Publications by authors named "M V Ryzhova"

97 Publications

ABCB1 inhibition provides a novel therapeutic target to block TWIST1-induced migration in medulloblastoma.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab030. Epub 2021 Apr 28.

Children's Brain Tumour Research Centre, Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham, UK.

Background: Therapeutic intervention in metastatic medulloblastoma is dependent on elucidating the underlying metastatic mechanism. We investigated whether an epithelial-mesenchymal transition (EMT)-like pathway could drive medulloblastoma metastasis.

Methods: A 3D Basement Membrane Extract (3D-BME) model was used to investigate medulloblastoma cell migration. Cell line growth was quantified with AlamarBlue metabolic assays and the morphology assessed by time-lapse imaging. Gene expression was analyzed by qRT-PCR and protein expression by immunohistochemistry of patient tissue microarrays and mouse orthotopic xenografts. Chromatin immunoprecipitation was used to determine whether the EMT transcription factor TWIST1 bound to the promoter of the multidrug pump . TWIST1 was overexpressed in MED6 cells by lentiviral transduction (MED6-TWIST1). Inhibition of ABCB1 was mediated by vardenafil, and TWIST1 expression was reduced by either Harmine or shRNA.

Results: Metastatic cells migrated to form large metabolically active aggregates, whereas non-tumorigenic/non-metastatic cells formed small aggregates with decreasing metabolic activity. TWIST1 expression was upregulated in the 3D-BME model. TWIST1 and ABCB1 were significantly associated with metastasis in patients ( = .041 and = .04, respectively). High nuclear TWIST1 expression was observed in the invasive edge of the MED1 orthotopic model, and TWIST1 knockdown in cell lines was associated with reduced cell migration ( < .05). TWIST1 bound to the promoter ( = .03) and induced cell aggregation in metastatic and TWIST1-overexpressing, non-metastatic (MED6-TWIST1) cells, which was significantly attenuated by vardenafil ( < .05).

Conclusions: In this study, we identified a TWIST1-ABCB1 signaling axis during medulloblastoma migration, which can be therapeutically targeted with the clinically approved ABCB1 inhibitor, vardenafil.
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http://dx.doi.org/10.1093/noajnl/vdab030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080134PMC
April 2021

Cross-species genomics reveals oncogenic dependencies in ZFTA/C11orf95 fusion-positive supratentorial ependymomas.

Cancer Discov 2021 Apr 20. Epub 2021 Apr 20.

Department of Neuropathology, Charite Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health.

Molecular groups of supratentorial ependymomas comprise tumors with ZFTA-RELA or YAP1-involving fusions and fusion-negative subependymoma. However, occasionally supratentorial ependymomas cannot be readily assigned to any of these groups due to lack of detection of a typical fusion and/or ambiguous DNA methylation-based classification. An unbiased approach with a cohort of unprecedented size revealed distinct methylation clusters composed of tumors with ependymal but also various other histological features containing alternative translocations that shared ZFTA as a partner gene. Somatic overexpression of ZFTA-associated fusion genes in the developing cerebral cortex is capable of inducing tumor formation in vivo, and cross-species comparative analyses identified GLI2 as a key downstream regulator of tumorigenesis in all tumors. Targeting GLI2 with arsenic trioxide caused extended survival of tumor-bearing animals, indicating a potential therapeutic vulnerability in ZFTA fusion-positive tumors.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0963DOI Listing
April 2021

[Stereotactic irradiation in the complex treatment of patients with intracranial pilocytic astrocytoma].

Zh Vopr Neirokhir Im N N Burdenko 2021 ;85(2):34-46

Burdenko Neurosurgical Center, Moscow, Russia.

Complex management of patients with intracranial pilocytic astrocytoma (PA) consists of surgical treatment, drug therapy (mainly in young children) and radiotherapy. For many years, radiotherapy (RT) has been a standard for residual tumors, recurrence or continued growth of PA. Currently, stereotactic radiosurgery and radiotherapy are preferred for PA, because these procedures are characterized by high conformity and selectivity, precise irradiation of tumor with minimal damage to surrounding intact tissues. Stereotaxic approach is very important since PAs are localized near functionally significant and radiosensitive brain structures in most cases. There is significant experience of single-center studies devoted to radiotherapy of patients with PA at the Department of Neuroradiosurgery of the Burdenko Neurosurgery Center. In this research, the authors analyzed the results of stereotactic irradiation of 430 patients with PA for the period from 2005 to 2018.
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http://dx.doi.org/10.17116/neiro20218502134DOI Listing
April 2021

[Influence of resection quality on postoperative outcomes in children with atypical teratoid-rhabdoid tumor of the central nervous system].

Zh Vopr Neirokhir Im N N Burdenko 2021 ;85(2):17-25

Voino-Yasenetsky Research and Practical Center for Specialized Medical Care, Moscow, Russia.

The purpose of this study was to assess the influence of resection quality on overall survival and disease-free survival in children with atypical teratoid-rhabdoid tumors (ATRT). The study included children younger than 18 years old for the period from 2008 to 2019. There were 134 interventions in 105 patients with ATRT including 11 redo resections («second-look» surgery) and 18 procedures for tumor recurrence. Age of patients ranged from 2 to 168 months (median 21 months). Patients with supratentorial tumors prevailed (50.5%), infratentorial neoplasms were diagnosed in 45.7% of patients, spinal cord lesion - 3.8% of cases. At the first stage, all patients underwent surgical treatment. Total resection was achieved in 34 (32.4%) patients, subtotal - 37 (35.2%) patients, partial resection - 30 (28.6%) patients. Biopsy was performed in 4 (3.8%) patients. Quality of resection and age at surgery significantly influenced overall and disease-free survival. Extended resection of tumor followed by adjuvant chemo- and radiotherapy are required to improve survival although ATRTs are high-grade neoplasms with poor prognosis.
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http://dx.doi.org/10.17116/neiro20218502117DOI Listing
April 2021

[Central neurocytomas: long-term treatment outcomes].

Zh Vopr Neirokhir Im N N Burdenko 2021 ;85(2):5-16

Burdenko Neurosurgical Center, Moscow, Russia.

Central neurocytoma is a rare benign brain tumor. These tumors may be giant and accompanied by compression of ventricular system and surrounding structures. Modern treatment of brain neurocytoma includes extended resection and restoration of normal CSF circulation. Surgical treatment does not often lead to total resection of these tumors. Redo resection was preferred in patients with tumor progression for a long time. In the last decade, various authors report stereotactic irradiation for continued tumor growth to ensure local growth control. This study was aimed at evaluation of postoperative outcomes in patients with brain neurocytomas, as well as treatment of tumor progression in long-term period.

Objective: To analyze recurrence-free survival in patients with brain neurocytomas, risk factors of recurrence-free survival, effectiveness of various treatments for tumor progression and delayed complications.

Material And Methods: Long-term postoperative follow-up data of patients with brain neurocytomas are reported in the manuscript. We analyzed recurrence-free survival and risk factors of recurrence-free survival, treatment outcomes in patients with progression of brain neurocytomas, long-term complications and their prevention.

Results: Follow-up included 84 out of 115 patients with brain neurocytoma after surgical treatment in 2008-2017. Follow-up period ranged from 2 to 10 years (mean 6 years) after resection. Most patients had regression of neurological symptoms after surgery. Continued tumor growth within 12-96 months after surgery occurred in 26 (30.19%) out of 84 patients (19 cases after partial resection and 7 cases after total resection according to MRI data). Two-year recurrence-free survival was 94%, 5-year survival - 83%. Risk factors of continued tumor growth were resection quality and Ki-67 index. Redo resection was performed in 7 cases. Eleven patients underwent stereotactic irradiation for tumor progression. Indications for stereotactic irradiation of central neurocytoma are MR data on continued growth of lateral ventricle tumor without signs of ICH and CSF flow impairment. There were no cases of hemorrhage inside the residual tumor and CSF flow impairment in early postoperative period after redo resection. In all cases (=11), stereotactic irradiation (mean follow-up 2.5 years) ensured satisfactory control of tumor growth with reduction of the neoplasm in 4 cases and no tumor growth in 7 cases.

Conclusion: Resection of central neurocytoma ensures long-term recurrence-free period. The main causes of tumor recurrence are partial resection and high proliferative activity (Ki-67 index over 5%). Redo resection is advisable for tumor progression followed by CSF flow impairment. In case of continued growth of neurocytoma without signs of intracranial hypertension, stereotactic irradiation with various fractionation modes ensures effective and safe control of tumor growth.
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http://dx.doi.org/10.17116/neiro2021850215DOI Listing
April 2021