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    Π˜ΠΌΠΌΡƒΠ½ΠΎΠ»ΠΎΠ³ΠΈΡ ΠΈ пСрспСктивы ΠΈΠΌΠΌΡƒΠ½ΠΎΡ‚Π΅Ρ€Π°ΠΏΠΈΠΈ злокачСствСнных Π³Π»ΠΈΠΎΠΌ: использованиС Ρ„Π°ΠΊΡ‚ΠΎΡ€ΠΎΠ² Π³ΡƒΠΌΠΎΡ€Π°Π»ΡŒΠ½ΠΎΠ³ΠΎ ΠΈΠΌΠΌΡƒΠ½ΠΈΡ‚Π΅Ρ‚Π°

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    High-grade gliomas are aggressive brain tumors with limited survival rates. To date the maximum of survival benefit of conventional therapeutic options has been already reached and innovative treatment strategies, based on tumor biology are urgently needed. Generally, malignant gliomas, including glioblastoma, are immunologically β€œcold: neoplasms, with weak anti-tumor immune response and peritumoral inflammation, caused by reduced expression of neoantigens by tumor cells and restricted immunoreactivity of the microenvironment. The reduced immunogenicity of brain structures is conditioned by the absence of homing molecules for white blood cells on them, as well as the suppression of activated (CD178+) T cells by brain gangliosides. The cell population infiltrating malignant glioma is impoverished with cytotoxic T cells (CD8+ FOXP3–) and oppositely enriched with regulatory T cells and type 2 macrophages (M2). An effective anti-glioma immune response is resulted in increasing the total number of tumor-infiltrating lymphocytes and the CD8+ cell content; switching the functional activity of macrophages from M2 to M1 type. Integration of immunotherapeutic technologies (vaccines and monoclonal antibodies) into treatment strategies of malignant gliomas is relevant and promising approach based on biological features of the tumor.Π“Π»ΠΈΠΎΠΌΡ‹ высокой стСпСни злокачСствСнности – агрСссивныС ΠΎΠΏΡƒΡ…ΠΎΠ»ΠΈ Ρ†Π΅Π½Ρ‚Ρ€Π°Π»ΡŒΠ½ΠΎΠΉ Π½Π΅Ρ€Π²Π½ΠΎΠΉ систСмы. Бтандартная химиолучСвая тСрапия Π΄Π°Π½Π½Ρ‹Ρ… Π½ΠΎΠ²ΠΎΠΎΠ±Ρ€Π°Π·ΠΎΠ²Π°Π½ΠΈΠΉ Π½Π΅ являСтся ΠΊΡƒΡ€Π°Ρ‚ΠΈΠ²Π½ΠΎΠΉ ΠΎΠΏΡ†ΠΈΠ΅ΠΉ, поэтому ΠΏΠΎΠΏΡ‹Ρ‚ΠΊΠΈ усилСния ΠΈ ΠΈΠ½Π΄ΠΈΠ²ΠΈΠ΄ΡƒΠ°Π»ΠΈΠ·Π°Ρ†ΠΈΠΈ ΠΈΡ… лСчСния Π½Π° сСгодняшний дСнь ΠΏΡ€Π΅Π΄ΠΏΠΎΠ»Π°Π³Π°ΡŽΡ‚ воздСйствиС Π½Π° патогСнСтичСскиС ΠΌΠ΅Ρ…Π°Π½ΠΈΠ·ΠΌΡ‹ роста ΠΎΠΏΡƒΡ…ΠΎΠ»ΠΈ Π½Π° ΠΊΠ»Π΅Ρ‚ΠΎΡ‡Π½ΠΎΠΌ ΠΈ молСкулярно-гСнСтичСском уровнях. ЗлокачСствСнныС Π³Π»ΠΈΠΎΠΌΡ‹, Π² ΠΏΠ΅Ρ€Π²ΡƒΡŽ ΠΎΡ‡Π΅Ρ€Π΅Π΄ΡŒ глиобластомы, ΡΠ²Π»ΡΡŽΡ‚ΡΡ Β«Ρ…ΠΎΠ»ΠΎΠ΄Π½Ρ‹ΠΌΠΈΒ» опухолями, Π² ΠΊΠΎΡ‚ΠΎΡ€Ρ‹Ρ… ΠΈΠΌΠΌΡƒΠ½Π½Ρ‹ΠΉ ΠΎΡ‚Π²Π΅Ρ‚ ΠΈ ΠΏΠ΅Ρ€ΠΈΡ‚ΡƒΠΌΠΎΡ€Π°Π»ΡŒΠ½ΠΎΠ΅ воспалСниС ΠΏΡ€ΠΎΡΠ²Π»ΡΡŽΡ‚ΡΡ слабо. Π­Ρ‚ΠΎ ΠΎΠ±ΡŠΡΡΠ½ΡΠ΅Ρ‚ΡΡ сниТСнной экспрСссиСй Π½Π΅ΠΎΠ°Π½Ρ‚ΠΈΠ³Π΅Π½ΠΎΠ² ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²Ρ‹ΠΌΠΈ ΠΊΠ»Π΅Ρ‚ΠΊΠ°ΠΌΠΈ ΠΈ Π½ΠΈΠ·ΠΊΠΎΠΉ ΠΈΠΌΠΌΡƒΠ½ΠΎΡ€Π΅Π°ΠΊΡ‚ΠΈΠ²Π½ΠΎΡΡ‚ΡŒΡŽ микроокруТСния. ΠšΠ»Π΅Ρ‚ΠΊΠΈ Ρ†Π΅Π½Ρ‚Ρ€Π°Π»ΡŒΠ½ΠΎΠΉ Π½Π΅Ρ€Π²Π½ΠΎΠΉ систСмы Π»ΠΈΡˆΠ΅Π½Ρ‹ ΠΌΠΎΠ»Π΅ΠΊΡƒΠ» для Ρ…ΠΎΠΌΠΈΠ½Π³Π° Π»Π΅ΠΉΠΊΠΎΡ†ΠΈΡ‚ΠΎΠ², Π° повСрхностныС соСдинСния – Π³Π°Π½Π³Π»ΠΈΠΎΠ·ΠΈΠ΄Ρ‹ – ΠΎΠΊΠ°Π·Ρ‹Π²Π°ΡŽΡ‚ прямоС ΠΈΠ½Π³ΠΈΠ±ΠΈΡ€ΡƒΡŽΡ‰Π΅Π΅ воздСйствиС Π½Π° CD178+-цитотоксичСскиС Π’-Π»ΠΈΠΌΡ„ΠΎΡ†ΠΈΡ‚Ρ‹. Π­Ρ‚ΠΎ ΠΏΡ€ΠΈΠ²ΠΎΠ΄ΠΈΡ‚ ΠΊ Ρ‚ΠΎΠΌΡƒ, Ρ‡Ρ‚ΠΎ популяция Π»Π΅ΠΉΠΊΠΎΡ†ΠΈΡ‚ΠΎΠ², ΠΈΠ½Ρ„ΠΈΠ»ΡŒΡ‚Ρ€ΠΈΡ€ΡƒΡŽΡ‰ΠΈΡ… ΠΎΠΏΡƒΡ…ΠΎΠ»ΡŒ, прСдставлСна Π² основном ΠΊΠ»Π΅Ρ‚ΠΊΠ°ΠΌΠΈ, ΠΎΡ‚Ρ€ΠΈΡ†Π°Ρ‚Π΅Π»ΡŒΠ½ΠΎ Ρ€Π΅Π³ΡƒΠ»ΠΈΡ€ΡƒΡŽΡ‰ΠΈΠΌΠΈ ΠΈΠΌΠΌΡƒΠ½Π½Ρ‹ΠΉ ΠΎΡ‚Π²Π΅Ρ‚ (рСгуляторными (CD4+ CD25+ FOXP3+) T-Π»ΠΈΠΌΡ„ΠΎΡ†ΠΈΡ‚Π°ΠΌΠΈ ΠΈ ΠΌΠ°ΠΊΡ€ΠΎΡ„Π°Π³Π°ΠΌΠΈ 2-Π³ΠΎ Ρ‚ΠΈΠΏΠ°). ΠœΠ°ΠΊΡ€ΠΎΡ„Π°Π³ΠΈ 2-Π³ΠΎ Ρ‚ΠΈΠΏΠ° ΠΈΠ½Π³ΠΈΠ±ΠΈΡ€ΡƒΡŽΡ‚ ΠΊΠ»Π΅Ρ‚ΠΎΡ‡Π½Ρ‹ΠΉ ΠΈΠΌΠΌΡƒΠ½Π½Ρ‹ΠΉ ΠΎΡ‚Π²Π΅Ρ‚, ΡΡ‚ΠΈΠΌΡƒΠ»ΠΈΡ€ΡƒΡŽΡ‚ Π½Π΅ΠΎΠ°Π½Π³ΠΈΠΎΠ³Π΅Π½Π΅Π· ΠΈ ΡΠΎΠ·Π΄Π°ΡŽΡ‚ условия для мСтастатичСского распространСния ΠΊΠ»Π΅Ρ‚ΠΎΠΊ ΠΎΠΏΡƒΡ…ΠΎΠ»ΠΈ.Π˜Π½Ρ‚Π΅Π³Ρ€Π°Ρ†ΠΈΡ Π² Π»Π΅Ρ‡Π΅Π½ΠΈΠΈ ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅ΠΉ Ρ†Π΅Π½Ρ‚Ρ€Π°Π»ΡŒΠ½ΠΎΠΉ Π½Π΅Ρ€Π²Π½ΠΎΠΉ систСмы иммунотСрапСвтичСских ΠΏΠΎΠ΄Ρ…ΠΎΠ΄ΠΎΠ², Π² Ρ‚ΠΎΠΌ числС ΠΏΡ€ΠΈΠΌΠ΅Π½Π΅Π½ΠΈΠ΅ Π²Π°ΠΊΡ†ΠΈΠ½ ΠΈ ΠΌΠΎΠ½ΠΎΠΊΠ»ΠΎΠ½Π°Π»ΡŒΠ½Ρ‹Ρ… Π°Π½Ρ‚ΠΈΡ‚Π΅Π», являСтся Π°ΠΊΡ‚ΡƒΠ°Π»ΡŒΠ½ΠΎΠΉ стратСгиСй, основанной Π½Π° биологичСских свойствах ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²ΠΎΠΉ Ρ‚ΠΊΠ°Π½ΠΈ

    Geographical Distribution, Incidence, Malignancies, and Outcome of 136 Eastern Slavic Patients With Nijmegen Breakage Syndrome and NBN Founder Variant c.657_661del5

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    Nijmegen breakage syndrome (NBS) is a DNA repair disorder characterized by combined immunodeficiency and a high predisposition to lymphoid malignancies. The majority of NBS patients are identified with a homozygous five base pair deletion in the Nibrin (NBN) gene (c.657_661del5, p.K219fsX19) with a founder effect observed in Caucasian European populations, especially of Slavic origin. We present here an analysis of a cohort of 136 NBS patients of Eastern Slav origin across Belarus, Ukraine, Russia, and Latvia with a focus on understanding the geographic distribution, incidence of malignancy, and treatment outcomes of this cohort. Our analysis shows that Belarus had the highest prevalence of NBS (2.3 per 1,000,000), followed by Ukraine (1.3 per 1,000,000), and Russia (0.7 per 1,000,000). Of note, the highest concentration of NBS cases was observed in the western regions of Belarus and Ukraine, where NBS prevalence exceeds 20 cases per 1,000,000 people, suggesting the presence of an β€œEastern Slavic NBS hot spot.” The median age at diagnosis of this cohort ranged from 4 to 5 years, and delay in diagnosis was more pervasive in smaller cities and rural regions. A total of 62 (45%) patients developed malignancies, more commonly in males than females (55.2 vs. 34.2%; p=0.017). In 27 patients, NBS was diagnosed following the onset of malignancies (mean age: 8 years). Malignancies were mostly of lymphoid origin and predominantly non-Hodgkin lymphoma (NHL) (n=42, 68%); 38% of patients had diffuse large B-cell lymphoma. The 20-year overall survival rate of patients with malignancy was 24%. However, females with cancer experienced poorer event-free survival rates than males (16.6% vs. 46.8%, p=0.036). Of 136 NBS patients, 13 underwent hematopoietic stem cell transplantation (HSCT) with an overall survival of 3.5 years following treatment (range: 1 to 14 years). Indications for HSCT included malignancy (n=7) and immunodeficiency (n=6). Overall, 9% of patients in this cohort reached adulthood. Adult survivors reported diminished quality of life with significant physical and cognitive impairments. Our study highlights the need to improve timely diagnosis and clinical management of NBS among Eastern Slavs. Genetic counseling and screening should be offered to individuals with a family history of NBS, especially in hot spot regions. Β© Copyright Β© 2021 Sharapova, Pashchenko, Bondarenko, Vakhlyarskaya, Prokofjeva, Fedorova, Savchak, Mareika, Valiev, Popa, Tuzankina, Vlasova, Sakovich, Polyakova, Rumiantseva, Naumchik, Kulyova, Aleshkevich, Golovataya, Minakovskaya, Belevtsev, Latysheva, Latysheva, Beznoshchenko, Akopyan, Makukh, Kozlova, Varabyou, Ballow, Ong, Walter, Kondratenko, Kostyuchenko and Aleinikova.We thank all doctors for clinical help for patients. We also appreciate the support of patient and their parents for agreeing to take part in this study. TP thanks Sergey?Nikulshin, Marika Grutupa, and Zanna Kovalova. We thank Joseph Dasso for editing this manuscript, primarily for proper English
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