTION] => Array
                (
                    [0] => 
                    [1] => 
                    [2] => 
                    [3] => 
                )

            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [0] => 692
                    [1] => 693
                    [2] => 607
                    [3] => 282
                )

            [~DESCRIPTION] => Array
                (
                    [0] => 
                    [1] => 
                    [2] => 
                    [3] => 
                )

            [~NAME] => Ключевые слова
            [~DEFAULT_VALUE] => 
        )

    [SUBMITTED] => Array
        (
            [ID] => 20
            [TIMESTAMP_X] => 2015-09-02 17:21:42
            [IBLOCK_ID] => 2
            [NAME] => Дата подачи
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => SUBMITTED
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 20
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => DateTime
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 8414
            [VALUE] => 14.09.2016
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 14.09.2016
            [~DESCRIPTION] => 
            [~NAME] => Дата подачи
            [~DEFAULT_VALUE] => 
        )

    [ACCEPTED] => Array
        (
            [ID] => 21
            [TIMESTAMP_X] => 2015-09-02 17:21:42
            [IBLOCK_ID] => 2
            [NAME] => Дата принятия
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => ACCEPTED
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 21
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => DateTime
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 8415
            [VALUE] => 25.11.2016
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 25.11.2016
            [~DESCRIPTION] => 
            [~NAME] => Дата принятия
            [~DEFAULT_VALUE] => 
        )

    [PUBLISHED] => Array
        (
            [ID] => 22
            [TIMESTAMP_X] => 2015-09-02 17:21:42
            [IBLOCK_ID] => 2
            [NAME] => Дата публикации
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => PUBLISHED
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 22
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => DateTime
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 
            [VALUE] => 
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 
            [~DESCRIPTION] => 
            [~NAME] => Дата публикации
            [~DEFAULT_VALUE] => 
        )

    [CONTACT] => Array
        (
            [ID] => 23
            [TIMESTAMP_X] => 2015-09-03 14:43:05
            [IBLOCK_ID] => 2
            [NAME] => Контакт
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => CONTACT
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => E
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 23
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 3
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => Y
            [VERSION] => 1
            [USER_TYPE] => EAutocomplete
            [USER_TYPE_SETTINGS] => Array
                (
                    [VIEW] => E
                    [SHOW_ADD] => Y
                    [MAX_WIDTH] => 0
                    [MIN_HEIGHT] => 24
                    [MAX_HEIGHT] => 1000
                    [BAN_SYM] => ,;
                    [REP_SYM] =>  
                    [OTHER_REP_SYM] => 
                    [IBLOCK_MESS] => N
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8416
            [VALUE] => 691
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 691
            [~DESCRIPTION] => 
            [~NAME] => Контакт
            [~DEFAULT_VALUE] => 
        )

    [AUTHORS] => Array
        (
            [ID] => 24
            [TIMESTAMP_X] => 2015-09-03 10:45:07
            [IBLOCK_ID] => 2
            [NAME] => Авторы
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => AUTHORS
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => E
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => Y
            [XML_ID] => 24
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 3
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => Y
            [VERSION] => 1
            [USER_TYPE] => EAutocomplete
            [USER_TYPE_SETTINGS] => Array
                (
                    [VIEW] => E
                    [SHOW_ADD] => Y
                    [MAX_WIDTH] => 0
                    [MIN_HEIGHT] => 24
                    [MAX_HEIGHT] => 1000
                    [BAN_SYM] => ,;
                    [REP_SYM] =>  
                    [OTHER_REP_SYM] => 
                    [IBLOCK_MESS] => N
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => Array
                (
                    [0] => 8471
                )

            [VALUE] => Array
                (
                    [0] => 691
                )

            [DESCRIPTION] => Array
                (
                    [0] => 
                )

            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [0] => 691
                )

            [~DESCRIPTION] => Array
                (
                    [0] => 
                )

            [~NAME] => Авторы
            [~DEFAULT_VALUE] => 
        )

    [AUTHOR_RU] => Array
        (
            [ID] => 25
            [TIMESTAMP_X] => 2015-09-02 18:01:20
            [IBLOCK_ID] => 2
            [NAME] => Авторы
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => AUTHOR_RU
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 25
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8418
            [VALUE] => Array
                (
                    [TEXT] => <sup>1</sup>Юрий А. Серов, <sup>1</sup>Ильдар M. Бархатов, <sup>1</sup>Антон С. Климов, <sup>2</sup>Андрей С. Беркос
                    [TYPE] => HTML
                )

            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [TEXT] => 1Юрий А. Серов, 1Ильдар M. Бархатов, 1Антон С. Климов, 2Андрей С. Беркос
                    [TYPE] => HTML
                )

            [~DESCRIPTION] => 
            [~NAME] => Авторы
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [ORGANIZATION_RU] => Array
        (
            [ID] => 26
            [TIMESTAMP_X] => 2015-09-02 18:01:20
            [IBLOCK_ID] => 2
            [NAME] => Организации
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => ORGANIZATION_RU
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 26
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8419
            [VALUE] => Array
                (
                    [TEXT] => <sup>1</sup>НИИ детской онкологии, гематологии и трансплантации им. Р. М. Горбачевой, Первый Санкт-Петербургский<br>
 государственный медицинский университет им. И. П. Павлова, Санкт-Петебург, Россия;<br>
 <sup>2</sup>Российский НИИ гематологии и трансфузиологии, Санкт-Петербург, Россия<br>
                    [TYPE] => HTML
                )

            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [TEXT] => 1НИИ детской онкологии, гематологии и трансплантации им. Р. М. Горбачевой, Первый Санкт-Петербургский

 государственный медицинский университет им. И. П. Павлова, Санкт-Петебург, Россия;

 2Российский НИИ гематологии и трансфузиологии, Санкт-Петербург, Россия

                    [TYPE] => HTML
                )

            [~DESCRIPTION] => 
            [~NAME] => Организации
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [SUMMARY_RU] => Array
        (
            [ID] => 27
            [TIMESTAMP_X] => 2015-09-02 18:01:20
            [IBLOCK_ID] => 2
            [NAME] => Описание/Резюме
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => SUMMARY_RU
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 27
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8420
            [VALUE] => Array
                (
                    [TEXT] => Область генома, кодирующая лейкоциты антигенов человека (HLA) – это сегмент длиной 3,6 миллиона пар оснований на хромосоме 6(p21). Сложная по антигенному составу система HLA содержит важные молекулы, участвующие в трансплантационном иммунитете. Специфические генные последовательности генов HLA довольно сложно расшифровать с помощью классических методов прямого секвенирования в связи с их техническими ограничениями, сложным составом генов HLA, и возрастающим числом новых аллелей, что требует новых методов генотипирования. Секвенирование следуюшего поколения (NGS) является методом, который может обеспечить полное решение проблемы HLA-типирования. За последнее десятилетие разработка NGS обеспечила более легкий способ полногеномного анализа у человека, в том числе для типирования генов HLA. Несколько вариантов высокопроизводительных методов оценки HLA, основанные на мультиплексных аналитических технологиях NGS были разработаны на основе различных технологических платформ. В этом обзоре мы обсуждаем возможные области применения и прогресс в оборудовании для NGS в плане глубокого типирования системы HLA, с особым вниманием к будущим аспектам его клинического использования. Общеизвестный полиморфизм генов HLA и минимальные межаллельные различия представляют собой особую проблему. Поэтому некоторые вопросы, связанные с биоинформатикой и углубленной обработкой данных для более эффективного анализа HLA в контексте оценки совместимости донора и реципиента. В этом плане различными производителями предложены специализированные компьютерные программы для анализа больших баз данных, получаемых посредством технологий NGS. Наконец, эти высокопроизводительные подходы позволяют минимизировать финансовые затраты на 1 образец, особенно в крупных HLA-лабораториях, где соответствующие расходы на NGS-исследования стали теперь значительно затрат, возникающих при использовании классических технологий секвенирования по Сэнгеру.
                    [TYPE] => HTML
                )

            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [TEXT] => Область генома, кодирующая лейкоциты антигенов человека (HLA) – это сегмент длиной 3,6 миллиона пар оснований на хромосоме 6(p21). Сложная по антигенному составу система HLA содержит важные молекулы, участвующие в трансплантационном иммунитете. Специфические генные последовательности генов HLA довольно сложно расшифровать с помощью классических методов прямого секвенирования в связи с их техническими ограничениями, сложным составом генов HLA, и возрастающим числом новых аллелей, что требует новых методов генотипирования. Секвенирование следуюшего поколения (NGS) является методом, который может обеспечить полное решение проблемы HLA-типирования. За последнее десятилетие разработка NGS обеспечила более легкий способ полногеномного анализа у человека, в том числе для типирования генов HLA. Несколько вариантов высокопроизводительных методов оценки HLA, основанные на мультиплексных аналитических технологиях NGS были разработаны на основе различных технологических платформ. В этом обзоре мы обсуждаем возможные области применения и прогресс в оборудовании для NGS в плане глубокого типирования системы HLA, с особым вниманием к будущим аспектам его клинического использования. Общеизвестный полиморфизм генов HLA и минимальные межаллельные различия представляют собой особую проблему. Поэтому некоторые вопросы, связанные с биоинформатикой и углубленной обработкой данных для более эффективного анализа HLA в контексте оценки совместимости донора и реципиента. В этом плане различными производителями предложены специализированные компьютерные программы для анализа больших баз данных, получаемых посредством технологий NGS. Наконец, эти высокопроизводительные подходы позволяют минимизировать финансовые затраты на 1 образец, особенно в крупных HLA-лабораториях, где соответствующие расходы на NGS-исследования стали теперь значительно затрат, возникающих при использовании классических технологий секвенирования по Сэнгеру.
                    [TYPE] => HTML
                )

            [~DESCRIPTION] => 
            [~NAME] => Описание/Резюме
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [DOI] => Array
        (
            [ID] => 28
            [TIMESTAMP_X] => 2016-04-06 14:11:12
            [IBLOCK_ID] => 2
            [NAME] => DOI
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => DOI
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 80
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 28
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => 
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 8421
            [VALUE] => 10.18620/ctt-1866-8836-2016-5-4-63-70
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 10.18620/ctt-1866-8836-2016-5-4-63-70
            [~DESCRIPTION] => 
            [~NAME] => DOI
            [~DEFAULT_VALUE] => 
        )

    [AUTHOR_EN] => Array
        (
            [ID] => 37
            [TIMESTAMP_X] => 2015-09-02 18:02:59
            [IBLOCK_ID] => 2
            [NAME] => Author
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => AUTHOR_EN
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 37
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8422
            [VALUE] => Array
                (
                    [TEXT] => <sup>1</sup>Youri A. Serov, <sup>1</sup>Ildar M. Barkhatov, <sup>1</sup>Anton S. Klimov, <sup>2</sup>Andrey S. Berkos
                    [TYPE] => HTML
                )

            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [TEXT] => 1Youri A. Serov, 1Ildar M. Barkhatov, 1Anton S. Klimov, 2Andrey S. Berkos
                    [TYPE] => HTML
                )

            [~DESCRIPTION] => 
            [~NAME] => Author
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [ORGANIZATION_EN] => Array
        (
            [ID] => 38
            [TIMESTAMP_X] => 2015-09-02 18:02:59
            [IBLOCK_ID] => 2
            [NAME] => Organization
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => ORGANIZATION_EN
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 38
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8423
            [VALUE] => Array
                (
                    [TEXT] => <sup>1</sup>Research Institute of Children Oncology, Hematology and Transplantation, The First State I. Pavlov Medical University,<br>
 St. Petersburg, Russia<br>
 <sup>2</sup>Russian Research Institute of Hematology and Transfusiology, Federal Medical-Biological Agency, St. Petersburg, Russia<br>
 <br>
 Youri A. Serov, MD, Ph. D., CHS(ABHI), The Head of Biobank<br>
 Research Unit, Raisa Gorbacheva Memorial Institute of Children’s<br>
 Hematology, Oncology and Transplantation, The First<br>
 St. Petersburg I. P. Pavlov State Medical University, Leo Tolstoy<br>
 str. 6-8, 197022, St. Petersburg, Russia<br>
 <br>
 Phone: +7(812) 338-6260 (office); +7(981) 973-8041 (mob.)<br>
                    [TYPE] => HTML
                )

            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [TEXT] => 1Research Institute of Children Oncology, Hematology and Transplantation, The First State I. Pavlov Medical University,

 St. Petersburg, Russia

 2Russian Research Institute of Hematology and Transfusiology, Federal Medical-Biological Agency, St. Petersburg, Russia

 

 Youri A. Serov, MD, Ph. D., CHS(ABHI), The Head of Biobank

 Research Unit, Raisa Gorbacheva Memorial Institute of Children’s

 Hematology, Oncology and Transplantation, The First

 St. Petersburg I. P. Pavlov State Medical University, Leo Tolstoy

 str. 6-8, 197022, St. Petersburg, Russia

 

 Phone: +7(812) 338-6260 (office); +7(981) 973-8041 (mob.)

                    [TYPE] => HTML
                )

            [~DESCRIPTION] => 
            [~NAME] => Organization
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [SUMMARY_EN] => Array
        (
            [ID] => 39
            [TIMESTAMP_X] => 2015-09-02 18:02:59
            [IBLOCK_ID] => 2
            [NAME] => Description / Summary
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => SUMMARY_EN
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 39
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8424
            [VALUE] => Array
                (
                    [TEXT] => The region encoding human leukocyte antigens (HLA) is a 3.6-Mb segment at chromosome 6p21. A highly complex HLA system comprises important molecules involved in transplantation immunity, classical direct sequencing methods making it very complicating to resolve the genomic specificities of HLA genes, due of the complex nature of them. Current limitations of existing methods and the increasing rate of new alleles, strongly demanding for a new methodology approach for the HLA genotyping. Next-Generation Sequencing (NGS) is a method that can provide a complete solution to the HLA typing problem. Last decade, the development of (NGS) has shown the easy way for whole-genome analysis in individuals. HLA typing has also benefited from NGS technologies. Several high-throughput HLA- NGS-based typing methods were developed using different technological platforms. In this review, we summarize the possible applications and instrumentation developments of NGS in the in-depth HLA typing, with a focus on future clinical applications. However, some issues of bioinformatics and data mining remain an obstacle to more effective analysis of HLA analysis in the context of donor/recipient compatibility assessment.
                    [TYPE] => HTML
                )

            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [TEXT] => The region encoding human leukocyte antigens (HLA) is a 3.6-Mb segment at chromosome 6p21. A highly complex HLA system comprises important molecules involved in transplantation immunity, classical direct sequencing methods making it very complicating to resolve the genomic specificities of HLA genes, due of the complex nature of them. Current limitations of existing methods and the increasing rate of new alleles, strongly demanding for a new methodology approach for the HLA genotyping. Next-Generation Sequencing (NGS) is a method that can provide a complete solution to the HLA typing problem. Last decade, the development of (NGS) has shown the easy way for whole-genome analysis in individuals. HLA typing has also benefited from NGS technologies. Several high-throughput HLA- NGS-based typing methods were developed using different technological platforms. In this review, we summarize the possible applications and instrumentation developments of NGS in the in-depth HLA typing, with a focus on future clinical applications. However, some issues of bioinformatics and data mining remain an obstacle to more effective analysis of HLA analysis in the context of donor/recipient compatibility assessment.
                    [TYPE] => HTML
                )

            [~DESCRIPTION] => 
            [~NAME] => Description / Summary
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [NAME_EN] => Array
        (
            [ID] => 40
            [TIMESTAMP_X] => 2015-09-03 10:49:47
            [IBLOCK_ID] => 2
            [NAME] => Name
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => NAME_EN
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 80
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 40
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => Y
            [VERSION] => 1
            [USER_TYPE] => 
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 8425
            [VALUE] => Current methods and opportunities of next-generation sequencing (NGS) for HLA typing
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Current methods and opportunities of next-generation sequencing (NGS) for HLA typing
            [~DESCRIPTION] => 
            [~NAME] => Name
            [~DEFAULT_VALUE] => 
        )

    [FULL_TEXT_RU] => Array
        (
            [ID] => 42
            [TIMESTAMP_X] => 2015-09-07 20:29:18
            [IBLOCK_ID] => 2
            [NAME] => Полный текст
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => FULL_TEXT_RU
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 42
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 
            [VALUE] => 
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 
            [~DESCRIPTION] => 
            [~NAME] => Полный текст
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [PDF_RU] => Array
        (
            [ID] => 43
            [TIMESTAMP_X] => 2015-09-09 16:05:20
            [IBLOCK_ID] => 2
            [NAME] => PDF RUS
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => PDF_RU
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => F
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 43
            [FILE_TYPE] => doc, txt, rtf, pdf
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => 
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 8472
            [VALUE] => 278
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 278
            [~DESCRIPTION] => 
            [~NAME] => PDF RUS
            [~DEFAULT_VALUE] => 
        )

    [PDF_EN] => Array
        (
            [ID] => 44
            [TIMESTAMP_X] => 2015-09-09 16:05:20
            [IBLOCK_ID] => 2
            [NAME] => PDF ENG
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => PDF_EN
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => F
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 44
            [FILE_TYPE] => doc, txt, rtf, pdf
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => 
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 8473
            [VALUE] => 279
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 279
            [~DESCRIPTION] => 
            [~NAME] => PDF ENG
            [~DEFAULT_VALUE] => 
        )

    [NAME_LONG] => Array
        (
            [ID] => 45
            [TIMESTAMP_X] => 2023-04-13 00:55:00
            [IBLOCK_ID] => 2
            [NAME] => Название (для очень длинных заголовков)
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => NAME_LONG
            [DEFAULT_VALUE] => Array
                (
                    [TYPE] => HTML
                    [TEXT] => 
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 45
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 80
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 
            [VALUE] => 
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 
            [~DESCRIPTION] => 
            [~NAME] => Название (для очень длинных заголовков)
            [~DEFAULT_VALUE] => Array
                (
                    [TYPE] => HTML
                    [TEXT] => 
                )

        )

)
					

						Array
(
    [KEYWORDS] => Array
        (
            [ID] => 19
            [TIMESTAMP_X] => 2015-09-03 10:46:01
            [IBLOCK_ID] => 2
            [NAME] => Ключевые слова
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => KEYWORDS
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => E
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => Y
            [XML_ID] => 19
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 4
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => Y
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => EAutocomplete
            [USER_TYPE_SETTINGS] => Array
                (
                    [VIEW] => E
                    [SHOW_ADD] => Y
                    [MAX_WIDTH] => 0
                    [MIN_HEIGHT] => 24
                    [MAX_HEIGHT] => 1000
                    [BAN_SYM] => ,;
                    [REP_SYM] =>  
                    [OTHER_REP_SYM] => 
                    [IBLOCK_MESS] => Y
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => Array
                (
                    [0] => 8474
                    [1] => 8475
                    [2] => 8476
                    [3] => 8477
                )

            [VALUE] => Array
                (
                    [0] => 696
                    [1] => 697
                    [2] => 698
                    [3] => 699
                )

            [DESCRIPTION] => Array
                (
                    [0] => 
                    [1] => 
                    [2] => 
                    [3] => 
                )

            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [0] => 696
                    [1] => 697
                    [2] => 698
                    [3] => 699
                )

            [~DESCRIPTION] => Array
                (
                    [0] => 
                    [1] => 
                    [2] => 
                    [3] => 
                )

            [~NAME] => Ключевые слова
            [~DEFAULT_VALUE] => 
        )

    [SUBMITTED] => Array
        (
            [ID] => 20
            [TIMESTAMP_X] => 2015-09-02 17:21:42
            [IBLOCK_ID] => 2
            [NAME] => Дата подачи
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => SUBMITTED
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 20
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => DateTime
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 8445
            [VALUE] => 10.10.2016
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 10.10.2016
            [~DESCRIPTION] => 
            [~NAME] => Дата подачи
            [~DEFAULT_VALUE] => 
        )

    [ACCEPTED] => Array
        (
            [ID] => 21
            [TIMESTAMP_X] => 2015-09-02 17:21:42
            [IBLOCK_ID] => 2
            [NAME] => Дата принятия
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => ACCEPTED
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 21
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => DateTime
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 8446
            [VALUE] => 25.11.2016
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 25.11.2016
            [~DESCRIPTION] => 
            [~NAME] => Дата принятия
            [~DEFAULT_VALUE] => 
        )

    [PUBLISHED] => Array
        (
            [ID] => 22
            [TIMESTAMP_X] => 2015-09-02 17:21:42
            [IBLOCK_ID] => 2
            [NAME] => Дата публикации
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => PUBLISHED
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 22
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => DateTime
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 
            [VALUE] => 
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 
            [~DESCRIPTION] => 
            [~NAME] => Дата публикации
            [~DEFAULT_VALUE] => 
        )

    [CONTACT] => Array
        (
            [ID] => 23
            [TIMESTAMP_X] => 2015-09-03 14:43:05
            [IBLOCK_ID] => 2
            [NAME] => Контакт
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => CONTACT
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => E
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 23
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 3
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => Y
            [VERSION] => 1
            [USER_TYPE] => EAutocomplete
            [USER_TYPE_SETTINGS] => Array
                (
                    [VIEW] => E
                    [SHOW_ADD] => Y
                    [MAX_WIDTH] => 0
                    [MIN_HEIGHT] => 24
                    [MAX_HEIGHT] => 1000
                    [BAN_SYM] => ,;
                    [REP_SYM] =>  
                    [OTHER_REP_SYM] => 
                    [IBLOCK_MESS] => N
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8447
            [VALUE] => 695
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 695
            [~DESCRIPTION] => 
            [~NAME] => Контакт
            [~DEFAULT_VALUE] => 
        )

    [AUTHORS] => Array
        (
            [ID] => 24
            [TIMESTAMP_X] => 2015-09-03 10:45:07
            [IBLOCK_ID] => 2
            [NAME] => Авторы
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => AUTHORS
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => E
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => Y
            [XML_ID] => 24
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 3
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => Y
            [VERSION] => 1
            [USER_TYPE] => EAutocomplete
            [USER_TYPE_SETTINGS] => Array
                (
                    [VIEW] => E
                    [SHOW_ADD] => Y
                    [MAX_WIDTH] => 0
                    [MIN_HEIGHT] => 24
                    [MAX_HEIGHT] => 1000
                    [BAN_SYM] => ,;
                    [REP_SYM] =>  
                    [OTHER_REP_SYM] => 
                    [IBLOCK_MESS] => N
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => Array
                (
                    [0] => 8478
                )

            [VALUE] => Array
                (
                    [0] => 695
                )

            [DESCRIPTION] => Array
                (
                    [0] => 
                )

            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [0] => 695
                )

            [~DESCRIPTION] => Array
                (
                    [0] => 
                )

            [~NAME] => Авторы
            [~DEFAULT_VALUE] => 
        )

    [AUTHOR_RU] => Array
        (
            [ID] => 25
            [TIMESTAMP_X] => 2015-09-02 18:01:20
            [IBLOCK_ID] => 2
            [NAME] => Авторы
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => AUTHOR_RU
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 25
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8449
            [VALUE] => Array
                (
                    [TEXT] => Ильдар М. Бархатов, Николай Ю. Цветков, Даниил Е. Ершов, Марина Ю. Лаврухина, Алена И. Шакирова, Алиса Я.<br>
 Поттер, Анна Г. Смирнова, Людмила С. Зубаровская, Борис В. Афанасьев<br>
                    [TYPE] => HTML
                )

            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [TEXT] => Ильдар М. Бархатов, Николай Ю. Цветков, Даниил Е. Ершов, Марина Ю. Лаврухина, Алена И. Шакирова, Алиса Я.

 Поттер, Анна Г. Смирнова, Людмила С. Зубаровская, Борис В. Афанасьев

                    [TYPE] => HTML
                )

            [~DESCRIPTION] => 
            [~NAME] => Авторы
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [ORGANIZATION_RU] => Array
        (
            [ID] => 26
            [TIMESTAMP_X] => 2015-09-02 18:01:20
            [IBLOCK_ID] => 2
            [NAME] => Организации
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => ORGANIZATION_RU
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 26
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8450
            [VALUE] => Array
                (
                    [TEXT] => Первый Санкт-Петербургский государственный медицинский Университет им. акад. И. П. Павлова Министерства<br>
 Здравоохранения РФ, Санкт-Петербург, Россия<br>
                    [TYPE] => HTML
                )

            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [TEXT] => Первый Санкт-Петербургский государственный медицинский Университет им. акад. И. П. Павлова Министерства

 Здравоохранения РФ, Санкт-Петербург, Россия

                    [TYPE] => HTML
                )

            [~DESCRIPTION] => 
            [~NAME] => Организации
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [SUMMARY_RU] => Array
        (
            [ID] => 27
            [TIMESTAMP_X] => 2015-09-02 18:01:20
            [IBLOCK_ID] => 2
            [NAME] => Описание/Резюме
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => SUMMARY_RU
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 27
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8451
            [VALUE] => Array
                (
                    [TEXT] => Наблюдаемая в ряде случаев гипофункция транс-
плантата является нередкой и обусловливает не-
обходимость разработки функциональных тестов
исследования клеток стромы с целью обоснования
показаний к совместной трансплантации гемопоэ-
тических и стромальных клеток костного мозга. Це-
лью данного исследования являлось изучение роли
стромальных клеток костного мозга в процессе при-
живления донорского костного мозга и их значения
в развитии осложнений после ТГСК. При анализе
функциональных характеристик стромальных кле-
ток у 38 реципиентов аллогенного трансплантата ге-
мопоэтических стволовых клеток было показано уве-
личение активности остеогенной дифференцировки
на фоне укорочения сроков восстановления кро-
ветворения. Вместе с тем, наличие более выражен-
ной способности к адипогенной дифференцировке
ассоциировано с меньшей вероятностью развития
гипофункции трансплантата. При исследовании ге-
мостимулирующей активности стромальных клеток
реципиента были отмечены факты, указывающие
на преимущественное влияние короткодистантных
ростовых факторов на посттрансплантационную
реконституцию гемопоэза. При этом более выра-
женная экспрессия молекул, опосредующих хоу-
минг ГСК в стромальных клетках реципиента перед
трансплантацией ассоциировано с более быстрым
восстановлением гемопоэза у трансплантированных
больных.
                    [TYPE] => HTML
                )

            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [TEXT] => Наблюдаемая в ряде случаев гипофункция транс-
плантата является нередкой и обусловливает не-
обходимость разработки функциональных тестов
исследования клеток стромы с целью обоснования
показаний к совместной трансплантации гемопоэ-
тических и стромальных клеток костного мозга. Це-
лью данного исследования являлось изучение роли
стромальных клеток костного мозга в процессе при-
живления донорского костного мозга и их значения
в развитии осложнений после ТГСК. При анализе
функциональных характеристик стромальных кле-
ток у 38 реципиентов аллогенного трансплантата ге-
мопоэтических стволовых клеток было показано уве-
личение активности остеогенной дифференцировки
на фоне укорочения сроков восстановления кро-
ветворения. Вместе с тем, наличие более выражен-
ной способности к адипогенной дифференцировке
ассоциировано с меньшей вероятностью развития
гипофункции трансплантата. При исследовании ге-
мостимулирующей активности стромальных клеток
реципиента были отмечены факты, указывающие
на преимущественное влияние короткодистантных
ростовых факторов на посттрансплантационную
реконституцию гемопоэза. При этом более выра-
женная экспрессия молекул, опосредующих хоу-
минг ГСК в стромальных клетках реципиента перед
трансплантацией ассоциировано с более быстрым
восстановлением гемопоэза у трансплантированных
больных.
                    [TYPE] => HTML
                )

            [~DESCRIPTION] => 
            [~NAME] => Описание/Резюме
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [DOI] => Array
        (
            [ID] => 28
            [TIMESTAMP_X] => 2016-04-06 14:11:12
            [IBLOCK_ID] => 2
            [NAME] => DOI
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => DOI
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 80
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 28
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => 
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 8452
            [VALUE] => 10.18620/ctt-1866-8836-2016-5-4-71-77
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 10.18620/ctt-1866-8836-2016-5-4-71-77
            [~DESCRIPTION] => 
            [~NAME] => DOI
            [~DEFAULT_VALUE] => 
        )

    [AUTHOR_EN] => Array
        (
            [ID] => 37
            [TIMESTAMP_X] => 2015-09-02 18:02:59
            [IBLOCK_ID] => 2
            [NAME] => Author
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => AUTHOR_EN
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 37
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8453
            [VALUE] => Array
                (
                    [TEXT] => Ildar M. Barkhatov, Nikolay Yu Tsvetkov, Daniil E. Ershov, Marina Y. Lavrukhina, Alena I. Shakirova, Alisa Ya. Potter,<br>
 Anna G. Smirnova, Ludmila S. Zubarovskaya, Boris V. Afanasyev<br>
                    [TYPE] => HTML
                )

            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [TEXT] => Ildar M. Barkhatov, Nikolay Yu Tsvetkov, Daniil E. Ershov, Marina Y. Lavrukhina, Alena I. Shakirova, Alisa Ya. Potter,

 Anna G. Smirnova, Ludmila S. Zubarovskaya, Boris V. Afanasyev

                    [TYPE] => HTML
                )

            [~DESCRIPTION] => 
            [~NAME] => Author
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [ORGANIZATION_EN] => Array
        (
            [ID] => 38
            [TIMESTAMP_X] => 2015-09-02 18:02:59
            [IBLOCK_ID] => 2
            [NAME] => Organization
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => ORGANIZATION_EN
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 38
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8454
            [VALUE] => Array
                (
                    [TEXT] => R. M. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, and Chair of Hematology,<br>
 Transfusiology and Transplantation, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russian<br>
 Federation<br>
 <br>
 Dr. Ildar M.Barkhatov, PhD, Laboratory Head, R. M. Gorbacheva<br>
 Memorial Research Institute of Children Oncology,<br>
 Hematology and Transplantation, The First St. Petersburg<br>
 State I. Pavlov Medical University, L.Tolstoy St. 6/8, 197022,<br>
 St. Petersburg, Russian Federation<br>
 <br>
 Phone: +7(911) 778 2785<br>
 E-mail: <a href="mailto:i.barkhatov@gmail.com">i.barkhatov@gmail.com</a><br>
                    [TYPE] => HTML
                )

            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [TEXT] => R. M. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, and Chair of Hematology,

 Transfusiology and Transplantation, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russian

 Federation

 

 Dr. Ildar M.Barkhatov, PhD, Laboratory Head, R. M. Gorbacheva

 Memorial Research Institute of Children Oncology,

 Hematology and Transplantation, The First St. Petersburg

 State I. Pavlov Medical University, L.Tolstoy St. 6/8, 197022,

 St. Petersburg, Russian Federation

 

 Phone: +7(911) 778 2785

 E-mail: i.barkhatov@gmail.com

                    [TYPE] => HTML
                )

            [~DESCRIPTION] => 
            [~NAME] => Organization
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [SUMMARY_EN] => Array
        (
            [ID] => 39
            [TIMESTAMP_X] => 2015-09-02 18:02:59
            [IBLOCK_ID] => 2
            [NAME] => Description / Summary
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => SUMMARY_EN
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 39
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 8455
            [VALUE] => Array
                (
                    [TEXT] => Functional insufficiency of stem cell grafts is not rare in
hematopoietic stem cell transplantation (HSCT), thus
requiring further development of functional tests for recipient’s
stromal cells, in order to substantiate clinical indications
for co-transplantation of hematopoietic and
stromal bone marrow cells. The aim of this study was to
investigate a role of bone marrow stromal cells (BMSC) in
the donor bone marrow engraftment, and their importance
for development of complications after HSCT. Functional
analysis of BMSC cultures from thirty-eight recipients of
allogeneic hematopoietic stem cells has been shown that
induced osteogenic differentiation correlated with faster
hematopoiesis recovery in transplanted patients. Moreover,
a pronounced ability for adipogenic differentiation proved
to be associated with lower probability of the graft hypofunction.
A pronounced hemostimulatory activity of stromal
cells was observed in our study, thus suggesting effects
of short-range hematopoietic growth factors from BMSC
upon hematopoietic reconstitution. At the same time, a
more pronounced pre-transplant expression of molecules
which promote donor HSC homing by the recipient stromal
cells was associated with faster hematopoietic recovery
after transplantation.
                    [TYPE] => HTML
                )

            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Array
                (
                    [TEXT] => Functional insufficiency of stem cell grafts is not rare in
hematopoietic stem cell transplantation (HSCT), thus
requiring further development of functional tests for recipient’s
stromal cells, in order to substantiate clinical indications
for co-transplantation of hematopoietic and
stromal bone marrow cells. The aim of this study was to
investigate a role of bone marrow stromal cells (BMSC) in
the donor bone marrow engraftment, and their importance
for development of complications after HSCT. Functional
analysis of BMSC cultures from thirty-eight recipients of
allogeneic hematopoietic stem cells has been shown that
induced osteogenic differentiation correlated with faster
hematopoiesis recovery in transplanted patients. Moreover,
a pronounced ability for adipogenic differentiation proved
to be associated with lower probability of the graft hypofunction.
A pronounced hemostimulatory activity of stromal
cells was observed in our study, thus suggesting effects
of short-range hematopoietic growth factors from BMSC
upon hematopoietic reconstitution. At the same time, a
more pronounced pre-transplant expression of molecules
which promote donor HSC homing by the recipient stromal
cells was associated with faster hematopoietic recovery
after transplantation.
                    [TYPE] => HTML
                )

            [~DESCRIPTION] => 
            [~NAME] => Description / Summary
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [NAME_EN] => Array
        (
            [ID] => 40
            [TIMESTAMP_X] => 2015-09-03 10:49:47
            [IBLOCK_ID] => 2
            [NAME] => Name
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => NAME_EN
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 80
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 40
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => Y
            [VERSION] => 1
            [USER_TYPE] => 
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 8456
            [VALUE] => Impact of recipient marrow stromal cells functional characteristics on engraftment after allo-HSCT
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => Impact of recipient marrow stromal cells functional characteristics on engraftment after allo-HSCT
            [~DESCRIPTION] => 
            [~NAME] => Name
            [~DEFAULT_VALUE] => 
        )

    [FULL_TEXT_RU] => Array
        (
            [ID] => 42
            [TIMESTAMP_X] => 2015-09-07 20:29:18
            [IBLOCK_ID] => 2
            [NAME] => Полный текст
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => FULL_TEXT_RU
            [DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 42
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 200
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 
            [VALUE] => 
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 
            [~DESCRIPTION] => 
            [~NAME] => Полный текст
            [~DEFAULT_VALUE] => Array
                (
                    [TEXT] => 
                    [TYPE] => HTML
                )

        )

    [PDF_RU] => Array
        (
            [ID] => 43
            [TIMESTAMP_X] => 2015-09-09 16:05:20
            [IBLOCK_ID] => 2
            [NAME] => PDF RUS
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => PDF_RU
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => F
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 43
            [FILE_TYPE] => doc, txt, rtf, pdf
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => 
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 8479
            [VALUE] => 280
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 280
            [~DESCRIPTION] => 
            [~NAME] => PDF RUS
            [~DEFAULT_VALUE] => 
        )

    [PDF_EN] => Array
        (
            [ID] => 44
            [TIMESTAMP_X] => 2015-09-09 16:05:20
            [IBLOCK_ID] => 2
            [NAME] => PDF ENG
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => PDF_EN
            [DEFAULT_VALUE] => 
            [PROPERTY_TYPE] => F
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 44
            [FILE_TYPE] => doc, txt, rtf, pdf
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => 
            [USER_TYPE_SETTINGS] => 
            [HINT] => 
            [PROPERTY_VALUE_ID] => 8480
            [VALUE] => 281
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 281
            [~DESCRIPTION] => 
            [~NAME] => PDF ENG
            [~DEFAULT_VALUE] => 
        )

    [NAME_LONG] => Array
        (
            [ID] => 45
            [TIMESTAMP_X] => 2023-04-13 00:55:00
            [IBLOCK_ID] => 2
            [NAME] => Название (для очень длинных заголовков)
            [ACTIVE] => Y
            [SORT] => 500
            [CODE] => NAME_LONG
            [DEFAULT_VALUE] => Array
                (
                    [TYPE] => HTML
                    [TEXT] => 
                )

            [PROPERTY_TYPE] => S
            [ROW_COUNT] => 1
            [COL_COUNT] => 30
            [LIST_TYPE] => L
            [MULTIPLE] => N
            [XML_ID] => 45
            [FILE_TYPE] => 
            [MULTIPLE_CNT] => 5
            [TMP_ID] => 
            [LINK_IBLOCK_ID] => 0
            [WITH_DESCRIPTION] => N
            [SEARCHABLE] => N
            [FILTRABLE] => N
            [IS_REQUIRED] => N
            [VERSION] => 1
            [USER_TYPE] => HTML
            [USER_TYPE_SETTINGS] => Array
                (
                    [height] => 80
                )

            [HINT] => 
            [PROPERTY_VALUE_ID] => 
            [VALUE] => 
            [DESCRIPTION] => 
            [VALUE_ENUM] => 
            [VALUE_XML_ID] => 
            [VALUE_SORT] => 
            [~VALUE] => 
            [~DESCRIPTION] => 
            [~NAME] => Название (для очень длинных заголовков)
            [~DEFAULT_VALUE] => Array
                (
                    [TYPE] => HTML
                    [TEXT] => 
                )

        )

)