Candidate Variants in DNA Replication and Repair Genes in Early-Onset Renal Cell Carcinoma Patients Referred for Germline Testing

Background: Early-onset renal cell carcinoma (eoRCC) is typically associated with pathogenic germline variants (PGVs) in RCC familial syndrome genes. However, most eoRCC patients lack PGVs in familial RCC genes and their genetic risk remains undefined. Methods: Here, we analyzed biospecimens from 22 eoRCC patients that were seen at our institution for genetic counseling and tested negative for PGVs in RCC familial syndrome genes. Results: Analysis of whole-exome sequencing (WES) data found enrichment of candidate pathogenic germline variants in DNA repair and replication genes, including multiple DNA polymerases. Induction of DNA damage in peripheral blood monocytes (PBMCs) significantly elevated numbers of [Formula: see text]H2AX foci, a marker of double-stranded breaks, in PBMCs from eoRCC patients versus PBMCs from matched cancer-free controls. Knockdown of candidate variant genes in Caki RCC cells increased [Formula: see text]H2AX foci. Immortalized patient-derived B cell lines bearing the candidate variants in DNA polymerase genes (POLD1, POLH, POLE, POLK) had DNA replication defects compared to control cells. Renal tumors carrying these DNA polymerase variants were microsatellite stable but had a high mutational burden. Direct biochemical analysis of the variant Pol δ and Pol η polymerases revealed defective enzymatic activities. Conclusions: Together, these results suggest that constitutional defects in DNA repair underlie a subset of eoRCC cases. Screening patient lymphocytes to identify these defects may provide insight into mechanisms of carcinogenesis in a subset of genetically undefined eoRCCs. Evaluation of DNA repair defects may also provide insight into the cancer initiation mechanisms for subsets of eoRCCs and lay the foundation for targeting DNA repair vulnerabilities in eoRCC

Diabetes mellitus type 1 in adults

Public organization “Russian Association of Endocrinologists”. Clinical guidlines

Diabetes mellitus type 2 in adults

Public organization “Russian Association of Endocrinologists”. Clinical guidelines.&nbsp

Modeling of GERDA Phase II data

The GERmanium Detector Array (GERDA) experiment at the Gran Sasso underground laboratory (LNGS) of INFN is searching for neutrinoless double-beta ($0\nu\beta\beta$) decay of $^{76}$Ge. The technological challenge of GERDA is to operate in a "background-free" regime in the region of interest (ROI) after analysis cuts for the full 100$\,$kg$\cdot$yr target exposure of the experiment. A careful modeling and decomposition of the full-range energy spectrum is essential to predict the shape and composition of events in the ROI around $Q_{\beta\beta}$ for the $0\nu\beta\beta$ search, to extract a precise measurement of the half-life of the double-beta decay mode with neutrinos ($2\nu\beta\beta$) and in order to identify the location of residual impurities. The latter will permit future experiments to build strategies in order to further lower the background and achieve even better sensitivities. In this article the background decomposition prior to analysis cuts is presented for GERDA Phase II. The background model fit yields a flat spectrum in the ROI with a background index (BI) of $16.04^{+0.78}_{-0.85} \cdot 10^{-3}\,$cts/(kg$\cdot$keV$\cdot$yr) for the enriched BEGe data set and $14.68^{+0.47}_{-0.52} \cdot 10^{-3}\,$cts/(kg$\cdot$keV$\cdot$yr) for the enriched coaxial data set. These values are similar to the one of Gerda Phase I despite a much larger number of detectors and hence radioactive hardware components

Modeling of GERDA Phase II data

The GERmanium Detector Array (Gerda) experiment at the Gran Sasso underground laboratory (LNGS) of INFN is searching for neutrinoless double-beta (0νββ) decay of 76Ge. The technological challenge of Gerda is to operate in a “background-free” regime in the region of interest (ROI) after analysis cuts for the full 100 kg·yr target exposure of the experiment. A careful modeling and decomposition of the full-range energy spectrum is essential to predict the shape and composition of events in the ROI around Qββ for the 0νββ search, to extract a precise measurement of the half-life of the double-beta decay mode with neutrinos (2νββ) and in order to identify the location of residual impurities. The latter will permit future experiments to build strategies in order to further lower the background and achieve even better sensitivities. In this article the background decomposition prior to analysis cuts is presented for Gerda Phase II. The background model fit yields a flat spectrum in the ROI with a background index (BI) of 16.04+0.78−0.85⋅10−3 cts/(keV·kg·yr) for the enriched BEGe data set and 14.68+0.47−0.52⋅10−3 cts/(keV·kg·yr) for the enriched coaxial data set. These values are similar to the one of Phase I despite a much larger number of detectors and hence radioactive hardware components

Моделирование процесса образования личностных качеств менеджера в профессиональной подготовке

The subject of the study is the achievement of manager personhood qualities in the process of dedicated training. The article gives the author’s model of manager personality, according to which the achievement of manager personhood qualities in the process of dedicated training is as the result of a complex interaction of his personality levels (such as organismic, individual, self-personality) with the general characteristics of the process control (communicative space, communicative time, energy, information, material factors of management, specific management situation). In the experimental part of the article on the basis of the proposed methods of psycho-diagnostics, as well as statistical comparison the analysis and interpretation of the results are provided. In the course of which there were correlated personality traits with a particular process control, based on the levels of the individual, each associated with one of the authors of selected qualities emerging in the process of professional development. Comparative statistical analysis of the study of the development levels of personal qualities and their relationship with the students and leaders at different stages of professional development has enabled to establish that the conditions of achievement of personhood formation are differentПредметом исследования является становление качеств личности менеджера в процессе профессиональной подготовки. В статье представлена авторская модель личности менеджера, согласно которой в процессе профессиональной подготовки становление качеств личности менеджера происходит в результате сложного взаимодействия уровней его личности (организмический, индивидуальный, собственно-личностный) с всеобщими характеристиками процесса управления (коммуникативное пространство, коммуникативное время, энергия, информация, материально-вещественные факторы управления, конкретная управленческая ситуация). В экспериментальной части статьи на базе предложенных методик психодиагностики, а также статистического сравнения представлен анализ и интерпретация результатов работы. В ходе которого были соотнесены качества личности с тем или иным процессом управления, исходя из уровней личности, каждый из которых связан авторами с одним из выделенных качеств, формирующихся в процессе профессионального становления. Сравнительный статистический анализ изучения уровней развития личностных качеств и их соотношение у студентов и руководителей на разных этапах профессионального становления дали нам возможность установить, что условия становления личностных качеств различны

Моделирование процесса образования личностных качеств менеджера в профессиональной подготовке

The subject of the study is the achievement of manager personhood qualities in the process of dedicated training. The article gives the author’s model of manager personality, according to which the achievement of manager personhood qualities in the process of dedicated training is as the result of a complex interaction of his personality levels (such as organismic, individual, self-personality) with the general characteristics of the process control (communicative space, communicative time, energy, information, material factors of management, specific management situation). In the experimental part of the article on the basis of the proposed methods of psycho-diagnostics, as well as statistical comparison the analysis and interpretation of the results are provided. In the course of which there were correlated personality traits with a particular process control, based on the levels of the individual, each associated with one of the authors of selected qualities emerging in the process of professional development. Comparative statistical analysis of the study of the development levels of personal qualities and their relationship with the students and leaders at different stages of professional development has enabled to establish that the conditions of achievement of personhood formation are differentПредметом исследования является становление качеств личности менеджера в процессе профессиональной подготовки. В статье представлена авторская модель личности менеджера, согласно которой в процессе профессиональной подготовки становление качеств личности менеджера происходит в результате сложного взаимодействия уровней его личности (организмический, индивидуальный, собственно-личностный) с всеобщими характеристиками процесса управления (коммуникативное пространство, коммуникативное время, энергия, информация, материально-вещественные факторы управления, конкретная управленческая ситуация). В экспериментальной части статьи на базе предложенных методик психодиагностики, а также статистического сравнения представлен анализ и интерпретация результатов работы. В ходе которого были соотнесены качества личности с тем или иным процессом управления, исходя из уровней личности, каждый из которых связан авторами с одним из выделенных качеств, формирующихся в процессе профессионального становления. Сравнительный статистический анализ изучения уровней развития личностных качеств и их соотношение у студентов и руководителей на разных этапах профессионального становления дали нам возможность установить, что условия становления личностных качеств различны

Rheumatoid Factor Positivity Is Associated with Increased Joint Destruction and Upregulation of Matrix Metalloproteinase 9

We evaluated changes in gene expression of mTOR, p21, caspase-3, ULK1, TNFα, matrix metalloproteinase (MMP)-9, and cathepsin K in the whole blood of rheumatoid arthritic (RA) patients treated with methotrexate (MTX) in relation to their rheumatoid factor status, clinical, immunological, and radiological parameters, and therapeutic response after a 24-month follow-up. The study group consisted of 35 control subjects and 33 RA patients without previous history of MTX treatment. Gene expression was measured using real-time RT-PCR. Decreased disease activity in patients at the end of the study was associated with significant downregulation of TNFα expression. Downregulation of mTOR was observed in seronegative patients, while no significant changes in the expression of p21, ULK1, or caspase-3 were noted in any RA patients at the end of the study. The increase in erosion numbers observed in the seropositive patients at the end of the follow-up was accompanied by upregulation of MMP-9 and cathepsin K, while seronegative patients demonstrated an absence of significant changes in MMP-9 and cathepsin K expression and no increase in the erosion score. Our results suggest that increased expression of MMP-9 and cathepsin K genes in the peripheral blood might indicate higher bone tissue destruction activity in RA patients treated with methotrexate. The clinical study registration number is 0120.0810610