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Introduction

Ornithine transcarbamylase deficiency (OTCD) is an X-linked genetic urea cycle disorder (UCD) caused by the mutation of the ornithine transcarbamylase (OTC, Xp2.1) gene. OTC is a mitochondrial enzyme synthesized in the cytoplasm. Following OTC transfer to the mitochondria, carbamoyl phosphate and ornithine are catalytically converted to citrulline. Then citrulline is transported to the cytoplasm to participate in the urea cycle reactions. The OTC gene mutations block normal urea metabolism. Therefore, increased blood ammonia, decreased blood citrulline and increased urine orotic acid are typical biochemical phenotypes of OTCD. High blood ammonia could cause the nervous system damage, epilepsy-like symptoms, disturbed consciousness, and cognitive impairment appear.

Early-onset OTCD mainly occurs in male heterozygous infants, usually with a rapid onset and a high mortality in the neonatal period [1]. The patient can be normal at birth. Then irritability, deteriorating feeding, drowsiness and tachypnea appear soon. It often develops into metabolic encephalopathy rapidly and leads to death if treatment is not applied. Severe intellectual impairment will be left in survivors due to the extensive damage to the brain caused by elevated blood ammonia [2]. Late-onset OTCD can occur in hemizygous males and heterozygous females. The clinical symptoms are variable and mild compared with early-onset OTCD.

The main principle of treatment is to control diet, reduce protein intake, avoid hyperammonemia, and use drugs to promote blood ammonia metabolism. However, excessive restriction of protein intake can lead to hypertrophy of endogenous protein catabolism, increase blood ammonia, and affect the patient's intelligence and physical development [3]. If the drug treatment is not effective, dialysis treatment should be considered as soon as possible.

Liver transplantation (LTx) is the most effective treatment of this disease, since OTC activity is mainly expressed in liver tissue. In these cases, the patients can stop anti-hyperammonemia drugs and return to normal diet after LTx. Hyperammonemia will not occur again, and the quality of life is significantly improved [4, 5]. Though LTx can correct the patient's urea cycle disorder and reduce blood ammonia substantially, it cannot reverse the nervous system damage that has occurred before LTx [5].

Indications for surgery

For the neonatal-onset patients, LTx should be performed as soon as possible if the patient’s condition is stable, independently on the blood ammonia levels. Considering the patient's tolerance for surgery and the risk of post-transplant hyperammonemia, the age of 3 months to 1 year, or body mass of >5 kg are appropriate pre-requisites for surgery [3]. It is usually done at six months of age. Early transplantation in the neonatal-onset patients may be associated with normal neurodevelopment compared with those without LTx.

For late-onset patients, it is now generally believed that, even with mild current manifestations, there is a risk of sudden, potentially life-threatening hyperammonemia at any age. Therefore, surgery should be considered for any OTCD patient. Final decision of LTx depends on the individual circumstances.

The peak of death with OTCD is noted at the age of 12-15 years in female patients, thus considering LTx before that time [6]. LTx in adolescents may also promote normal neurodevelopment. The patients should undergo LTx at peak blood ammonia levels of >300 μmol/L [7]. In cases of severe progressive liver disease, repeated metabolic abnormalities after standard treatment or poor compliance with current treatment, LTx can be also performed [3].

Analysis of data on the patients under 18 year subjected to LTx between February 2002 and September 2020, the waiting list time and male sex were associated with long-term risk for a cognitive delay. Minimizing the waiting time is quite important, in order to maintain the patient's cognition capacities at later terms and improve the quality of life [8].

All the patients with OTCD should be considered for LTx to prevent progressive neurological injury. But the decision is usually taken in cases of unstable condition and frequent episodes of hyperammonemia.

Donor selection

Liver transplants from either living or deceased donors are acceptable for the children of 1.5 to 3.0 years old. Three patients received cadaveric LTx at this age period. They developed well after this operation, and no recurrences were observed within follow-up for 13 years [9].

LTx from living donors is the most effective method in these cases. Living donors for the LTx should be in healthy condition, but sometimes there is no time to wait for another donor, except for subjects heterozygous for the mutated gene. A symptom-free carrier may be a donor for LTx, if OTC enzyme activity is high enough, and if no other options exist. The mutation carrier must undergo careful and comprehensive examination. OTC activity in liver biopsy samples must be tested to determine the suitability of heterozygote to be a donor [10]. According to Wakiya, T, the OTC activity of late-onset patients requiring LTx, ranges from 4.4% to 18.7%. Meanwhile, in those cases where LTx is not necessary, the residual enzyme activity ranges from 33% to 38% [11]. Rahayatri et al. [12] reported two 5-year-old girls who received liver transplants from heterozygous mutation carriers. The OTC activity in the first case and in her donor was 15% and 62%, respectively. She developed hyperammonemia within 2 months after the surgery. OTC activity in the second case and the donor was 9.7% and 42.6%, respectively. She developed hyperammonemia within 12 days after the surgery. Following continuous intravenous/venous hemodialysis, they were performing well without intensive care [12].

However, this method has potential risks. The enzyme activity in selected biopsy samples cannot represent its activity in other parts of the liver. Hence, one cannot accurately predict, whether the transplanted liver lobe exhibits sufficient activity, nor to predict whether total enzyme activity retained in the left liver is sufficient for heterozygous carrier donors.

Transplantation of hepatocytes may be another treatment option. Enosawa et al. reported an 11-day-old baby who underwent hepatocyte transplantation. The patient needed urgent LTx, but there was no source of liver, thus requiring hepatocyte transplantation. The patient was later in good condition and without recurrence within 3 months after the operation [13]. For the patients with poor overall clinical conditions, hepatocyte transplantation is less risky than liver grafting. Following hepatocyte transplantation, biochemical parameters of a 12-year-old patient with repeated metabolic decompensation showed decreased levels of plasma ammonia and increased urea production. However, the patient died because of a nosocomial fungal sepsis [14].

Surgical methods

Orthotopic LTx is still the best choice in OTCD. It has fewer complications than auxiliary LTx [5]. Over recent years, a domino cross-auxiliary LTx has been tried in the clinical setting. This method is based on exchanging part of liver tissue with patients suffering from other metabolic diseases aiming to achieve metabolic complementation. It does not require additional organ donation. Of the three OTCD patients in China, subjected to domino cross-auxiliary LTx, two cases recovered well after the operation, without any complications during the follow-up period. One patient experienced occult graft rejection resulting into graft dysfunction and eventual disease recurrence [15]. The domino cross-auxiliary LTx is a feasible method, without any problems caused by the operation itself.

Post-transplant management

Due to long-term therapy with immunosuppressive drugs and postoperative weakness, one should notice prevention of postsurgical infections, which may cause failure of this intervention and death of the patient.

Following transplantation, the liver function should be tested regularly, to discern graft injury. The graft-derived cell-free DNA in blood may be of similar discriminative value, it was also able to differentiate between the trend for graft injury and normal liver function. However, this technique is not as convenient as routine liver function tests [16]. The peak blood ammonia level of >356 μmol/L predicted poor neurodevelopmental outcomes in the patients undergoing LTx [17].

Clinical effect

According to the data from United Network for Organ Sharing (UNOS) database including 403 patients with urea cycle disorders (46.2% were OTCD) who underwent transplantation, the 1-, 3-, and 5-year graft survival rates were 90.4%, 86.3%, and 85.2%, respectively. Increased mass of the liver graft and male sex are related to decreased risk of graft loss [8]. In Japan, the 1-, 5-, 10-, and 15-year graft survival rates comprised 91.2%, 87.9%, 87.0%, and 79.3% among pediatric patients with metabolic disorders (OTCD, 20.6% of total) as shown by Kasahara et al. [18].

The 1-, 5-, and 10-year overall survival rates among 278 UCD patients who underwent LTx between 1987 and 2010 were 93%, 89%, and 87%, respectively, according to the UNOS database [19]. However, the article only stated that most UCD patients are OTCD, without any specific data on OTCD patients.

13 of 69 Chinese OTCD patients received LTx, at a median age of 3 years and one-year survival rate of 100% [20]. In Japan, the 1-, 5-, 10- and 15-year survival rates in 194 pediatric patients with metabolic disorders (OTCD=40) who underwent living donor LTx, were 91.2%, 87.9%, 86.1%, and 74.4% [18].

Hence, LTx can improve long-term survival rates of the patients, prevent recurrent hyperammonemia, and reduce the blood ammonia level. However, it did not improve neurodevelopmental outcomes in the patients with severe symptomatics, because hyperammonemia exerts early brain damage. Urgent LTx in another UCD, i.e., arginine succinate synthase deficiency, may improve the longitudinal cognitive and behavioural outcomes [17].

Conclusions

LTx can improve the long-term survival rate of patients with OTCD, but it cannot reverse the nervous system damage that occurred previously, and cannot improve cognitive impairment. However, neurodevelopment may normally proceed after LTx if it is performed early in childhood. The patients with late-onset disease should also be transplanted when required. Donorship of heterozygote carriers is still risky and should only be used when there are no other options. Hepatocyte transplantation can be tried if necessary. Prevention of infection, long-term monitoring of liver function and blood ammonia are required post-transplant.

Conflict of interest

The authors declare that they have no conflicts of interest.

References

Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr. 2008; 97(10):1420-1425. doi: 10.1111/j.1651-2227.2008.00952.x
Msall M, Batshaw ML, Suss R, Brusilow SW, Mellits ED. Neurologic outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies. N Engl J Med. 1984; 310(23):1500-1505. doi: 10.1056/NEJM198406073102304
Haberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. 2019; 42(6): 1192-1230. doi: 10.1002/jimd.12100
Kim IK, Niemi AK, Krueger C, Bonham CA, Concepcion W, Cowan TM, et al. Liver transplantation for urea cycle disorders in pediatric patients: a single-center experience. Pediatr Transplant. 2013; 17(2): 158-167. doi: 10.1111/petr.12041
Morioka D, Kasahara M, Takada Y, Shirouzu Y, Taira K, Sakamoto S, et al. Current role of liver transplantation for the treatment of urea cycle disorders: a review of the worldwide English literature and 13 cases at Kyoto University. Liver Transpl. 2005; 11(11):1332-1342. doi: 10.1002/lt.20587
Division of Genetics and Metabolism, Child Diseases and Health Care Branch, Chinese Association for Maternal and Child Health. Consensus on diagnosis and treatment of ornithine trans-carbamylase deficiency, J Zhejiang Univ (Med Sci), 2020; 49(5):539-547
(In Chinese). doi: 10.3785/j.issn.1008-9292.2020.04.11
Kido J, Matsumoto S, Mitsubuchi H, Endo F, Nakamura K. Early liver transplantation in neonatal-onset and moderate urea cycle disorders may lead to normal neurodevelopment. Metab Brain Dis. 2018; 33(5): 1517-1523. doi: 10.1007/s11011-018-0259-6
Ziogas IA, Wu WK, Matsuoka LK, Pai AK, Hafberg ET, Gillis LA, et al. Liver transplantation in children with urea cycle disorders: the importance of minimizing waiting time. Liver Transpl. 2021, May 31. doi: 10.1002/lt.26186
Zhu Z, Sun L, Wei L, et al. Liver transplantation for the treatment of hyperammonemia due to urea cycle disorder: report of four cases. Zhonghua Er Ke Za Zhi (Chinese Journal of Pediatrics). 2015; 53(2): 136-139 (In Chinese). doi: 10.1159/000416533
Wakiya T, Sanada Y, Urahashi T, Ihara Y, Yamada N, Okada N, et al. Living donor liver transplantation from an asymptomatic mother who was a carrier for ornithine transcarbamylase deficiency. Pediatr Transplant. 2012; 16(6):E196-200. doi: 10.1111/j.1399-3046.2012.01716.x
Wakiya T, Sanada Y, Urahashi T, Ihara Y, Yamada N, Okada N, et al. Impact of enzyme activity assay on indication in liver transplantation for ornithine transcarbamylase deficiency. Mol Genet Metab. 2012; 105(3): 404-407. doi: 10.1016/j.ymgme.2011.12.019
Rahayatri TH, Uchida H, Sasaki K, Shigeta T, Hirata Y, Kanazawa H, et al. Hyperammonemia in ornithine transcarbamylase-deficient recipients following living donor liver transplantation from heterozygous carrier donors. Pediatr Transplant. 2017; 21(1).
doi: 10.1111/petr.12848
Enosawa S, Horikawa R, Yamamoto A, Sakamoto S, Shigeta T, Nosaka S, et al., Hepatocyte transplantation using a living donor reduced graft in a baby with ornithine transcarbamylase deficiency: a novel source of hepatocytes. Liver Transpl. 2014; 20(3): 391-393. doi: 10.1002/lt.23800
Ribes-Koninckx C, Ibars ER, Calzado Agrasot MA, Bonora-Centelles A, Miquel BP, Vila Carbó JJ, et al. Clinical outcome of hepatocyte transplantation in four pediatric patients with inherited metabolic diseases. Cell Transplant. 2012; 21(10): 2267-2282. doi: 10.3727/096368912X637505
Qu W, Wei L, Zhu ZJ, Sun LY, Liu Y, Zeng ZG. Considerations for use of domino cross-auxiliary liver transplantation in metabolic liver diseases: A review of case studies. Transplantation. 2019; 103(9):1916-1920. doi: 10.1097/TP.0000000000002602
Ng HI, Sun LY, Zhu ZJ. Application of graft-derived cell-free DNA in ornithine transcarbamylase deficiency patient after living donor liver transplantation: Two case reports. Medicine (Baltimore). 2018; 97(51): e13843. doi: 10.1097/MD.0000000000013843
Kido J, Matsumoto S, Haberle J, Inomata Y, Kasahara M, Sakamoto S, et al. Role of liver transplantation in urea cycle disorders: Report from a nationwide study in Japan. J Inherit Metab Dis. 2021. doi: 10.1002/jimd.12415
Kasahara M, Sakamoto S, Horikawa R, Koji U, Mizuta K, Shinkai M, et al. Living donor liver transplantation for pediatric patients with metabolic disorders: the Japanese multicenter registry. Pediatr Transplant. 2014; 18(1): 6-15. doi: 10.1111/petr.12196
Yu L, Rayhill SC, Hsu EK, Landis CS. Liver transplantation for urea cycle disorders: analysis of the united network for organ sharing database. Transplant Proc. 2015; 47(8): 2413-2418. doi: 10.1016/j.transproceed.2015.09.020
Lu D, Han F, Qiu W, Zhang H, Ye J, Liang L, et al. Clinical and molecular characteristics of 69 Chinese patients with ornithine transcarbamylase deficiency. Orphanet J Rare Dis. 2020; 15(1): 340. doi: 10.1186/s13023-020-01606-2

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Introduction

Indications for surgery

Donor selection

Surgical methods

Post-transplant management

Clinical effect

Conclusions

Conflict of interest

The authors declare that they have no conflicts of interest.

References

Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr. 2008; 97(10):1420-1425. doi: 10.1111/j.1651-2227.2008.00952.x
Msall M, Batshaw ML, Suss R, Brusilow SW, Mellits ED. Neurologic outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies. N Engl J Med. 1984; 310(23):1500-1505. doi: 10.1056/NEJM198406073102304
Haberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. 2019; 42(6): 1192-1230. doi: 10.1002/jimd.12100
Kim IK, Niemi AK, Krueger C, Bonham CA, Concepcion W, Cowan TM, et al. Liver transplantation for urea cycle disorders in pediatric patients: a single-center experience. Pediatr Transplant. 2013; 17(2): 158-167. doi: 10.1111/petr.12041
Morioka D, Kasahara M, Takada Y, Shirouzu Y, Taira K, Sakamoto S, et al. Current role of liver transplantation for the treatment of urea cycle disorders: a review of the worldwide English literature and 13 cases at Kyoto University. Liver Transpl. 2005; 11(11):1332-1342. doi: 10.1002/lt.20587
Division of Genetics and Metabolism, Child Diseases and Health Care Branch, Chinese Association for Maternal and Child Health. Consensus on diagnosis and treatment of ornithine trans-carbamylase deficiency, J Zhejiang Univ (Med Sci), 2020; 49(5):539-547
(In Chinese). doi: 10.3785/j.issn.1008-9292.2020.04.11
Kido J, Matsumoto S, Mitsubuchi H, Endo F, Nakamura K. Early liver transplantation in neonatal-onset and moderate urea cycle disorders may lead to normal neurodevelopment. Metab Brain Dis. 2018; 33(5): 1517-1523. doi: 10.1007/s11011-018-0259-6
Ziogas IA, Wu WK, Matsuoka LK, Pai AK, Hafberg ET, Gillis LA, et al. Liver transplantation in children with urea cycle disorders: the importance of minimizing waiting time. Liver Transpl. 2021, May 31. doi: 10.1002/lt.26186
Zhu Z, Sun L, Wei L, et al. Liver transplantation for the treatment of hyperammonemia due to urea cycle disorder: report of four cases. Zhonghua Er Ke Za Zhi (Chinese Journal of Pediatrics). 2015; 53(2): 136-139 (In Chinese). doi: 10.1159/000416533
Wakiya T, Sanada Y, Urahashi T, Ihara Y, Yamada N, Okada N, et al. Living donor liver transplantation from an asymptomatic mother who was a carrier for ornithine transcarbamylase deficiency. Pediatr Transplant. 2012; 16(6):E196-200. doi: 10.1111/j.1399-3046.2012.01716.x
Wakiya T, Sanada Y, Urahashi T, Ihara Y, Yamada N, Okada N, et al. Impact of enzyme activity assay on indication in liver transplantation for ornithine transcarbamylase deficiency. Mol Genet Metab. 2012; 105(3): 404-407. doi: 10.1016/j.ymgme.2011.12.019
Rahayatri TH, Uchida H, Sasaki K, Shigeta T, Hirata Y, Kanazawa H, et al. Hyperammonemia in ornithine transcarbamylase-deficient recipients following living donor liver transplantation from heterozygous carrier donors. Pediatr Transplant. 2017; 21(1).
doi: 10.1111/petr.12848
Enosawa S, Horikawa R, Yamamoto A, Sakamoto S, Shigeta T, Nosaka S, et al., Hepatocyte transplantation using a living donor reduced graft in a baby with ornithine transcarbamylase deficiency: a novel source of hepatocytes. Liver Transpl. 2014; 20(3): 391-393. doi: 10.1002/lt.23800
Ribes-Koninckx C, Ibars ER, Calzado Agrasot MA, Bonora-Centelles A, Miquel BP, Vila Carbó JJ, et al. Clinical outcome of hepatocyte transplantation in four pediatric patients with inherited metabolic diseases. Cell Transplant. 2012; 21(10): 2267-2282. doi: 10.3727/096368912X637505
Qu W, Wei L, Zhu ZJ, Sun LY, Liu Y, Zeng ZG. Considerations for use of domino cross-auxiliary liver transplantation in metabolic liver diseases: A review of case studies. Transplantation. 2019; 103(9):1916-1920. doi: 10.1097/TP.0000000000002602
Ng HI, Sun LY, Zhu ZJ. Application of graft-derived cell-free DNA in ornithine transcarbamylase deficiency patient after living donor liver transplantation: Two case reports. Medicine (Baltimore). 2018; 97(51): e13843. doi: 10.1097/MD.0000000000013843
Kido J, Matsumoto S, Haberle J, Inomata Y, Kasahara M, Sakamoto S, et al. Role of liver transplantation in urea cycle disorders: Report from a nationwide study in Japan. J Inherit Metab Dis. 2021. doi: 10.1002/jimd.12415
Kasahara M, Sakamoto S, Horikawa R, Koji U, Mizuta K, Shinkai M, et al. Living donor liver transplantation for pediatric patients with metabolic disorders: the Japanese multicenter registry. Pediatr Transplant. 2014; 18(1): 6-15. doi: 10.1111/petr.12196
Yu L, Rayhill SC, Hsu EK, Landis CS. Liver transplantation for urea cycle disorders: analysis of the united network for organ sharing database. Transplant Proc. 2015; 47(8): 2413-2418. doi: 10.1016/j.transproceed.2015.09.020
Lu D, Han F, Qiu W, Zhang H, Ye J, Liang L, et al. Clinical and molecular characteristics of 69 Chinese patients with ornithine transcarbamylase deficiency. Orphanet J Rare Dis. 2020; 15(1): 340. doi: 10.1186/s13023-020-01606-2

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Это генетическое нарушение обмена веществ проявляется гипераммониемией. Лекарства и гемодиализ могут снизить уровень аммиака в крови у пациентов. Трансплантация печени может улучшить долгосрочную выживаемость пациентов, но не может излечить необратимые повреждения нервной системы, возникшие ранее, и не может улучшить когнитивные функции. Если трансплантацию печени проводят в раннем детстве, впоследствии нервное развитие может быть нормальным. При необходимости пациентам с поздним дебютом также следует проводить трансплантацию. Гетерозиготность по ДОТК у донора все же представляет существенный риск, и ее следует использовать только тогда, когда нет других вариантов. При необходимости можно попытаться сделать трансплантацию гепатоцитов. После трансплантации необходима профилактика инфекции, длительный контроль функции печени и содержания аммиака в крови. Трансплантация печени должна рассматриваться для всех пациентов с генетическим ДОТК. Окончательное решение о том, следует ли и как использовать этот режим лечения, зависит от индивидуальной клинической ситуации. <h2>Ключевые слова</h2> Дефицит орнитин-транскарбамилазы, нарушение цикла мочевины, трансплантация печени." 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Джингуа Вэй, Бо Хюи

Департамент неврологии, Госпиталь Сиджин, 4-й Военно-Медицинский университет, Сиань, Китай

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Дефицит орнитин-транскарбамилазы (ДОТК) представляет собой наследственное заболевание с нарушением цикла обмена мочевины, характеризующееся высокой летальностью. Это генетическое нарушение обмена веществ проявляется гипераммониемией. Лекарства и гемодиализ могут снизить уровень аммиака в крови у пациентов. Трансплантация печени может улучшить долгосрочную выживаемость пациентов, но не может излечить необратимые повреждения нервной системы, возникшие ранее, и не может улучшить когнитивные функции. Если трансплантацию печени проводят в раннем детстве, впоследствии нервное развитие может быть нормальным. При необходимости пациентам с поздним дебютом также следует проводить трансплантацию. Гетерозиготность по ДОТК у донора все же представляет существенный риск, и ее следует использовать только тогда, когда нет других вариантов. При необходимости можно попытаться сделать трансплантацию гепатоцитов. После трансплантации необходима профилактика инфекции, длительный контроль функции печени и содержания аммиака в крови. Трансплантация печени должна рассматриваться для всех пациентов с генетическим ДОТК. Окончательное решение о том, следует ли и как использовать этот режим лечения, зависит от индивидуальной клинической ситуации.

Ключевые слова

Дефицит орнитин-транскарбамилазы, нарушение цикла мочевины, трансплантация печени.

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Jingya Wei, Bo Hui

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Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, China

Correspondence:
Dr. Jingya Wei, Department of Neurology, Xijing Hospital, Fourth Military Medical University, 15 Changle-xi Road, Xi’an 710032, Shaanxi province, China
Phone: +86 29 8477 1055
E-mail: iamtrn@126.com

Citation: Wei J, Hui B. Liver transplantation in the treatment of ornithine transcarbamylase deficiency. Cell Ther Transplant 2021; 10(3-4): 26-29.

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Ornithine transcarbamylase deficiency (OTCD) is a genetic disorder causing disturbed urea metabolic cycle with a high mortality rates. It’s a genetic metabolic disease manifesting as hyperammonemia. Drugs and hemodialysis may reduce blood ammonia levels in the patients. Liver transplantation may improve the long-term survival rate of patients, but it cannot reverse the nervous system damage that has occurred before, and cannot improve cognition. If the liver transplant is performed early in childhood, neurodevelopment may be normal at later terms. Late-onset patients should also be transplanted when required. Heterozygosity for OTCD in the donor is still risky and should only be used when there are no other options. Hepatocyte transplantation can be tried if necessary. Prevention of infection, long-term monitoring of liver function and blood ammonia are required posttransplant. Liver transplantation should be considered for all patients with genetic OTCD. The final decision of whether and how to use this treatment mode depends on individual clinical circumstances.

Keywords

Ornithine transcarbamylase deficiency, urea cycle disorder, liver transplantation, hepatocyte transplantation.

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Jingya Wei, Bo Hui

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Keywords

Ornithine transcarbamylase deficiency, urea cycle disorder, liver transplantation, hepatocyte transplantation.

Keywords

Ornithine transcarbamylase deficiency, urea cycle disorder, liver transplantation, hepatocyte transplantation.

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Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, China

Citation: Wei J, Hui B. Liver transplantation in the treatment of ornithine transcarbamylase deficiency. Cell Ther Transplant 2021; 10(3-4): 26-29.

Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, China

Citation: Wei J, Hui B. Liver transplantation in the treatment of ornithine transcarbamylase deficiency. Cell Ther Transplant 2021; 10(3-4): 26-29.

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Джингуа Вэй, Бо Хюи

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Ключевые слова

Дефицит орнитин-транскарбамилазы, нарушение цикла мочевины, трансплантация печени.

Ключевые слова

Дефицит орнитин-транскарбамилазы, нарушение цикла мочевины, трансплантация печени.

Департамент неврологии, Госпиталь Сиджин, 4-й Военно-Медицинский университет, Сиань, Китай

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Introduction

It is generally known that intestinal microbiota is a symbiotic community including many types of bacteria, fungi and viruses. It is a dynamic biological system with an average weight of 2-3 kg, producing many metabolites (metabolic substances, vitamins, neurotransmitters, etc.) necessary for existence and growth of the host organism. The gut microbiota interacts with intestinal epithelial cell layers which are exposed both to endogenous pathogenic (e.g., blood-borne) viruses, and to intestinal bacterial populations. In turn, the gut microbed strains are affected by various bacteriophage populations causing their lysis. The surviving bacteria may acquire mobile gene elements, including those providing resistance to antibiotics (Fig. 1). These polyresistant bacteria are an important cause of life-threatening infections in immunocompromised patients, e.g., after intensive cytostatic therapy and hematopoietic stem cell transplantation (HSCT).

Figure 1. Intestinal epithelium is exposed to endogenous host viruses (bottom), and interacts with gut bacteria (light green) which could be lysed by bacteriophages (top left). Some of them may harbor and transfer antibiotic resistance genes to the bacteria (top right)

Moreover, the host immune system develops in permanent contact with the surrounding microbial and viral antigens, especially with the endogenous intestinal microbiota, which includes all these components [1]. Microbial and viral antigens of the intestinal microbiota, passing through the epithelial barriers of the mucous membranes, penetrate into the regional blood vessels and lymph nodes, form an adaptive B- and T-cell immune response, being a key factor in the normal maturation and functioning of the immune system.

For decades, the main attention of bacteriologists was paid to cultivated, mainly aerobic microorganisms – Escherichia, Klebsiella, Enterococci that were studied in details for decades. Cultivable anaerobic gut bacteria were also exhaustively studied over last decades. However, with development of high-throughput DNA diagnostics, the spectrum of known microbial bacteria extended to sufficient degree. Currently, >1000 bacterial species are detectable in normal gut microbiota. Hence, over the past 10-20 years, the novel molecular biology approaches (multiple PCR, high-throughput DNA sequencing) enabled detailed classifying hundreds of species of anaerobic intestinal bacteria, which dominate the intestinal microbiota.

Human viral community (virome) is exhibiting even higher taxonomic and genetic complexity. Formerly, the main interest was drawn to the viruses of eukaryotic cells which could be pathogenic to humans. The modern NGS approach allows to detect both known viruses (herpes, anelloviruses, picobirnaviruses) and a number of previously unknown viral DNA sequences [2].

However, intestinal human virome is dominated by bacteriophages. These are largely represented by Caudiovirales. [3]. This order of phages includes 3 families (Myoviridae; Siphoviridae, and Podoviridae).

Along with double-stranded DNA phages, minor populations of single-stranded DNA and RNA phages are detectable in human gut virome which are also specific for distinct bacterial species as reviewed by Carding et al. [3].

The issues of viral sequences in bacterial and human cells (e.g., prophages, retroviral elements etc.) are also detectable by metagenomics but will not be covered here, because of undefined clinical significance and still undefined systemic approach. Hence, the question about functions and significance of virome abundance and diversity in healthy subjects and GIT disorders is still open.

Current methodology

Unlike the bacterial microbiota, viral intestinal population (gut virome) has been studied to a much lesser extent. Whereas bacterial species have the common target gene for sequencing, i.e., 16SrRNA (the main object for NGS analysis), the viruses lack such a common marker gene, thus hampering easy assessment of their diversity in biological samples.

Currently, there is a broad diagnostic choice in clinical virology, starting with cytopathogenic tests, large arrays of immune diagnostic sets, and modern whole-scale panels of PCR assays. To diagnose some pathogenic viruses (up to 10-15 species), multiplex PCR was developed, and it is commonly used in clinical laboratories. However, these commercial PCR panels cannot cover the entire spectrum of potential viral agents, usually targeting up to 10-12 pathogens.

Therefore, the most comprehensive approach to studying the entire viral community is whole-genome screening of viral sequences by means of NGS followed by extensive bioinformatics. E.g., a random metagenomic analysis may also allow detection of human pathogenic viruses. Methodology of metagenomic studies are well reviewed in [4].

Diversity of human viruses and bacteriophages

A number of endogenous viruses persisting lifelong may be found in stools under certain conditions, e.g., in immunocompromised patients or during immunosuppressive therapy.

Herperviruses in gut are often activated in the patients with inflammatory bowel diseases. E.g., the Japanese group, using high-capacity multiplex PCR with microchip electrophoresis, has detected as much as 191 different bacterial species and 206 viruses in 215 stool samples (71.7% positivity) from immunocompromised patients and subjects with ulcerative colitis [5]. Among viral pathogens, Epstein-Barr virus (EBV) was revealed in 90 samples (30.0%); HHV-6, in 53 cases (17.7%), and cytomegalovirus (CMV) in 37 specimens (12.3%).

Most often, however, human intestinal microbiome is extensively studied in search of the viruses known to be pathogenic (i.e., noroviruses, rotaviruses, astroviruses, adenoviruses etc.). Biological diversity of human pathogenic viruses was first studied in Asian countries, with high incidence of gastroenteritis in pediatric setting [6]. The authors examined stool samples from 7 children positive for picobirnavirus and identified, by means of metagenomics, enterovirus, gyrovirus, parechovirus in these samples, which are potentially pathogenic in gastroenteritis. In addition, a metagenomic study of stool microbiota allows detecting bacterial-viral associations (for example, C.difficile associated with a number of viruses) in intestinal syndromes as shown by a group from the USA [7]. Metagenomic analysis was also used for NGS analysis of stool samples in gastroenteritis, and, except of common noroviruses, additional pathogens were found from the genus Astroviridae and Caliciviridae [8].

Gut human virome after HSCT

A limited number of works concerned presence of intestinal viruses posttransplant. E.g., Legoff et al. have detected different viruses in stool and plasma following HSCT using electrospray ionization with mass-spectrometric [9]. The workers have revealed high adenovirus (AdV) viral load in stool samples. In an earlier study, AdV DNA was found in stools of 21 HSCT patients with AdV infection, from a total group of 182 patients. Of note, time dynamics of AdV viral loads in stool specimens was predictive for AdV viraemia, thus suggesting intestinal source to be the primary site of the viral infection [10].

Cytomegalovirus (CMV) viral load was assessed in stool of HSCT as possible marker of acute intestinal graft-versus-host disease posttransplant [11]. CMV DNA was found in 20 of 121 HSCT recipients. However, the authors did not find any correlation between CMV DNA loads and intestinal graft-versus-host disease (aGVHD), as well between viral contents in plasma and stools.

In view of scarce NGS-based virome studies in HSCT, it is very important to detect and realize significance of multiple viral species in progression of intestinal syndrome. Over the past 5 years, several papers have been published on the metagenomics of viruses after HSCT [12]. The authors traced the virome dynamics in 44 HSCT recipients using metagenomics techniques (NexTera, HiSeq platforms). Following transplantation (i.e., during transient immune deficiency), Anelloviridae, herpes viruses, papilloma and polyoma viruses, especially picobirnavirus were “flourishing” in intestinal GVHD. Moreover, decreased detection rates were noted for bacteriophages, except for Siphoviridae. A similar work was carried out by a Dutch group [13]. The authors used the original ViroCap system to study fecal samples, with a large panel of probes for 34 families of DNA and RNA viruses (a total of 337 species). After enrichment of viral DNA in the samples, the NGS procedures were performed. At the same time, it was possible to identify, along with known noro- and adenoviruses, also rhinovirus, herpesvirus-7, VK virus, astrovirus at higher sensitivity, than with conventional PCR tests. This approach revealed new associations between the findings of viral sequences and intestinal GVHD. Temporal changes of the patient's microbiota after GVHD and weekly fecal microbiota transplantation in a single patient was studied by Chinese workers [14]. Biodiversity of bacterial species gradually increased after successful TFM, whereas the spectrum of viruses, in general, expanded with time after FMT, e.g., Caudivirales content was increased.

Intestinal phageome

Current metagenomic approaches allowed to look for the whole spectrum of virome, including human viruses and bacteriophages in human microbiota which seems to become a feasible task of clinical significance [15].

For more than 100 years, the bacteriophages were extensively studied using bacteriolysis in classical cultures, morphological and, later molecular PCR methods. Therefore, current criteria for bacteriophage classification are based on their biological properties (lytic or temperate forms; bacterial targets), morphology, main location site etc. [16].

Some of the bacteriophages are widely used in clinical practice to combat antibiotic-resistant bacteria [17].

However, the full-scale analysis of multiple phage populations became available only few years ago, with an advent of high-throughput metagenomic sequencing performed at various NGS platforms [18].

This approach makes it possible to assess the entire community of pathogenic viruses, especially, different bacteriophage species in fecal samples. Different bacteriophages are, generally, specific for distinct bacterial species [19]. Therefore, spectrum and content of intestinal bacteriophages, by definition, depends on the dynamics of the bacterial hosts in the microbiota, and vice versa. Dietary habits, age and antibiotic therapy may influence composition and dynamics of both bacteria and their phages. E.g., starting from birth, the Caudovirales content and phage biodiversity change significantly with age [18].

Shotgun metagenomic methods allow evaluating the entire population of genes in a sample (though at different detection efficiencies). E.c., French authors have applied this technique to study the intestinal bacterial microbiota upon exposure to antimicrobial drug (cefprozil) Immediately after therapy, the total content of metagenomic sequences was expected to decrease. However, 3 months after the therapy, new previously absent gene sequences appeared in the intestinal microbiota and, what is important, the content of antibiotic resistance signatures increased, especially in individuals with initially low biodiversity of the intestinal microbiota. [20]. Different mechanisms of horizontal gene transfer via bacteriophages are shown in Fig. 2.

Figure 2. Horizontal gene transfer can commonly occur through conjugation and natural transformation. Additionally, it may occur through transduction, where resistance is transmitted via bacteriophage. (From [21])

Metagenomic studies of intestinal phageome and resistance genes

Previous knowledge of intestinal virome was, mostly, based on classical studies of bacteriophages detectable by their bacteriolytic effects. Tremendous information on intestinal phages accumulated over XX century. The data on eukaryotic cell viruses are also quite extensive, mostly concerning distinct pathogenic viral species.

Current technical advances, i.e., next-generation sequencing (NGS) enabled coverage of the whole intestinal virome. Metagenomics makes it possible to identify and evaluate both temporal dynamics of phage populations, and their relationship with antibiotic resistance genes that promoting colonization of intestines by pathogenic bacterial strains.

Over the past 3-5 years, the work was started with searching phage sequences and antibiotic resistance genes using new generation sequencing (NGS) methods. Thus, Fernández-Orth et al. investigated DNA from samples of intestinal microbiota in healthy individuals and after treatment with ciprofloxacin, using deep sequencing methods (MySec, Illumina). Assembly of the sequences obtained was evaluated using Kraken software. The samples were found to contain from 4 to 266 viruses. Caudovirales predominated among bacteriophages, and the phages of Siphoviridae and Myoviridae families were also identified. Antibiotic resistance genes were also found in bacterial DNA, and their content was significantly increased after treatment with ciprofloxacin [22].

In other study, bioinformatic analysis of multiple viral sequences from human intestinal microbiome was carried out 4 weeks after a course of antibiotics. The authors found a significant increase in the number of gene signatures (scaffolds) of antibiotic-resistant genes after antibiotic therapy [23].

However, current evidence show that the antibiotic resistance genes can be inserted into plasmids and other mobile genetic elements, which can be transmitted both vertically and by horizontal transfer within the bacterial population, which is essential for accumulation of resistant strains within the intestinal microbiota. Such evidence has been obtained recently. For example, gene sequences were screened for 254 strains of Klebsiella pneumoniae, which most often acquires the drug resistance genes [24]. They showed that most of the studied strains contained intact prophage sequences. An additional analysis of 42 K.pneumoniae strains showed that these phages belong to the families Myoviridae, Siphoviridae, and Podoviridae. Interestingly, no virulence genes were detected in these prophages; however, in 2% of cases, these prophages also encoded genes related to antibiotic resistance factors.

Probable bacteria-phage interactions in HSCT patients

However, most of these clinical studies dealt with the state and ways of restoring the bacterial component of the microbiota, while missing possible role of bacteriophages in severe intestinal dysbiosis. The latter direction can also be promising, as shown by the data of NGS studies on the stability of intestinal bacteriophage populations during fecal transplantation [25]. Meanwhile, there are still no proven positive results from phage therapy in severe intestinal dysbiosis. It is believed that in the future it will be possible to develop modified bacteriophages adapted to specific resistant bacteria [26]. So far, however, there is a process of accumulating information about the bacterial-viral complex of the intestinal microbiota in severe intestinal syndromes of infectious origin.

Posttransplant period is often associated with severe colitis often associated to persistent infection with K.pneumoniae, pathogenic E.coli, C.difficile as reviewed in [27]. Meanwhile, treatment of bacterial infections using species-specific bacteriophages, in particular – those against Staphylococci, E. coli, etc. has been successfully used for decades. The history of these developments is well described [17]. However, the desirable clinical effects were temporary, often due to the development of resistance to phage therapy [19]. British scientists have discovered that optimal combinations of several bacteriophages are most effective in suppressing and preventing phage resistance of C.difficile, as was previously shown experimentally [28]. In hamster experiments, treatment with optimized phage mixtures led to rapid decrease in the C.difficile colonization. Clinical transplantation of intestinal microbiota also suggests possible clinical effects of non-bacterial pathogens. E.g., Ott et al. [29] administered sterile filtrates of donor stool through a nasal cannule to the patients with Clostridium difficile infection. Usage of this bacteria-free drug in 5 patients led to long-term normalization of intestinal disorder, as well as appropriate changes in bacterial and intestinal microbiota. The authors suggest that bacteriophages from the stool filtrate may cause similar positive effects. Hence, these findings enable search and identification of intestinal bacteriophages associated with positive and persistent effects of colitis therapy, especially at the present time, when effective methods of metagenomic DNA sequencing are developed for such studies.

Conclusion

Gut microbiota is a complex symbiosis of bacteria, viruses and fungi. However, unlike the bacterial microbiota (bacteriome), the viral gut community (gut virome) is studied to much lesser degree, due to absence of common target gene for nucleic acid sequencing in viruses. Over last years, the whole-genome screening techniques using next-generation sequencing (NGS) promoted our knowledge in the field. This approach allowed to estimate the biodiversity of human viruses and bacteriophages in the individual samples of intestinal microbiota in health and disease.

Studies of the virome changes after HSCT are now launched, however, being at initial stage. Meanwhile, the changes in bacteriophage community (phageome) and its diversity post-transplant may explain both therapy-associated changes of bacteriome, and development of bacterial antibiotic resistance, due to phage-mediated transfer of antibiotic resistance genes.

Conflicts of interest

None conflicts of interest are declared.

Acknowledgements

The authors are much appreciated to the Pediatric Research and Clinical Center for Infectious Diseases, and dedicate the present article to the 95^th anniversary of this institution.

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Gu W, Miller S, Chiu CY. Clinical Metagenomic Next-Generation Sequencing for Pathogen Detection. Annu Rev Pathol. 2019; 14:319-338. doi: 10.1146/annurev-pathmechdis-012418-012751
Nahar S, Iraha A, Hokama A, Uehara A, Parrott G, Ohira T, et al. Evaluation of a multiplex PCR assay for detection of cytomegalovirus in stool samples from patients with ulcerative colitis. World J Gastroenterol. 2015; 21(44):12667-75. doi: 10.3748/wjg.v21.i44.12667
Sun G, Zang Q, Gu Y, Niu G, Ding C, Zhang P. Viral metagenomics analysis of picobirnavirus-positive feces from children with sporadic diarrhea in China. Arch Virol. 2016; 161 (4): 971-5. doi: 10.1007/s00705-015-2726-2
Zhou Y, Wylie KM, El Feghaly RE, Mihindukulasuriya KA, Elward A, Haslam DB, Storch GA, Weinstock GM. Metagenomic Approach for Identification of the Pathogens Associated with Diarrhea in Stool Specimens. J Clin Microbiol. 2016; 54 (2): 368-75.
doi: 10.1128/JCM.01965-15
Fernandez-Cassi X, Martínez-Puchol S, Silva-Sales M, Cornejo T, Bartolome R, Bofill-Mas S, Girones R. Unveiling Viruses Associated with Gastroenteritis Using a Metagenomics Approach. Viruses. 2020; 12 (12): 1432. doi: 10.3390/v12121432
Legoff J, Feghoul L, Mercier-Delarue S, Dalle JH, Scieux C, Chérot J, et al. Broad-range PCR-electrospray ionization mass spectrometry for detection and typing of adenovirus and other opportunistic viruses in stem cell transplant patients. J Clin Microbiol. 2013; 51(12):4186-92. doi: 10.1128/JCM.01978-13
Jeulin H, Salmon A, Bordigoni P, Venard V. Diagnostic value of quantitative PCR for adenovirus detection in stool samples as compared with antigen detection and cell culture in haematopoietic stem cell transplant recipients. Clin Microbiol Infect. 2011;17(11):1674-80. doi: 10.1111/j.1469-0691.2011.03488.x
Bueno F, Albert E, Giménez E, Piñana JL, Pérez A, Gómez MD, et al., 2020. Cytomegalovirus DNA load monitoring in stool specimens for anticipating the occurrence of intestinal acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: Is it of any value? Transpl Infect Dis. 2020; 22(6):e13440. doi: 10.1111/tid.13440
Legoff J, Resche-Rigon M, Bouquet J, Robin M, Naccache SN, Mercier-Delarue S, et al. The eukaryotic gut virome in hematopoietic stem cell transplantation: new clues in enteric graft-versus-host disease. Nat Med. 2017; 23 (9): 1080-1085. doi: 10.1038/nm.4380
Jansen SA, Nijhuis W, Leavis HL, Riezebos-Brilman A, Lindemans CA, Schuurman R. Broad virus detection and variant discovery in fecal samples of hematopoietic transplant recipients using targeted sequence capture metagenomics. Front Microbiol. 2020; 11: 560179. doi: 10.3389/ fmicb.2020.560179
Zhang F, Zuo T, Yeoh YK, Cheng FWT, Liu Q, Tang W, et al. Longitudinal dynamics of gut bacteriome, mycobiome and virome after fecal microbiota transplantation in graft-versus-host disease. Nat Commun. 2021; 12 (1): 65. doi: 10.1038/s41467-020-20240-x
Wang W, Jovel J, Halloran B, Wine E, Patterson J, Ford G, et al. Metagenomic analysis of microbiome in colon tissue from subjects with inflammatory bowel diseases reveals interplay of viruses and bacteria. Inflamm Bowel Dis. 2015; 21 (6): 1419-27.
doi: 10.1097/MIB.0000000000000344
Principi N, Silvestri E, Esposito S Advantages and Limitations of Bacteriophages for the Treatment of Bacterial Infections. Front. Pharmacol. 2019;10:513. doi: 10.3389/fphar.2019.00513
Brüssow H. Phage therapy for the treatment of human intestinal bacterial infections: soon to be a reality? Exp Rev Gastroenterol Hepatol. 2017. doi: 10.1080/17474124.2017.1342534
Townsend EM, Kelly L, Muscatt G, Box JD, Hargraves N, Lilley D, Jameson E. The human gut phageome: Origins and roles in the human gut microbiome. Front Cell Infect Microbiol. 2021; 11: 643214. doi: 10.3389/fcimb.2021.643214
Oechslin F. Resistance development to bacteriophages occurring during bacteriophage therapy. Viruses 2018, 10, 351.
doi: 10.3390/v10070351
Raymond F, Déraspe M, Boissinot M, Bergeron MG, Corbeil J. Partial recovery of microbiomes after antibiotic treatment. Gut Microbes. 2016; 7 (5): 428-34. doi: 10.1080/ 19490976.2016.1216747
Schroeder M, Brooks BD, Brooks AE. The Complex Relationship between Virulence and Antibiotic Resistance. Genes. 2017; 8(1):39. https://doi.org/10.3390/genes8010039
Fernández-Orth D, Miró E, Brown-Jaque M, Rodríguez-Rubio L, Espinal P, Rodriguez-Navarro J, et al. Faecal phageome of healthy individuals: presence of antibiotic resistance genes and variations caused by ciprofloxacin treatment. J Antimicrob Chemother. 2019; 74 (4): 854-864. doi: 10.1093/jac/dky540
Górska A, Peter S, Willmann M, Autenrieth I, Schlaberg R, Huson DH. Dynamics of the human gut phageome during antibiotic treatment Comput Biol Chem. 2018; 74: 420-427. doi: 10.1016/j.compbiolchem.2018.03.011
Baliga P, Shekar M, Kallappa GS. Genome-wide identification and analysis of chromosomally integrated putative prophages associated with clinical Klebsiella pneumoniae strains. Curr Microbiol 2021; 78 (5): 2015-2024. doi: 10.1007/s00284-021-02472-2
Broecker F, Russo G, Klumpp J, Moelling K. Stable core virome despite variable microbiome after fecal transfer. Gut Microbes. 2017; 8 (3): 214-220. doi: 10.1080/19490976.2016.1265196
Paule A, Frezza D, Edeas M. Microbiota and phage therapy: Future challenges in medicine. Med Sci (Basel). 2018; 6 (4): 86.
doi: 10.3390/medsci6040086
Goloshchapov OV, Kucher MA, Chukhlovin AB. Gut microbiome in hematopoietic stem cell transplantation: patient-and treatment-related factors. Cell Ther Transpant. 2018; 7(4): 16-28. doi: 10.18620/ctt-1866-8836-2018-7-4-16-28
Nale JY, Spencer J, Hargreaves KR, Buckley AM, Trzepiński P, Douce GR, Clokie MR. Bacteriophage combinations significantly reduce Clostridium difficile growth in vitro and proliferation in vivo. Antimicrob Agents Chemother. 2015; 60 (2): 968-981.
doi: 10.1128/AAC.01774-15
Ott SJ, Waetzig GH, Rehman A, Moltzau-Anderson J, Bharti R, Grasis JA, et al. Efficacy of sterile fecal filtrate transfer for treating patients with Clostridium difficile infection. Gastroenterology. 2017; 152 (4): 799-811.e7. doi: 10.1053/ j.gastro.2016.11.010

" ["~DETAIL_TEXT"]=> string(29610) "

Introduction

Current methodology

Diversity of human viruses and bacteriophages

A number of endogenous viruses persisting lifelong may be found in stools under certain conditions, e.g., in immunocompromised patients or during immunosuppressive therapy.

Gut human virome after HSCT

Intestinal phageome

Some of the bacteriophages are widely used in clinical practice to combat antibiotic-resistant bacteria [17].

However, the full-scale analysis of multiple phage populations became available only few years ago, with an advent of high-throughput metagenomic sequencing performed at various NGS platforms [18].

Metagenomic studies of intestinal phageome and resistance genes

Probable bacteria-phage interactions in HSCT patients

Conclusion

Conflicts of interest

None conflicts of interest are declared.

Acknowledgements

The authors are much appreciated to the Pediatric Research and Clinical Center for Infectious Diseases, and dedicate the present article to the 95^th anniversary of this institution.

References

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Carding SR, Davis N, Hoyles L. Review article: the human intestinal virome in health and disease. Aliment Pharmacol Ther. 2017; 46(9):800-815. doi: 10.1111/apt.14280
Gu W, Miller S, Chiu CY. Clinical Metagenomic Next-Generation Sequencing for Pathogen Detection. Annu Rev Pathol. 2019; 14:319-338. doi: 10.1146/annurev-pathmechdis-012418-012751
Nahar S, Iraha A, Hokama A, Uehara A, Parrott G, Ohira T, et al. Evaluation of a multiplex PCR assay for detection of cytomegalovirus in stool samples from patients with ulcerative colitis. World J Gastroenterol. 2015; 21(44):12667-75. doi: 10.3748/wjg.v21.i44.12667
Sun G, Zang Q, Gu Y, Niu G, Ding C, Zhang P. Viral metagenomics analysis of picobirnavirus-positive feces from children with sporadic diarrhea in China. Arch Virol. 2016; 161 (4): 971-5. doi: 10.1007/s00705-015-2726-2
Zhou Y, Wylie KM, El Feghaly RE, Mihindukulasuriya KA, Elward A, Haslam DB, Storch GA, Weinstock GM. Metagenomic Approach for Identification of the Pathogens Associated with Diarrhea in Stool Specimens. J Clin Microbiol. 2016; 54 (2): 368-75.
doi: 10.1128/JCM.01965-15
Fernandez-Cassi X, Martínez-Puchol S, Silva-Sales M, Cornejo T, Bartolome R, Bofill-Mas S, Girones R. Unveiling Viruses Associated with Gastroenteritis Using a Metagenomics Approach. Viruses. 2020; 12 (12): 1432. doi: 10.3390/v12121432
Legoff J, Feghoul L, Mercier-Delarue S, Dalle JH, Scieux C, Chérot J, et al. Broad-range PCR-electrospray ionization mass spectrometry for detection and typing of adenovirus and other opportunistic viruses in stem cell transplant patients. J Clin Microbiol. 2013; 51(12):4186-92. doi: 10.1128/JCM.01978-13
Jeulin H, Salmon A, Bordigoni P, Venard V. Diagnostic value of quantitative PCR for adenovirus detection in stool samples as compared with antigen detection and cell culture in haematopoietic stem cell transplant recipients. Clin Microbiol Infect. 2011;17(11):1674-80. doi: 10.1111/j.1469-0691.2011.03488.x
Bueno F, Albert E, Giménez E, Piñana JL, Pérez A, Gómez MD, et al., 2020. Cytomegalovirus DNA load monitoring in stool specimens for anticipating the occurrence of intestinal acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: Is it of any value? Transpl Infect Dis. 2020; 22(6):e13440. doi: 10.1111/tid.13440
Legoff J, Resche-Rigon M, Bouquet J, Robin M, Naccache SN, Mercier-Delarue S, et al. The eukaryotic gut virome in hematopoietic stem cell transplantation: new clues in enteric graft-versus-host disease. Nat Med. 2017; 23 (9): 1080-1085. doi: 10.1038/nm.4380
Jansen SA, Nijhuis W, Leavis HL, Riezebos-Brilman A, Lindemans CA, Schuurman R. Broad virus detection and variant discovery in fecal samples of hematopoietic transplant recipients using targeted sequence capture metagenomics. Front Microbiol. 2020; 11: 560179. doi: 10.3389/ fmicb.2020.560179
Zhang F, Zuo T, Yeoh YK, Cheng FWT, Liu Q, Tang W, et al. Longitudinal dynamics of gut bacteriome, mycobiome and virome after fecal microbiota transplantation in graft-versus-host disease. Nat Commun. 2021; 12 (1): 65. doi: 10.1038/s41467-020-20240-x
Wang W, Jovel J, Halloran B, Wine E, Patterson J, Ford G, et al. Metagenomic analysis of microbiome in colon tissue from subjects with inflammatory bowel diseases reveals interplay of viruses and bacteria. Inflamm Bowel Dis. 2015; 21 (6): 1419-27.
doi: 10.1097/MIB.0000000000000344
Principi N, Silvestri E, Esposito S Advantages and Limitations of Bacteriophages for the Treatment of Bacterial Infections. Front. Pharmacol. 2019;10:513. doi: 10.3389/fphar.2019.00513
Brüssow H. Phage therapy for the treatment of human intestinal bacterial infections: soon to be a reality? Exp Rev Gastroenterol Hepatol. 2017. doi: 10.1080/17474124.2017.1342534
Townsend EM, Kelly L, Muscatt G, Box JD, Hargraves N, Lilley D, Jameson E. The human gut phageome: Origins and roles in the human gut microbiome. Front Cell Infect Microbiol. 2021; 11: 643214. doi: 10.3389/fcimb.2021.643214
Oechslin F. Resistance development to bacteriophages occurring during bacteriophage therapy. Viruses 2018, 10, 351.
doi: 10.3390/v10070351
Raymond F, Déraspe M, Boissinot M, Bergeron MG, Corbeil J. Partial recovery of microbiomes after antibiotic treatment. Gut Microbes. 2016; 7 (5): 428-34. doi: 10.1080/ 19490976.2016.1216747
Schroeder M, Brooks BD, Brooks AE. The Complex Relationship between Virulence and Antibiotic Resistance. Genes. 2017; 8(1):39. https://doi.org/10.3390/genes8010039
Fernández-Orth D, Miró E, Brown-Jaque M, Rodríguez-Rubio L, Espinal P, Rodriguez-Navarro J, et al. Faecal phageome of healthy individuals: presence of antibiotic resistance genes and variations caused by ciprofloxacin treatment. J Antimicrob Chemother. 2019; 74 (4): 854-864. doi: 10.1093/jac/dky540
Górska A, Peter S, Willmann M, Autenrieth I, Schlaberg R, Huson DH. Dynamics of the human gut phageome during antibiotic treatment Comput Biol Chem. 2018; 74: 420-427. doi: 10.1016/j.compbiolchem.2018.03.011
Baliga P, Shekar M, Kallappa GS. Genome-wide identification and analysis of chromosomally integrated putative prophages associated with clinical Klebsiella pneumoniae strains. Curr Microbiol 2021; 78 (5): 2015-2024. doi: 10.1007/s00284-021-02472-2
Broecker F, Russo G, Klumpp J, Moelling K. Stable core virome despite variable microbiome after fecal transfer. Gut Microbes. 2017; 8 (3): 214-220. doi: 10.1080/19490976.2016.1265196
Paule A, Frezza D, Edeas M. Microbiota and phage therapy: Future challenges in medicine. Med Sci (Basel). 2018; 6 (4): 86.
doi: 10.3390/medsci6040086
Goloshchapov OV, Kucher MA, Chukhlovin AB. Gut microbiome in hematopoietic stem cell transplantation: patient-and treatment-related factors. Cell Ther Transpant. 2018; 7(4): 16-28. doi: 10.18620/ctt-1866-8836-2018-7-4-16-28
Nale JY, Spencer J, Hargreaves KR, Buckley AM, Trzepiński P, Douce GR, Clokie MR. Bacteriophage combinations significantly reduce Clostridium difficile growth in vitro and proliferation in vivo. Antimicrob Agents Chemother. 2015; 60 (2): 968-981.
doi: 10.1128/AAC.01774-15
Ott SJ, Waetzig GH, Rehman A, Moltzau-Anderson J, Bharti R, Grasis JA, et al. Efficacy of sterile fecal filtrate transfer for treating patients with Clostridium difficile infection. Gastroenterology. 2017; 152 (4): 799-811.e7. doi: 10.1053/ j.gastro.2016.11.010

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Состав и соотношение бактериальных популяций серьезно нарушаются при тяжелых колитах и болезни «трансплантат против хозяина» (GVHD), возникающих после трансплантации гемопоэтических стволовых клеток (HSCT), особенно при развитии устойчивых к антибиотикам бактериальных штаммов. В отличие от хорошо известной бактериальной микробиоты, изученной с помощью классической бактериологии и секвенирования гена 16S рРНК, вирусные популяции кишечной микробиоты (например, бактериофагов) в этих клинических условиях изучены недостаточно из-за отсутствия общего вирусного гена, пригодного для сравнительного молекулярно-генетического анализа. Оценка соотношений вирусной и бактериальной кишечной микробиоты возможна с помощью метагеномных методов анализа множества видов ДНК в образцах биоматериала. Объектом клинического исследования являются пациенты с инфекционными осложнениями, вызванными массивным антибактериальным и цитостатическим лечением. Особое внимание следует обратить на тяжелый колит с инфекцией C.difficile и устойчивой к антибиотикам K. pneumoniae, а также другими патогенами, как при трансплантации фекальной микробиоты (FMT), так и без нее. Обычная оценка кишечной микробиоты будет осуществляться путем секвенирования следующего поколения (NGS) на основе генного разнообразия 16S рДНК для бактериальных генов и метагеномного анализа NGS, чтобы оценить соотношение различных вирусов эукариотических клеток и, в частности, бактериофагов в случае дисбактериоза кишечника. Следует установить типичные нарушения кишечного вирома, а также их роль в колонизации кишечными бактериями, устойчивыми к антибиотикам, после интенсивной антибиотикотерапии и химиотерапии. <h2>Ключевые слова</h2> Кишечные инфекции, трансплантация, иммунологические осложнения, кишечная микробиота, вирусы, бактериофаги, антибиотикорезистентность, секвенирование нового поколения (NGS), ген 16S rRNA, метагеномика. 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"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(5) "28405" ["VALUE"]=> array(2) { ["TEXT"]=> string(188) "Олег В. Голощапов1, Алексей Б. Чухловин1,2, Олег С. Глотов2" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(140) "

Олег В. Голощапов¹, Алексей Б. Чухловин^1,2, Олег С. Глотов²

" ["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(5) "28406" ["VALUE"]=> array(2) { ["TEXT"]=> string(594) "1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия 2 Детский научно-практический центр инфекционных болезней ФМБА, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(552) "

¹ НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
² Детский научно-практический центр инфекционных болезней ФМБА, 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(5) "28407" ["VALUE"]=> array(2) { ["TEXT"]=> string(4017) " Микробиота кишечника (сложный симбиоз бактерий, грибов и вирусов) – это динамическая биологическая система, необходимая для существования и роста человеческого организма. Состав и соотношение бактериальных популяций серьезно нарушаются при тяжелых колитах и болезни «трансплантат против хозяина» (GVHD), возникающих после трансплантации гемопоэтических стволовых клеток (HSCT), особенно при развитии устойчивых к антибиотикам бактериальных штаммов. В отличие от хорошо известной бактериальной микробиоты, изученной с помощью классической бактериологии и секвенирования гена 16S рРНК, вирусные популяции кишечной микробиоты (например, бактериофагов) в этих клинических условиях изучены недостаточно из-за отсутствия общего вирусного гена, пригодного для сравнительного молекулярно-генетического анализа. Оценка соотношений вирусной и бактериальной кишечной микробиоты возможна с помощью метагеномных методов анализа множества видов ДНК в образцах биоматериала. Объектом клинического исследования являются пациенты с инфекционными осложнениями, вызванными массивным антибактериальным и цитостатическим лечением. Особое внимание следует обратить на тяжелый колит с инфекцией C.difficile и устойчивой к антибиотикам K. pneumoniae, а также другими патогенами, как при трансплантации фекальной микробиоты (FMT), так и без нее. Обычная оценка кишечной микробиоты будет осуществляться путем секвенирования следующего поколения (NGS) на основе генного разнообразия 16S рДНК для бактериальных генов и метагеномного анализа NGS, чтобы оценить соотношение различных вирусов эукариотических клеток и, в частности, бактериофагов в случае дисбактериоза кишечника. Следует установить типичные нарушения кишечного вирома, а также их роль в колонизации кишечными бактериями, устойчивыми к антибиотикам, после интенсивной антибиотикотерапии и химиотерапии. <h2>Ключевые слова</h2> Кишечные инфекции, трансплантация, иммунологические осложнения, кишечная микробиота, вирусы, бактериофаги, антибиотикорезистентность, секвенирование нового поколения (NGS), ген 16S rRNA, метагеномика. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3915) "

Микробиота кишечника (сложный симбиоз бактерий, грибов и вирусов) – это динамическая биологическая система, необходимая для существования и роста человеческого организма. Состав и соотношение бактериальных популяций серьезно нарушаются при тяжелых колитах и болезни «трансплантат против хозяина» (GVHD), возникающих после трансплантации гемопоэтических стволовых клеток (HSCT), особенно при развитии устойчивых к антибиотикам бактериальных штаммов. В отличие от хорошо известной бактериальной микробиоты, изученной с помощью классической бактериологии и секвенирования гена 16S рРНК, вирусные популяции кишечной микробиоты (например, бактериофагов) в этих клинических условиях изучены недостаточно из-за отсутствия общего вирусного гена, пригодного для сравнительного молекулярно-генетического анализа. Оценка соотношений вирусной и бактериальной кишечной микробиоты возможна с помощью метагеномных методов анализа множества видов ДНК в образцах биоматериала. Объектом клинического исследования являются пациенты с инфекционными осложнениями, вызванными массивным антибактериальным и цитостатическим лечением.

Особое внимание следует обратить на тяжелый колит с инфекцией C.difficile и устойчивой к антибиотикам K. pneumoniae, а также другими патогенами, как при трансплантации фекальной микробиоты (FMT), так и без нее. Обычная оценка кишечной микробиоты будет осуществляться путем секвенирования следующего поколения (NGS) на основе генного разнообразия 16S рДНК для бактериальных генов и метагеномного анализа NGS, чтобы оценить соотношение различных вирусов эукариотических клеток и, в частности, бактериофагов в случае дисбактериоза кишечника. Следует установить типичные нарушения кишечного вирома, а также их роль в колонизации кишечными бактериями, устойчивыми к антибиотикам, после интенсивной антибиотикотерапии и химиотерапии.

Ключевые слова

Кишечные инфекции, трансплантация, иммунологические осложнения, кишечная микробиота, вирусы, бактериофаги, антибиотикорезистентность, секвенирование нового поколения (NGS), ген 16S rRNA, метагеномика.

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Oleg V. Goloshchapov¹, Alexei B. Chukhlovin^1,2, Oleg S. Glotov²

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¹ RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
² Children's Scientific and Clinical Center for Infectious Diseases of the Federal Medical and Biological Agency, St. Petersburg, Russia

Correspondence:
Dr. Alexei B. Chukhlovin, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L. Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (921) 325-00-94
E-mail: alexei.chukh@mail.ru

Citation: Goloshchapov OV, Chukhlovin AB, Glotov OS. Possible role of intestinal human viruses and bacteriophages following hematopoietic stem cell transplantation: a mini-review. Cell Ther Transplant 2021; 10(3-4): 19-25.

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Gut microbiota (a complex community of bacteria, fungi and viruses) is a dynamic biological system adapted for co-existence and symbiosis with host organism. Composition and ratio of bacterial populations is severely impaired in severe colitis and graft-versus-host disease (GVHD) occurring after hematopoietic stem cell transplantation (HSCT), especially, upon development of antibiotic-resistant bacterial strains. In contrast to the well-known bacterial microbiota studied by classic bacteriology and 16S rRNA gene sequencing, the viral populations of intestinal microbiota (e.g., bacteriophages) in are poorly studied in these clinical conditions, due to absence of a common viral gene suitable for comparative molecular genetic analysis. Assessing the ratios for viral and bacterial intestinal microbiota is feasible by means of metagenomic methods assaying multiple DNA species in the samples of biomaterial. As an object of clinical research, the patients with infectious complications caused by massive antibacterial and cytostatic treatment. Special attention should be drawn to severe colitis with C.difficile infection and antibiotic-resistant K.pneumonia and other pathogens with/without fecal microbiota transplantation (FMT). Conventional assessment of intestinal microbiota will be accomplished by next-generation sequencing (NGS) based on 16S rDNA gene diversity for bacterial genes, and metagenomic NGS analysis, in order to assess the ratio of various viruses of eukaryotic cells and, in particular, bacteriophages in cases of gut dysbiosis. Typical disturbances of the gut virome should be established, as well as role of bacteriophages in emergence of antibiotic-resistant intestinal bacteria after intensive antibiotic and chemotherapy.

Keywords

Intestinal microbiota, gut microbiota, viruses, bacteriophages, transplantation, immune complications, antibiotic resistance, NGS sequencing, 16S rRNA gene, metagenomics.

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Oleg V. Goloshchapov¹, Alexei B. Chukhlovin^1,2, Oleg S. Glotov²

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Keywords

Intestinal microbiota, gut microbiota, viruses, bacteriophages, transplantation, immune complications, antibiotic resistance, NGS sequencing, 16S rRNA gene, metagenomics.

Keywords

Intestinal microbiota, gut microbiota, viruses, bacteriophages, transplantation, immune complications, antibiotic resistance, NGS sequencing, 16S rRNA gene, metagenomics.

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Олег В. Голощапов¹, Алексей Б. Чухловин^1,2, Олег С. Глотов²

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Ключевые слова

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Introduction

During the development of malignant neoplasia, a specific cellular environment is formed in the chronic inflammation site termed "inflammatory microenvironment of the tumour" (TME). This cell community consists of tumour-associated macrophages (MF), dendritic cells (DC), myeloid suppressor cells (MSC), neutrophils (NF), mast cells, natural killer cells (NK), T- and B-lymphocytes, cancer-associated fibroblasts (CAF) and endothelial cells. The interaction between tumour cells, myeloid cells and lymphocytes is a dynamic, bidirectional process and includes intercellular contacts, constant exchange of secreted soluble molecules, factors, vesicles, due to which an autonomous system is established that regulates tumour growth [1-5].

Neoplastic progression is associated with lack of oxygen, deficiency of nutrients causing hypoxia and development of metabolic acidosis in the tumour microenvironment. These factors promote selection of tumour cells with the gene mutations that allow them to survive under more severe microenvironmental conditions. Such adaptation of tumour cells is accompanied by increased production of various growth factors, cytokines, chemokines, which together present a triggering factor for enhancement of angiogenesis, metastases, and inhibition of local immune response. In turn, the normal TME cells also begin to secrete factors promoting tumour progression. As a result, a closed-circuit regulatory system is formed [6]. E.g., the content of IL-4 increases in TME, thus inducing differentiation of macrophages to the second-type (M2) resident cells. The M2 subpopulation may account for up to 50 % of the tumour mass and contribute to activation of pro-tumourigenic processes accompanied by the synthesis of IL-1, IL-1RA, IL-4, IL-6, IL-10, IL-12, L-arginine, prostaglandin E2, TNF-α, TGF-β, VEGF-A, and a variety of chemokines and their receptors CCL1, CCL5, CCL17, CCL22, CCL24, CCR2, CXCL10, CXCL16 [7-9]. These mediators are involved in angiogenesis, immunosuppression, and metastasis.

In tumour cells, increased production of some amino acid metabolism enzymes is revealed, e.g., of indolamine 2,3-dioxygenase, arginase-1. Activation of iNOS, as well as STAT3 transcription factor is noted, thereby initiating the differentiation of dendritic cells into tolerogenic tumour-associated dendritic cells (TADC) [10]. These cells produce TGF-β which promotes immunosuppression by stimulating Th2, Th17 and T regulatory cells [11].

Of interest, differentiation of neutrophils in the TME structures depends on the stage of the disease. Thus, the normally pro-inflammatory neutrophils differentiate at later phase to an immunosuppressive phenotype under the influence of TGF-β and angiotensin II [12]. The tumour-associated neutrophils synthesise collagenase IV, heparanase, elastase and matrix metalloproteinases (MMPs) which contribute to extracellular matrix degradation, tumour cell invasion and metastasis. The secreted proteinases destroy extracellular matrix, and degrade the pro-inflammatory cytokines, thus causing anti-inflammatory effects [13]. Neutrophils also produce oncostatin M, which enhances angiogenesis, as well as CXCL1, CXCL8, CCL-3, CXCL6, TGF-β, and prostaglandin E2 synthesis, thus supporting the neoplastic progression [14].

The CSF-1, HIF-1α, CCL2, CCL7, CXCL1 peptide factors synthesised by the TME cell populations are able to alter the metabolism of myeloid cells, leading to transition to MSC [15]. MSC enhance the synthesis of reactive oxygen species, arginase-1, prostaglandin E2, IL-4, IL-6, inhibit the function of T-lymphocytes [16], support the stemness of tumour cells [17], increase angiogenesis and metastasis [18]. It should be noted that MSC create background for spreading the tumour not only locally, but also to the target organ, inducing expression of adhesion molecules on the surface of endotheliocytes, e.g., E-selectin, intercellular adhesion molecules 1 (ICAM-1), and vascular cell adhesion molecules 1 (VCAM-1), promoting residence of tumour cells in the target organ [19].

M2 macrophages and MSCs are the main producers of IL-1β, which initiates a whole spectrum of procarcinogenic effects [20–23]. IL-1β provides both direct and indirect effects upon angiogenesis, by inducing the synthesis of various cytokines and angiogenesis factors [24]. Direct effects of IL-1β include activation of FGF-β expression in endothelial cells [24], VEGF-A and its receptors [25], regulation of endothelial progenitor cells, thus contributing to neovascularisation [25]. IL-1β also affects Bv8, CCL2, and CCL3 secretion, leading to (i) enhanced synthesis of VEGF-A, PLGF, bFGF by endothelial cells, (ii) VEGF-A secretion by myeloid cells (CD34+ or Flk-1+) [26], (iii) FGF1 secretion by mononuclear cells [27], (iv) IL-8 secretion by macrophages [28]. In general, IL-1β may affect cell differentiation, causing synthesis of either pro-inflammatory, or angiogenetic factors [28]. Immunosuppressive effect of IL-1β proceeds via stimulated synthesis of anti-inflammatory factors (IL-10, TGF-β, arginase-1) by tumour-associated macrophages and MSCs. This effect results into suppression of T cell and M1 activities [28], and the non-canonical signalling pathway of the NF-κB transcription factor is triggered, thus, in turn, suppressing antitumour immunity of T-regulatory cells [29]. The effect of IL-1β was shown to be associated with PD-L1 overexpression, an additional factor of immunity inhibition [29].

The role of immune cells in TME may be either to suppress tumour growth (antitumour TME), or to promote tumour growth (immunosuppressive TME). Thus, depending on the TME factors and type of malignancy, the immune cells may exert pro- or antitumour effects (Fig. 1) [30].

Figure 1. Influence of various immune cell populations upon TME

Abbreviations: NK, natural killers; Neu, neutrophils; MI, type I macrophages; DC, dendritic cells.

Cancer-associated fibroblasts (CAF) synthesise factor(s) inducing differentiation of macrophages to M2 and depletion of CD8+ T cells, which also stimulates proliferation, invasion and metastasis of tumour cells [31]. Along with cytokine production, tumour cells may activate pro-tumourigenic processes, due to metabolic acidosis in the extracellular matrix. E.g., acidification of extracellular matrix triggers p53-dependent apoptosis of surrounding cells and degradation of the basement membrane [32], along with increased secretion of cathepsin B, metalloproteinases, urokinase plasminogen activator, hydrolysing components of the extracellular matrix [33]. Also, acidification of extracellular matrix alters the lysosomal distribution, thus further enhancing secretion of proteinases causing destruction of extracellular matrix [34] and disruption of intercellular adhesion contacts by degradation of E-cadherin [35].

Several studies suggest acidosis to be a factor of immune therapy efficiency, as shown in murine models of melanoma and pancreatic adenocarcinoma, where the increased TME acidity correlated with inhibited antitumour T cell-mediated immunity, associated with lower efficacy of immune drugs [36, 37].

Increased acidity of TME leads to decreased efficiency of anticancer drugs, due to decreased transfer of drugs into the cells. For example, anthracyclines (doxorubicin), anthraquinones and alkaloids are weak bases and require optimal pH range (7.5-9.5) for their transmembrane transport [38-40]. Under these conditions, activity of a well-known glycoprotein transporter (pGP) is enhanced, thus promoting efflux of anticancer drugs from malignant cells. This effect was observed in tumour cells adapted for low extracellular pH, with acquired TP53 gene mutations [41–43]. These adaptive processes cause multidrug resistance and limit the choice of therapeutic options.

Hence, malignant cells may stimulate differentiation of tumour-associated immune cells to immunosuppressive phenotypes by synthesising a wide range of signalling molecules. In turn, these immune cells produce anti-inflammatory factors, growth factors, proteinases, enhance expression of adhesion molecules, causing invasion and metastasis of tumours, activation of angiogenesis. TME acidification is not only a factor leading to selection of the most resistant and aggressive tumour phenotypes, but it also induces destruction of intercellular contacts and extracellular matrix, which ultimately triggers the processes of invasion and metastasis.

Mutual influence of tumour cells and normal TME populations promotes development of cell associations, and their extracellular milieu protects from external impacts, e.g., anticancer therapy, immune surveillance. Even a small number of tumour cells forms a microenvironment resistant to antitumour therapy, especially if they are represented by stem or ‘dormant’ cells. Hence, a prevalence of the distinct component of the cellular microenvironment presumes differentiated approach to treatment. The strategic purpose in oncology is to transform cancer into a long-term chronic disease which is well controlled by the low-toxicity approaches. To implement this task, three areas of research could be highlighted: (i) a search for specific key target molecules, in order to create targeted drugs; (ii) personalisation of treatment programs based on molecular and cellular characteristics of the tumour, and individual clinical prognosis; (iii) use of nanomaterials when creating novel drugs, thus providing higher efficiency of treatment. The latter approach may increase concentrations of active substances in the tumour foci and reduce the drug toxicity. Long-term studies provide convincing evidence that carcinogenesis is a multistage multicomponent process, including disturbances of apoptosis, proliferation, angiogenesis and cell metabolism leading to the formation of altered pathological microenvironment.

Multimodality of carcinogenesis requires usage of combined treatment methods aimed at different molecular targets. In the past ten years, a series of nanomaterials has been developed in various laboratories around the world that have great potential for therapeutic use in oncology, e.g., liposomes, polymer carriers, carbon nanoparticles, iron oxide and gold nanoparticles. Currently, there is a technical opportunity of creating structures that would deliver active substances to the target cells and undergo biodegradation. However, the mentioned nanocarriers have a number of disadvantages. Liposomes, polymers, dendrimers can provide a significant decrease in overall toxicity of cytotoxic drugs, but they have a low potential in terms of targeted delivery. Carbon nanomaterials make it possible to create multicomponent and multitarget therapeutic constructs. Graphene and its derivatives are considered the most promising carbon nanomaterials for these purposes.

Current experience with graphene carriers

Initial experiments with unmodified graphene demonstrated its systemic toxicity [44,45] associated with accumulation in lungs [46], reticuloendothelial system including liver and spleen [47, 48] and provoking an inflammatory response [49]. Recent studies have shown that modified graphene oxide is promising for manipulating the tumour microenvironment; however, an analysis of the literature suggests that research in this area has just begun. For example, the use of graphene oxide functionalised with polyethylene glycol (GO-PEG) in photodynamic therapy led to a decrease in the interleukin-4-dependent polarisation of M2 in macrophages of the tumour microenvironment. The antitumour action of GO-PEG was to reduce the migration and invasion of subcutaneous osteosarcoma cells in mice [50]. In [51], the combined effect of low-frequency ultrasound therapy and graphene oxide-doxorubicin (GO-DOX) conjugate on local damage to endothelial cells lining the neovascular network was shown. This effect increased the penetration of the GO-DOX conjugate into the interstitial space of mouse liver carcinoma through damaged capillaries. Over past few years, a series of works was published at the Department of General and Bioorganic Chemistry (Pavlov University, St. Petersburg) which demonstrated an opportunity of reducing toxicity to acceptable level, due to functionalisation of the graphene carrier [52-54]. Moreover, the graphene-based nanomaterials (GBN) have been shown to have a number of advantages: stimulation of immune response, inhibition of tumour stem cells, regulation of angiogenesis and hypoxia [55]. In particular, it should be noted that the GBNs exhibit photodynamic and photothermal activity, and can be effectively used as nanoplatforms for targeted delivery of cytostatic drugs.

Figure 2. General structure of graphene oxide

Graphene is known to consist of sp²-hybridised carbon atoms forming two-dimensional nanolayers, while graphene oxide (GO) contains various oxygen-containing oxygen functional groups: (i) carboxyl, carbonyl, and lactol, located at the edges of GO layers; (ii) epoxy and hydroxyl groups distributed on the surface of the GO plane [56-61] (Fig. 2). Reduced GO (rGO) is a variant of GO in which most of the oxygen-containing functional groups are reduced by means of hydrazine hydrate or biomolecules [54, 62].

A graphene monolayer was obtained in 2004 by A. Geim and K. Novoselov [63], while GO was first synthesised in 1859 by B. Brodie by oxidising graphite using a mixture of oxidising agents (potassium chlorate and fuming nitric acid) [64]. However, the most effective method was developed by W. Hammers and R. Offeman in 1957, with a mixture of sulphuric acid, sodium nitrate and potassium permanganate [65]. GO functionalisation can be carried out using various reactions (Fig. 3): amidation, esterification, 1,3-dipolar cycloaddition, halogenation, as well as through non-covalent functionalisation through the formation of hydrogen bonds, π-π stacking and hydrophobic interactions. These reactions make it possible to obtain unique nanomaterials having a medical potential in cancer treatment [66], delivery of drugs and biomolecules [67, 68], development of biosensors [69], as well as substances with antiviral [70], antibacterial [71] and antifungal activity [72]. Among GBN, GO has the greatest potential for use in medicine for the following reasons: (i) GO contains various functional groups that allow further surface functionalisation; (ii) functionalisation of GO increases its biocompatibility; (iii) the presence of oxygen-containing functional groups ensures stability of aqueous GO dispersions.

Figure 3. Basic ways to functionalise graphene oxide

Analysis of the literature revealed a number of research works devoted to synthesis and biological activity of GBN-based conjugates. Zhang et al. [73] reported that covalent GO functionalisation with sulphonic acid and folic acid (GO-SO3H-FA) groups increased the specific cytotoxicity for MCF-7 cells (breast cancer-derived strain). Conjugation of doxorubicin (DOX) and camptothecin (CPT) with GO through its non-covalent functionalisation (due to π-π stacking and hydrophobic interactions) significantly increases therapeutic efficacy as compared to individual drugs. The CPT and DOX loading in the mixed GO-SO₃H-FA-CPT-DOX conjugate was 4.5% and 400%, respectively.

Wang et al. [67] demonstrated that covalent functionalisation of GO with chlorotoxin (CTX) increases the efficiency of drug delivery to C6 glioma cells. At the same time, non-covalent DOX attachment with a loading of 570 mg DOX per gram of CTX-GO significantly increases efficiency of the conjugate (the release of the cytostatic drug was pH-dependent). Fan et al. [74] synthesised a covalent GO-based conjugate with adipic acid dihydrazide and sodium alginate (SA). Then, DOX.HCl was attached non-covalently to GO-SA. The maximum DOX loading was 1.8 mg per 1 mg GO-SA. The highest drug release rate was observed at pH 5.0. Cytotoxicity testing with HeLa (cervical carcinoma) cell line showed that the GO-SA conjugate is not cytotoxic, while GO-SA/DOX exhibits cytotoxicity due to the specific effect on CD44 receptors.

Qin et al. [75] synthesised GO non-covalently conjugated with polyvinylpyrrolidone (PVP, M=30 kDa), and then folic acid (FA) was covalently attached through the formation of an amide bond (carboxyl groups of GO and amino groups of FA). Next, the authors performed non-covalent DOX loading (due to π-π stacking and hydrophobic interactions).

The calculated value of the DOX loading on the FA-GO-PVP was 107.5 wt. %. The resulting conjugate demonstrated high antitumour efficacy against HeLa cells. Huang et al. [76] described the ability of FA-functionalised GO to efficiently bind the chlorine e₆ photosensitiser for photodynamic therapy. Tiwari et al. [77] used the GO-PVP noncovalent conjugate for double noncovalent addition of quercetin (QS) and gefitinib (GF) and compared it with the GO-PVP-QS and GO-PVP-GF conjugates. The authors found that the combined loading of the drugs showed higher cytotoxicity against PA-1 (ovarian cancer) cell line compared to individual drugs. The amount of QS and GF in GO-PVP-QS-GF was 20% and 46%, respectively.

Deb et al. [78] functionalised GO with polyethylene glycol (PEG), FA, and CPT via non-covalent π-π stacking interactions (CPT loading was 45%). The resulting conjugate (C=100 μg∙ml⁻¹) caused the death of 76% of cells compared with the control when using the MCF-7 cell line [78]. The same group functionalised GO with the natural polymer chitosan (CS) and FA, to deliver CPT and 3,3’-diindolylme- thane (DIM). The resulting conjugate (GO-CS-FA-CPT-DIM) demonstrated high cytotoxicity against the MCF-7 cell line (95.7% decrease in cell viability), which was significantly higher compared to individual DIM preparations (42.4%) and CPT (52.6%) [79]. Pei et al. [80] showed that simultaneous functionalisation of the GO surface with PEG (pGO) (pGO-CP-DOX, mass ratio: 1: 0.376: 0.376) with cisplatin (CP) and DOX leads to increased cytotoxicity towards Cal-27 (human squamous carcinoma) and MCF-7 cell lines. The authors observed higher inhibition of cell proliferation for the pGO-CP-DOX conjugate compared to individual preparations: IC₅₀ (MCF-7)=14.5 μg∙ml⁻¹ for pGO-CP-DOX, 22.5 μg∙ml⁻¹ for pGO-DOX, and 22 μg∙ml⁻¹ for pGO-CP [80]. Bullo et al. [81] demonstrated the ability of GO functionalisation using PEG, FA, and anticancer drugs: protocatechuic acid (23.5% PCA) and chlorogenic acid (18.3% CA). The authors investigated the effect of the GO-PEG-FA-PCA-CA conjugate on the HT29 (colon cancer) and HepG2 (liver cancer) cell lines. Cytotoxicity trials showed the following results: IC₅₀ (HT29)=50.7 μg∙ml⁻¹, IC₅₀ (HepG2)=40.4 μg∙ml⁻¹ [81]. Gong et al. [82] demonstrated that fluorinated graphene (FG) can be used to load a mixture of DOX and CPT after CS covalent functionalisation; DOX and CPT loading were 110% and 25%, respectively. The resulting FG-CS-DOX-CPT conjugate demonstrated a 60% and 75% decrease in the viability of HeLa cells with simultaneous laser irradiation (wavelength 808 nm) [82]. Gong et al. [83] evaluated the ability of non-covalent FG conjugation with a cytostatic DOX loading as high as 200%. The FG-DOX conjugate at 30 μg∙ml⁻¹ drug content reduced HeLa cell line viability to 94% after 48 h of incubation [83].

In an in vivo study, Shim et al. [84] showed that rGO functionalised with low-molecular weight heparin (LHT7) acts as a targeted drug for the delivery of DOX. The rGO-LHT7-DOX conjugate with rGO: DOX mass ratios of 2, 1, 0.5, 0.1 demonstrated a high antitumour effect at the KB human carcinoma cell line (cell viability was decreased by 61.1%), along with significant decrease in tumour size by (92.5±3.1)% [84]. Table 1 shows the results of studying cytotoxic conjugates based on GBN and cytostatic drugs.

Table 1. Cytotoxicity of GBN and non-covalently linked cytostatic drugs

Conclusion

Current data provide sufficient results concerning molecular and cellular events providing mutual influence of tumour cells and TME cells, as well as factors of cancer progression. It has been shown that the tumour cells per se and their cellular TME create an integrated system that promotes tumour progression and development of multiple drug resistance.

Thus, the following requirements must be met for modern therapeutic agents: targeted action, polyfunctionality with respect to ability of loading various molecules on the GBN surface, low toxicity, opportunity of selective inactivation of immunosuppressive components in the TME. The last issue deserves special attention. The chance to resolve this complex problem is shown by the example of GBN usage.

List of abbreviations

IL – interleukin
TNF-α – tumour necrosis factor alpha
TGF-β1 – transforming growth factor receptor-β1
VEGF-A – vascular endothelial growth factor A
CAF – cancer-associated fibroblasts
CCL – C-C motif ligand
CCR2 – C-C chemokine receptor type 2
CPT – camptothecin
CSF-1 – the colony stimulating factor 1
CTX – chlorotoxin
CXCL – the chemokine (C-X-C motif) ligand
DOX – doxorubicin
FA – folic acid
GBN – graphene-based nanomaterials
GO – graphene oxide
iNOS – Inducible nitric oxide synthase
bFGF – basic fibroblast growth factor
FGF1 – fibroblast growth factor 1
HIF-1α – hypoxia inducible factor 1 subunit alpha
PD-L1 – ligand of programmed death-1 receptor
PLGF – placental growth factor
STAT3 – signal transducer and activator of transcription 3
Th – T helper cells
TME – tumour microenvironment

Acknowledgement

This work was financially supported by the Ministry of Health of the Russian Federation (state assignment Э.03-2021; 121040200136-0).

Conflict of interests

The authors declared no potential conflict of interest.

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Tian J, Luo Y, Huang L, Feng Y, Ju H, Yu BY. Pegylated folate and peptide-decorated graphene oxide nanovehicle for in vivo targeted delivery of anticancer drugs and therapeutic self-monitoring. Biosens Bioelectron. 2016; 80:519-524. doi: 10.1016/j.bios.2016.02.018
Javanbakht S, Namazi H. Doxorubicin loaded carboxymethyl cellulose/graphene quantum dot nanocomposite hydrogel films as a potential anticancer drug delivery system. Mater Sci Eng C. 2018; 87:50-59. doi: 10.1016/j.msec.2018.02.010
Karki N, Tiwari H, Pal M, Chaurasia A, Bal R, Joshi P, et al. Functionalized graphene oxides for drug loading, release and delivery of poorly water soluble anticancer drug: A comparative study. Colloids Surfaces B Biointerfaces. 2018; 169:265-272.
doi: 10.1016/j.colsurfb.2018.05.022

" ["~DETAIL_TEXT"]=> string(51376) "

Introduction

Figure 1. Influence of various immune cell populations upon TME

Abbreviations: NK, natural killers; Neu, neutrophils; MI, type I macrophages; DC, dendritic cells.

Current experience with graphene carriers

Figure 2. General structure of graphene oxide

Figure 3. Basic ways to functionalise graphene oxide

Table 1. Cytotoxicity of GBN and non-covalently linked cytostatic drugs

Conclusion

List of abbreviations

Acknowledgement

This work was financially supported by the Ministry of Health of the Russian Federation (state assignment Э.03-2021; 121040200136-0).

Conflict of interests

The authors declared no potential conflict of interest.

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Ma N, Liu J, He W, Li Z, Luan Y, Song Y, et al. Folic acid-grafted bovine serum albumin decorated graphene oxide: An efficient drug carrier for targeted cancer therapy. J Colloid Interface Sci. 2017; 490:598-607. doi: 10.1016/j.jcis.2016.11.097
Tian J, Luo Y, Huang L, Feng Y, Ju H, Yu BY. Pegylated folate and peptide-decorated graphene oxide nanovehicle for in vivo targeted delivery of anticancer drugs and therapeutic self-monitoring. Biosens Bioelectron. 2016; 80:519-524. doi: 10.1016/j.bios.2016.02.018
Javanbakht S, Namazi H. Doxorubicin loaded carboxymethyl cellulose/graphene quantum dot nanocomposite hydrogel films as a potential anticancer drug delivery system. Mater Sci Eng C. 2018; 87:50-59. doi: 10.1016/j.msec.2018.02.010
Karki N, Tiwari H, Pal M, Chaurasia A, Bal R, Joshi P, et al. Functionalized graphene oxides for drug loading, release and delivery of poorly water soluble anticancer drug: A comparative study. Colloids Surfaces B Biointerfaces. 2018; 169:265-272.
doi: 10.1016/j.colsurfb.2018.05.022

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В данном обзоре обобщены экспериментальные данные по созданию ковалентных и нековалентных конъюгатов на основе оксида графена и показана их эффективность in vitro на различных опухолевых клеточных линиях. Отдельно представлены немногочисленные данные по влиянию наноматериалов на основе оксида графена на опухолевое микроокружение. <h2>Ключевые слова</h2> Опухоль, микроокружение, прогрессирование, цитокины, ацидоз, иммунная система, углеродные наноматериалы." ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(279) "Взаимное влияние опухолевых клеток и клеток микроокружения опухоли. Перспективы манипулирования опухолевым микроокружением с помощью наноматериалов" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(279) "Взаимное влияние опухолевых клеток и клеток микроокружения опухоли. Перспективы манипулирования опухолевым микроокружением с помощью наноматериалов" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(279) "Взаимное влияние опухолевых клеток и клеток микроокружения опухоли. Перспективы манипулирования опухолевым микроокружением с помощью наноматериалов" ["SECTION_META_TITLE"]=> string(279) "Взаимное влияние опухолевых клеток и клеток микроокружения опухоли. Перспективы манипулирования опухолевым микроокружением с помощью наноматериалов" ["SECTION_META_KEYWORDS"]=> string(279) "Взаимное влияние опухолевых клеток и клеток микроокружения опухоли. Перспективы манипулирования опухолевым микроокружением с помощью наноматериалов" ["SECTION_META_DESCRIPTION"]=> string(279) "Взаимное влияние опухолевых клеток и клеток микроокружения опухоли. Перспективы манипулирования опухолевым микроокружением с помощью наноматериалов" ["SECTION_PICTURE_FILE_ALT"]=> string(279) "Взаимное влияние опухолевых клеток и клеток микроокружения опухоли. Перспективы манипулирования опухолевым микроокружением с помощью наноматериалов" ["SECTION_PICTURE_FILE_TITLE"]=> string(279) "Взаимное влияние опухолевых клеток и клеток микроокружения опухоли. 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array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "28395" ["VALUE"]=> array(2) { ["TEXT"]=> string(460) "Анна М. Малкова1,2, Сергей В. Агеев1,2, Абделсаттар О. Е. Абделхалим2,3, Олег Е. Молчанов4, Дмитрий Н. Майстренко4, Константин Н. Семенов1,2,4, Владимир В. Шаройко1,2,4" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(364) "

Анна М. Малкова^1,2, Сергей В. Агеев^1,2, Абделсаттар О. Е. Абделхалим^2,3, Олег Е. Молчанов⁴, Дмитрий Н. Майстренко⁴, Константин Н. Семенов^1,2,4, Владимир В. Шаройко^1,2,4

" ["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(5) "28396" ["VALUE"]=> array(2) { ["TEXT"]=> string(976) "1 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия 2 Институт химии, Санкт-Петербургский государственный университет, Санкт-Петербург, Россия 3 Отдел исследования окружающей среды, Национальный центр социальных и криминологических исследований, Гиза, Арабская Республика Египет 4 Российский научный центр радиологии и хирургических технологий имени A. M. Гранова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(898) "

¹ Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
² Институт химии, Санкт-Петербургский государственный университет, Санкт-Петербург, Россия
³ Отдел исследования окружающей среды, Национальный центр социальных и криминологических исследований, Гиза, Арабская Республика Египет
⁴ Российский научный центр радиологии и хирургических технологий имени A. M. Гранова, 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(5) "28397" ["VALUE"]=> array(2) { ["TEXT"]=> string(3236) "Развитие и прогрессирование неоплазий происходит одновременно с изменениями окружающей стромы. Раковые клетки могут функционально формировать свое микроокружение за счет секреции различных цитокинов, хемокинов и формирования кислой среды. Данные факторы способствуют дифференциации иммунных клеток по иммуносупрессивному фенотипу, стимулируют синтез ряда ферментов обмена аминокислот, факторов роста, молекул адгезии, что промотирует инвазию, ангиогенез и метастазирование, а также снижает эффективность действия противоопухолевых препаратов и лучевой терапии. Для повышения эффективности химиотерапии возможно использование мультитаргетных углеродных наноматериалов. В частности, наноматериалы на основе модифицированного графена позволяют создавать многокомпонентные терапевтические конструкции, включающие макромолекулы, полимеры и эффекторные агенты. Первоначальные эксперименты с немодифицированными графенами продемонстрировали их токсичность, связанную с их накоплением в паренхиматозных органах и инициированием воспалительных процессов. В последние несколько лет вышла серия работ, в которых продемонстрирована возможность снижения токсичности оксида графена за счет функционализации. В данном обзоре обобщены экспериментальные данные по созданию ковалентных и нековалентных конъюгатов на основе оксида графена и показана их эффективность in vitro на различных опухолевых клеточных линиях. Отдельно представлены немногочисленные данные по влиянию наноматериалов на основе оксида графена на опухолевое микроокружение. <h2>Ключевые слова</h2> Опухоль, микроокружение, прогрессирование, цитокины, ацидоз, иммунная система, углеродные наноматериалы." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3168) "

Развитие и прогрессирование неоплазий происходит одновременно с изменениями окружающей стромы. Раковые клетки могут функционально формировать свое микроокружение за счет секреции различных цитокинов, хемокинов и формирования кислой среды. Данные факторы способствуют дифференциации иммунных клеток по иммуносупрессивному фенотипу, стимулируют синтез ряда ферментов обмена аминокислот, факторов роста, молекул адгезии, что промотирует инвазию, ангиогенез и метастазирование, а также снижает эффективность действия противоопухолевых препаратов и лучевой терапии. Для повышения эффективности химиотерапии возможно использование мультитаргетных углеродных наноматериалов. В частности, наноматериалы на основе модифицированного графена позволяют создавать многокомпонентные терапевтические конструкции, включающие макромолекулы, полимеры и эффекторные агенты. Первоначальные эксперименты с немодифицированными графенами продемонстрировали их токсичность, связанную с их накоплением в паренхиматозных органах и инициированием воспалительных процессов. В последние несколько лет вышла серия работ, в которых продемонстрирована возможность снижения токсичности оксида графена за счет функционализации. В данном обзоре обобщены экспериментальные данные по созданию ковалентных и нековалентных конъюгатов на основе оксида графена и показана их эффективность in vitro на различных опухолевых клеточных линиях. Отдельно представлены немногочисленные данные по влиянию наноматериалов на основе оксида графена на опухолевое микроокружение.

Ключевые слова

Опухоль, микроокружение, прогрессирование, цитокины, ацидоз, иммунная система, углеродные наноматериалы.

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Anna M. Malkova^1,2, Sergei V. Ageev^1,2, Abdelsattar O. E. Abdelhalim^2,3, Oleg E. Molchanov⁴, Dmitrii N. Maistrenko 4, Konstantin N. Semenov^1,2,4, Vladimir V. Sharoyko^1,2,4

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¹ Pavlov University, St. Petersburg, Russia
² Institute of Chemistry, St. Petersburg State University, Saint Petersburg, Russia
³ National Center for Social and Criminological Research, Giza, Arab Republic of Egypt
⁴ A. M. Granov Russian Research Centre for Radiology and Surgical Technologies, St. Petersburg, Russia

Correspondence:
Dr. Vladimir V. Sharoyko, Pavlov University, 6-8 L. Tolstoy St., 197022, St. Petersburg, Russia
Phone: +7 (981) 936-41-51
E-mail: sharoyko@gmail.com

Citation: Malkova AM, Ageev SV, Abdelhalim AOE et al. Mutual influence of malignant cells and cellular microenvironment: prospects for manipulating tumour microenvironment with nanomaterials. Cell Ther Transplant 2021; 10(3-4): 8-18.

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Development and progression of neoplasia occurs in parallel with changes in the surrounding stroma. Cancer cells may functionally reshape their microenvironment by secreting various cytokines, chemokines and generation of acidic medium. These factors contribute to differentiation of immune cells into immunosuppressive phenotype, stimulate the synthesis of a number of amino acid metabolism enzymes, growth factors, adhesion molecules, which promote invasion, angiogenesis and metastasis, and also reduce efficiency of anticancer drugs and radiation therapy. To increase effectiveness of the chemotherapy, multitargeted carbon nanomaterials may be applied. In particular, nanomaterials based on modified graphene make it possible to create multicomponent therapeutic constructs, including macromolecules, polymers, and effector agents. Initial experiments with unmodified graphenes demonstrated their toxicity associated with their accumulation in parenchymal organs and initiation of inflammatory processes. In the past few years, a series of works has been published in which the possibility of reducing the toxicity of graphene oxide through functionalisation has been demonstrated. This review summarises the experimental data on the creation of covalent and non-covalent conjugates based on graphene oxide and demonstrates their in vitro efficacy on various tumour cell lines. Separately, there are few data on the effect of nanomaterials based on graphene oxide on the tumour microenvironment.

Keywords

Tumour, microenvironment, progression, cytokines, acidosis, immune system, carbon nanomaterials.

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["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(5) "28399" ["VALUE"]=> array(2) { ["TEXT"]=> string(328) "Anna M. Malkova1,2, Sergei V. Ageev1,2, Abdelsattar O. E. Abdelhalim2,3, Oleg E. Molchanov4, Dmitrii N. Maistrenko 4, Konstantin N. Semenov1,2,4, Vladimir V. Sharoyko1,2,4" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(244) "

Anna M. Malkova^1,2, Sergei V. Ageev^1,2, Abdelsattar O. E. Abdelhalim^2,3, Oleg E. Molchanov⁴, Dmitrii N. Maistrenko 4, Konstantin N. Semenov^1,2,4, Vladimir V. Sharoyko^1,2,4

" } ["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(5) "28401" ["VALUE"]=> array(2) { ["TEXT"]=> string(1764) "Development and progression of neoplasia occurs in parallel with changes in the surrounding stroma. Cancer cells may functionally reshape their microenvironment by secreting various cytokines, chemokines and generation of acidic medium. These factors contribute to differentiation of immune cells into immunosuppressive phenotype, stimulate the synthesis of a number of amino acid metabolism enzymes, growth factors, adhesion molecules, which promote invasion, angiogenesis and metastasis, and also reduce efficiency of anticancer drugs and radiation therapy. To increase effectiveness of the chemotherapy, multitargeted carbon nanomaterials may be applied. In particular, nanomaterials based on modified graphene make it possible to create multicomponent therapeutic constructs, including macromolecules, polymers, and effector agents. Initial experiments with unmodified graphenes demonstrated their toxicity associated with their accumulation in parenchymal organs and initiation of inflammatory processes. In the past few years, a series of works has been published in which the possibility of reducing the toxicity of graphene oxide through functionalisation has been demonstrated. This review summarises the experimental data on the creation of covalent and non-covalent conjugates based on graphene oxide and demonstrates their in vitro efficacy on various tumour cell lines. Separately, there are few data on the effect of nanomaterials based on graphene oxide on the tumour microenvironment. <h2>Keywords</h2> Tumour, microenvironment, progression, cytokines, acidosis, immune system, carbon nanomaterials." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1696) "

Keywords

Tumour, microenvironment, progression, cytokines, acidosis, immune system, carbon nanomaterials.

Keywords

Tumour, microenvironment, progression, cytokines, acidosis, immune system, carbon nanomaterials.

" } ["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(5) "28398" ["VALUE"]=> string(39) "10.18620/ctt-1866-8836-2021-10-3-4-8-18" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(39) "10.18620/ctt-1866-8836-2021-10-3-4-8-18" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(39) "10.18620/ctt-1866-8836-2021-10-3-4-8-18" } ["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(5) "28402" ["VALUE"]=> string(136) "Mutual influence of malignant cells and cellular microenvironment: prospects for manipulating tumour microenvironment with nanomaterials" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(136) "Mutual influence of malignant cells and cellular microenvironment: prospects for manipulating tumour microenvironment with nanomaterials" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(136) "Mutual influence of malignant cells and cellular microenvironment: prospects for manipulating tumour microenvironment with nanomaterials" } ["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(5) "28400" ["VALUE"]=> array(2) { ["TEXT"]=> string(992) "1 Pavlov University, St. Petersburg, Russia 2 Institute of Chemistry, St. Petersburg State University, Saint Petersburg, Russia 3 National Center for Social and Criminological Research, Giza, Arab Republic of Egypt 4 A. M. Granov Russian Research Centre for Radiology and Surgical Technologies, St. Petersburg, Russia Correspondence: Dr. Vladimir V. Sharoyko, Pavlov University, 6-8 L. Tolstoy St., 197022, St. Petersburg, Russia Phone: +7 (981) 936-41-51 E-mail: sharoyko@gmail.com Citation: Malkova AM, Ageev SV, Abdelhalim AOE et al. Mutual influence of malignant cells and cellular microenvironment: prospects for manipulating tumour microenvironment with nanomaterials. Cell Ther Transplant 2021; 10(3-4): 8-18." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(836) "

Correspondence:
Dr. Vladimir V. Sharoyko, Pavlov University, 6-8 L. Tolstoy St., 197022, St. Petersburg, Russia
Phone: +7 (981) 936-41-51
E-mail: sharoyko@gmail.com

" } ["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(5) "28395" ["VALUE"]=> array(2) { ["TEXT"]=> string(460) "Анна М. Малкова1,2, Сергей В. Агеев1,2, Абделсаттар О. Е. Абделхалим2,3, Олег Е. Молчанов4, Дмитрий Н. Майстренко4, Константин Н. Семенов1,2,4, Владимир В. Шаройко1,2,4" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(364) "

" } ["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(5) "28397" ["VALUE"]=> array(2) { ["TEXT"]=> string(3236) "Развитие и прогрессирование неоплазий происходит одновременно с изменениями окружающей стромы. Раковые клетки могут функционально формировать свое микроокружение за счет секреции различных цитокинов, хемокинов и формирования кислой среды. Данные факторы способствуют дифференциации иммунных клеток по иммуносупрессивному фенотипу, стимулируют синтез ряда ферментов обмена аминокислот, факторов роста, молекул адгезии, что промотирует инвазию, ангиогенез и метастазирование, а также снижает эффективность действия противоопухолевых препаратов и лучевой терапии. Для повышения эффективности химиотерапии возможно использование мультитаргетных углеродных наноматериалов. В частности, наноматериалы на основе модифицированного графена позволяют создавать многокомпонентные терапевтические конструкции, включающие макромолекулы, полимеры и эффекторные агенты. Первоначальные эксперименты с немодифицированными графенами продемонстрировали их токсичность, связанную с их накоплением в паренхиматозных органах и инициированием воспалительных процессов. В последние несколько лет вышла серия работ, в которых продемонстрирована возможность снижения токсичности оксида графена за счет функционализации. В данном обзоре обобщены экспериментальные данные по созданию ковалентных и нековалентных конъюгатов на основе оксида графена и показана их эффективность in vitro на различных опухолевых клеточных линиях. Отдельно представлены немногочисленные данные по влиянию наноматериалов на основе оксида графена на опухолевое микроокружение. <h2>Ключевые слова</h2> Опухоль, микроокружение, прогрессирование, цитокины, ацидоз, иммунная система, углеродные наноматериалы." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3168) "

Ключевые слова

Опухоль, микроокружение, прогрессирование, цитокины, ацидоз, иммунная система, углеродные наноматериалы.

Ключевые слова

Опухоль, микроокружение, прогрессирование, цитокины, ацидоз, иммунная система, углеродные наноматериалы.

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