5 research outputs found
ΠΠΌΠΌΡΠ½ΠΎΠ»ΠΎΠ³ΠΈΡ ΠΈ ΠΏΠ΅ΡΡΠΏΠ΅ΠΊΡΠΈΠ²Ρ ΠΈΠΌΠΌΡΠ½ΠΎΡΠ΅ΡΠ°ΠΏΠΈΠΈ Π·Π»ΠΎΠΊΠ°ΡΠ΅ΡΡΠ²Π΅Π½Π½ΡΡ Π³Π»ΠΈΠΎΠΌ: ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π½ΠΈΠ΅ ΡΠ°ΠΊΡΠΎΡΠΎΠ² Π³ΡΠΌΠΎΡΠ°Π»ΡΠ½ΠΎΠ³ΠΎ ΠΈΠΌΠΌΡΠ½ΠΈΡΠ΅ΡΠ°
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 βcold: 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+ FOXP3β) 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.ΠΠ»ΠΈΠΎΠΌΡ Π²ΡΡΠΎΠΊΠΎΠΉ ΡΡΠ΅ΠΏΠ΅Π½ΠΈ Π·Π»ΠΎΠΊΠ°ΡΠ΅ΡΡΠ²Π΅Π½Π½ΠΎΡΡΠΈ β Π°Π³ΡΠ΅ΡΡΠΈΠ²Π½ΡΠ΅ ΠΎΠΏΡΡ
ΠΎΠ»ΠΈ ΡΠ΅Π½ΡΡΠ°Π»ΡΠ½ΠΎΠΉ Π½Π΅ΡΠ²Π½ΠΎΠΉ ΡΠΈΡΡΠ΅ΠΌΡ. Π‘ΡΠ°Π½Π΄Π°ΡΡΠ½Π°Ρ Ρ
ΠΈΠΌΠΈΠΎΠ»ΡΡΠ΅Π²Π°Ρ ΡΠ΅ΡΠ°ΠΏΠΈΡ Π΄Π°Π½Π½ΡΡ
Π½ΠΎΠ²ΠΎΠΎΠ±ΡΠ°Π·ΠΎΠ²Π°Π½ΠΈΠΉ Π½Π΅ ΡΠ²Π»ΡΠ΅ΡΡΡ ΠΊΡΡΠ°ΡΠΈΠ²Π½ΠΎΠΉ ΠΎΠΏΡΠΈΠ΅ΠΉ, ΠΏΠΎΡΡΠΎΠΌΡ ΠΏΠΎΠΏΡΡΠΊΠΈ ΡΡΠΈΠ»Π΅Π½ΠΈΡ ΠΈ ΠΈΠ½Π΄ΠΈΠ²ΠΈΠ΄ΡΠ°Π»ΠΈΠ·Π°ΡΠΈΠΈ ΠΈΡ
Π»Π΅ΡΠ΅Π½ΠΈΡ Π½Π° ΡΠ΅Π³ΠΎΠ΄Π½ΡΡΠ½ΠΈΠΉ Π΄Π΅Π½Ρ ΠΏΡΠ΅Π΄ΠΏΠΎΠ»Π°Π³Π°ΡΡ Π²ΠΎΠ·Π΄Π΅ΠΉΡΡΠ²ΠΈΠ΅ Π½Π° ΠΏΠ°ΡΠΎΠ³Π΅Π½Π΅ΡΠΈΡΠ΅ΡΠΊΠΈΠ΅ ΠΌΠ΅Ρ
Π°Π½ΠΈΠ·ΠΌΡ ΡΠΎΡΡΠ° ΠΎΠΏΡΡ
ΠΎΠ»ΠΈ Π½Π° ΠΊΠ»Π΅ΡΠΎΡΠ½ΠΎΠΌ ΠΈ ΠΌΠΎΠ»Π΅ΠΊΡΠ»ΡΡΠ½ΠΎ-Π³Π΅Π½Π΅ΡΠΈΡΠ΅ΡΠΊΠΎΠΌ ΡΡΠΎΠ²Π½ΡΡ
. ΠΠ»ΠΎΠΊΠ°ΡΠ΅ΡΡΠ²Π΅Π½Π½ΡΠ΅ Π³Π»ΠΈΠΎΠΌΡ, Π² ΠΏΠ΅ΡΠ²ΡΡ ΠΎΡΠ΅ΡΠ΅Π΄Ρ Π³Π»ΠΈΠΎΠ±Π»Π°ΡΡΠΎΠΌΡ, ΡΠ²Π»ΡΡΡΡΡ Β«Ρ
ΠΎΠ»ΠΎΠ΄Π½ΡΠΌΠΈΒ» ΠΎΠΏΡΡ
ΠΎΠ»ΡΠΌΠΈ, Π² ΠΊΠΎΡΠΎΡΡΡ
ΠΈΠΌΠΌΡΠ½Π½ΡΠΉ ΠΎΡΠ²Π΅Ρ ΠΈ ΠΏΠ΅ΡΠΈΡΡΠΌΠΎΡΠ°Π»ΡΠ½ΠΎΠ΅ Π²ΠΎΡΠΏΠ°Π»Π΅Π½ΠΈΠ΅ ΠΏΡΠΎΡΠ²Π»ΡΡΡΡΡ ΡΠ»Π°Π±ΠΎ. ΠΡΠΎ ΠΎΠ±ΡΡΡΠ½ΡΠ΅ΡΡΡ ΡΠ½ΠΈΠΆΠ΅Π½Π½ΠΎΠΉ ΡΠΊΡΠΏΡΠ΅ΡΡΠΈΠ΅ΠΉ Π½Π΅ΠΎΠ°Π½ΡΠΈΠ³Π΅Π½ΠΎΠ² ΠΎΠΏΡΡ
ΠΎΠ»Π΅Π²ΡΠΌΠΈ ΠΊΠ»Π΅ΡΠΊΠ°ΠΌΠΈ ΠΈ Π½ΠΈΠ·ΠΊΠΎΠΉ ΠΈΠΌΠΌΡΠ½ΠΎΡΠ΅Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡΡ ΠΌΠΈΠΊΡΠΎΠΎΠΊΡΡΠΆΠ΅Π½ΠΈΡ. ΠΠ»Π΅ΡΠΊΠΈ ΡΠ΅Π½ΡΡΠ°Π»ΡΠ½ΠΎΠΉ Π½Π΅ΡΠ²Π½ΠΎΠΉ ΡΠΈΡΡΠ΅ΠΌΡ Π»ΠΈΡΠ΅Π½Ρ ΠΌΠΎΠ»Π΅ΠΊΡΠ» Π΄Π»Ρ Ρ
ΠΎΠΌΠΈΠ½Π³Π° Π»Π΅ΠΉΠΊΠΎΡΠΈΡΠΎΠ², Π° ΠΏΠΎΠ²Π΅ΡΡ
Π½ΠΎΡΡΠ½ΡΠ΅ ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΡ β Π³Π°Π½Π³Π»ΠΈΠΎΠ·ΠΈΠ΄Ρ β ΠΎΠΊΠ°Π·ΡΠ²Π°ΡΡ ΠΏΡΡΠΌΠΎΠ΅ ΠΈΠ½Π³ΠΈΠ±ΠΈΡΡΡΡΠ΅Π΅ Π²ΠΎΠ·Π΄Π΅ΠΉΡΡΠ²ΠΈΠ΅ Π½Π° CD178+-ΡΠΈΡΠΎΡΠΎΠΊΡΠΈΡΠ΅ΡΠΊΠΈΠ΅ Π’-Π»ΠΈΠΌΡΠΎΡΠΈΡΡ. ΠΡΠΎ ΠΏΡΠΈΠ²ΠΎΠ΄ΠΈΡ ΠΊ ΡΠΎΠΌΡ, ΡΡΠΎ ΠΏΠΎΠΏΡΠ»ΡΡΠΈΡ Π»Π΅ΠΉΠΊΠΎΡΠΈΡΠΎΠ², ΠΈΠ½ΡΠΈΠ»ΡΡΡΠΈΡΡΡΡΠΈΡ
ΠΎΠΏΡΡ
ΠΎΠ»Ρ, ΠΏΡΠ΅Π΄ΡΡΠ°Π²Π»Π΅Π½Π° Π² ΠΎΡΠ½ΠΎΠ²Π½ΠΎΠΌ ΠΊΠ»Π΅ΡΠΊΠ°ΠΌΠΈ, ΠΎΡΡΠΈΡΠ°ΡΠ΅Π»ΡΠ½ΠΎ ΡΠ΅Π³ΡΠ»ΠΈΡΡΡΡΠΈΠΌΠΈ ΠΈΠΌΠΌΡΠ½Π½ΡΠΉ ΠΎΡΠ²Π΅Ρ (ΡΠ΅Π³ΡΠ»ΡΡΠΎΡΠ½ΡΠΌΠΈ (CD4+ CD25+ FOXP3+) T-Π»ΠΈΠΌΡΠΎΡΠΈΡΠ°ΠΌΠΈ ΠΈ ΠΌΠ°ΠΊΡΠΎΡΠ°Π³Π°ΠΌΠΈ 2-Π³ΠΎ ΡΠΈΠΏΠ°). ΠΠ°ΠΊΡΠΎΡΠ°Π³ΠΈ 2-Π³ΠΎ ΡΠΈΠΏΠ° ΠΈΠ½Π³ΠΈΠ±ΠΈΡΡΡΡ ΠΊΠ»Π΅ΡΠΎΡΠ½ΡΠΉ ΠΈΠΌΠΌΡΠ½Π½ΡΠΉ ΠΎΡΠ²Π΅Ρ, ΡΡΠΈΠΌΡΠ»ΠΈΡΡΡΡ Π½Π΅ΠΎΠ°Π½Π³ΠΈΠΎΠ³Π΅Π½Π΅Π· ΠΈ ΡΠΎΠ·Π΄Π°ΡΡ ΡΡΠ»ΠΎΠ²ΠΈΡ Π΄Π»Ρ ΠΌΠ΅ΡΠ°ΡΡΠ°ΡΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ ΡΠ°ΡΠΏΡΠΎΡΡΡΠ°Π½Π΅Π½ΠΈΡ ΠΊΠ»Π΅ΡΠΎΠΊ ΠΎΠΏΡΡ
ΠΎΠ»ΠΈ.ΠΠ½ΡΠ΅Π³ΡΠ°ΡΠΈΡ Π² Π»Π΅ΡΠ΅Π½ΠΈΠΈ ΠΎΠΏΡΡ
ΠΎΠ»Π΅ΠΉ ΡΠ΅Π½ΡΡΠ°Π»ΡΠ½ΠΎΠΉ Π½Π΅ΡΠ²Π½ΠΎΠΉ ΡΠΈΡΡΠ΅ΠΌΡ ΠΈΠΌΠΌΡΠ½ΠΎΡΠ΅ΡΠ°ΠΏΠ΅Π²ΡΠΈΡΠ΅ΡΠΊΠΈΡ
ΠΏΠΎΠ΄Ρ
ΠΎΠ΄ΠΎΠ², Π² ΡΠΎΠΌ ΡΠΈΡΠ»Π΅ ΠΏΡΠΈΠΌΠ΅Π½Π΅Π½ΠΈΠ΅ Π²Π°ΠΊΡΠΈΠ½ ΠΈ ΠΌΠΎΠ½ΠΎΠΊΠ»ΠΎΠ½Π°Π»ΡΠ½ΡΡ
Π°Π½ΡΠΈΡΠ΅Π», ΡΠ²Π»ΡΠ΅ΡΡΡ Π°ΠΊΡΡΠ°Π»ΡΠ½ΠΎΠΉ ΡΡΡΠ°ΡΠ΅Π³ΠΈΠ΅ΠΉ, ΠΎΡΠ½ΠΎΠ²Π°Π½Π½ΠΎΠΉ Π½Π° Π±ΠΈΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΈΡ
ΡΠ²ΠΎΠΉΡΡΠ²Π°Ρ
ΠΎΠΏΡΡ
ΠΎΠ»Π΅Π²ΠΎΠΉ ΡΠΊΠ°Π½ΠΈ
Geographical Distribution, Incidence, Malignancies, and Outcome of 136 Eastern Slavic Patients With Nijmegen Breakage Syndrome and NBN Founder Variant c.657_661del5
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 βEastern Slavic NBS hot spot.β 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