Alternative catalytic residues in the active site of Esco acetyltransferases.

Cohesin is a protein complex whose core subunits, Smc1, Smc3, Scc1, and SA1/SA2 form a ring-like structure encircling the DNA. Cohesins play a key role in the expression, repair, and segregation of eukaryotic genomes. Following a catalytic mechanism that is insufficiently understood, Esco1 and Esco2 acetyltransferases acetylate the cohesin subunit Smc3, thereby inducing stabilization of cohesin on DNA. As a prerequisite for structure-guided investigation of enzymatic activity, we determine here the crystal structure of the mouse Esco2/CoA complex at 1.8 Å resolution. We reconstitute cohesin as tri- or tetrameric assemblies and use those as physiologically-relevant substrates for enzymatic assays in vitro. Furthermore, we employ cell-based complementation studies in mouse embryonic fibroblast deficient for Esco1 and Esco2, as a means to identify catalytically-important residues in vivo. These analyses demonstrate that D567/S566 and E491/S527, located on opposite sides of the murine Esco2 active site cleft, are critical for catalysis. Our experiments support a catalytic mechanism of acetylation where residues D567 and E491 are general bases that deprotonate the ε-amino group of lysine substrate, also involving two nearby serine residues - S566 and S527- that possess a proton relay function

White matter predicts functional connectivity in premanifest Huntington's disease

Objectives The distribution of pathology in neurodegenerative disease can be predicted by the organizational characteristics of white matter in healthy brains. However, we have very little evidence for the impact these pathological changes have on brain function. Understanding any such link between structure and function is critical for understanding how underlying brain pathology influences the progressive behavioral changes associated with neurodegeneration. Here, we demonstrate such a link between structure and function in individuals with premanifest Huntington's. Methods Using diffusion tractography and resting state functional magnetic resonance imaging to characterize white matter organization and functional connectivity, we investigate whether characteristic patterns of white matter organization in the healthy human brain shape the changes in functional coupling between brain regions in premanifest Huntington's disease. Results We find changes in functional connectivity in premanifest Huntington's disease that link directly to underlying patterns of white matter organization in healthy brains. Specifically, brain areas with strong structural connectivity show decreases in functional connectivity in premanifest Huntington's disease relative to controls, while regions with weak structural connectivity show increases in functional connectivity. Furthermore, we identify a pattern of dissociation in the strongest functional connections between anterior and posterior brain regions such that anterior functional connectivity increases in strength in premanifest Huntington's disease, while posterior functional connectivity decreases. Interpretation Our findings demonstrate that organizational principles of white matter underlie changes in functional connectivity in premanifest Huntington's disease. Furthermore, we demonstrate functional antero–posterior dissociation that is in keeping with the caudo–rostral gradient of striatal pathology in HD. The distribution of pathology in neurodegenerative disease can be predicted by the organizational characteristics of white matter in healthy brains. However, we have very little evidence for the impact these pathological changes have on brain function. Understanding any such link between structure and function is critical for understanding how underlying brain pathology influences the progressive behavioral changes associated with neurodegeneration. Here, we demonstrate such a link between structure and function in individuals with premanifest Huntington's. Methods Using diffusion tractography and resting state functional magnetic resonance imaging to characterize white matter organization and functional connectivity, we investigate whether characteristic patterns of white matter organization in the healthy human brain shape the changes in functional coupling between brain regions in premanifest Huntington's disease. Results We find changes in functional connectivity in premanifest Huntington's disease that link directly to underlying patterns of white matter organization in healthy brains. Specifically, brain areas with strong structural connectivity show decreases in functional connectivity in premanifest Huntington's disease relative to controls, while regions with weak structural connectivity show increases in functional connectivity. Furthermore, we identify a pattern of dissociation in the strongest functional connections between anterior and posterior brain regions such that anterior functional connectivity increases in strength in premanifest Huntington's disease, while posterior functional connectivity decreases. Interpretation Our findings demonstrate that organizational principles of white matter underlie changes in functional connectivity in premanifest Huntington's disease. Furthermore, we demonstrate functional antero–posterior dissociation that is in keeping with the caudo–rostral gradient of striatal pathology in HD

Epidemiological Aspects of Malignant Skin Neoplasms Morbidity in Sverdlovsk Region

Sverdlovsk Region is one of the ten largest industrial regions, which accounts for 50.0 % of the total industrial production of the Russian Federation. The aim of the study is a comparative assessment of malignant skin neoplasms (MNS) incidence in the administrative districts of a large industrial region - the Sverdlovsk Region. Methods. We analyzed the data of state statistical reporting, approved by the Order of Rosstat dated December 29, 2011 No. 520 (as amended on December 30, 2015), annual forms of reporting documentation - form No. 7, form No. 35 for the period from 2003 to 2017 in the Sverdlovsk Region. The morbidity and mortality rates standardized by the world age standard were calculated, gender indicators, the morbidity structure in urban districts were estimated. Results. There was an increase in the incidence of MNS - both skin melanoma (SM) and skin cancer (SC) (an intensive increase by 49.1 and 69.8 %, respectively). The overall increase of SM and SC was higher among women: the increase of SM was 23.1 %, in men - 13.6; SC - women 52.7 %, men 40.5. Number of patients with SM of working age has increased by 41.7 % since 2003. Mortality from MNS has a tendency to decrease; however, the rates of first-year mortality are at a high level. Conclusion. There is an increase in the incidence of MNS in Sverdlovsk region - both SM and SC. However, the incidence rates of SC do not exceed the average Russian levels, in contrast to SM for the past 15 years. The highest incidence of MNS cases is registered on territories with functioning industrial enterprises (Gornozavodskoy and Yuzhniy Administrative Districts, Yekaterinburg) which require further study and preventive measuresСвердловская область относится к числу десяти крупнейших индустриальных регионов, на долю которых приходится 50,0 % всего промышленного производства Российской Федерации. Цель исследования – сравнительная оценка заболеваемости злокачественными новообразованиями кожи (ЗНК) в административных округах крупного промышленного региона – Свердловской области. Методы. Анализировались данные государственной статистической отчетности, утвержденные Приказом Росстата от 29.12.2011 г. № 520 (ред. от 30.12.2015), годовые формы отчетной документации – форма № 7, форма № 35 за период с 2003 по 2017 год по Свердловской области. Рассчитаны стандартизованные по мировому возрастному стандарту показатели заболеваемости и смертности, оценены гендерные показатели, структура заболеваемости по городским округам. Результаты. Отмечается рост заболеваемости ЗНК – как меланомой кожи (МК), так и раком кожи (РК) (рост интенсивного показателя на 49,1 и 69,8 % соответственно). Общий прирост МК и РК выше среди женщин: прирост МК у них составил 23,1 %, у мужчин 13,6; прирост РК у женщин 52,7 %, у мужчин 40,5. Больных МК трудоспособного возраста с 2003 года стало большое на 41,7 %. Смертность от ЗНК имеет тенденцию к снижению, однако показатели первогодичной смертности находятся на высоком уровне. Вывод. В Свердловской области отмечается рост заболеваемости ЗНК, как МК, так и РК. Однако уровни заболеваемости РК за последние 15 лет не превышают среднероссийские уровни в отличие от МК. Наибольшая частота случаев ЗНК регистрируется на территориях с функционирующими промышленными предприятиями (Горнозаводской, Южный административные округа и г. Екатеринбург), что требует дальнейшего изучения и проведения профилактических мероприяти

Epidemiological aspects of malignant skin neoplasms morbidity in Sverdlovsk region

Sverdlovsk Region is one of the ten largest industrial regions, which accounts for 50.0 % of the total industrial production of the Russian Federation. The aim of the study is a comparative assessment of malignant skin neoplasms (MNS) incidence in the administrative districts of a large industrial region - the Sverdlovsk Region. Methods. We analyzed the data of state statistical reporting, approved by the Order of Rosstat dated December 29, 2011 No. 520 (as amended on December 30, 2015), annual forms of reporting documentation - form No. 7, form No. 35 for the period from 2003 to 2017 in the Sverdlovsk Region. The morbidity and mortality rates standardized by the world age standard were calculated, gender indicators, the morbidity structure in urban districts were estimated. Results. There was an increase in the incidence of MNS - both skin melanoma (SM) and skin cancer (SC) (an intensive increase by 49.1 and 69.8 %, respectively). The overall increase of SM and SC was higher among women: the increase of SM was 23.1 %, in men - 13.6; SC - women 52.7 %, men 40.5. Number of patients with SM of working age has increased by 41.7 % since 2003. Mortality from MNS has a tendency to decrease; however, the rates of first-year mortality are at a high level. Conclusion. There is an increase in the incidence of MNS in Sverdlovsk region - both SM and SC. However, the incidence rates of SC do not exceed the average Russian levels, in contrast to SM for the past 15 years. The highest incidence of MNS cases is registered on territories with functioning industrial enterprises (Gornozavodskoy and Yuzhniy Administrative Districts, Yekaterinburg) which require further study and preventive measuresСвердловская область относится к числу десяти крупнейших индустриальных регионов, на долю которых приходится 50,0 % всего промышленного производства Российской Федерации. Цель исследования – сравнительная оценка заболеваемости злокачественными новообразованиями кожи (ЗНК) в административных округах крупного промышленного региона – Свердловской области. Методы. Анализировались данные государственной статистической отчетности, утвержденные Приказом Росстата от 29.12.2011 г. № 520 (ред. от 30.12.2015), годовые формы отчетной документации – форма № 7, форма № 35 за период с 2003 по 2017 год по Свердловской области. Рассчитаны стандартизованные по мировому возрастному стандарту показатели заболеваемости и смертности, оценены гендерные показатели, структура заболеваемости по городским округам. Результаты. Отмечается рост заболеваемости ЗНК – как меланомой кожи (МК), так и раком кожи (РК) (рост интенсивного показателя на 49,1 и 69,8 % соответственно). Общий прирост МК и РК выше среди женщин: прирост МК у них составил 23,1 %, у мужчин 13,6; прирост РК у женщин 52,7 %, у мужчин 40,5. Больных МК трудоспособного возраста с 2003 года стало большое на 41,7 %. Смертность от ЗНК имеет тенденцию к снижению, однако показатели первогодичной смертности находятся на высоком уровне. Вывод. В Свердловской области отмечается рост заболеваемости ЗНК, как МК, так и РК. Однако уровни заболеваемости РК за последние 15 лет не превышают среднероссийские уровни в отличие от МК. Наибольшая частота случаев ЗНК регистрируется на территориях с функционирующими промышленными предприятиями (Горнозаводской, Южный административные округа и г. Екатеринбург), что требует дальнейшего изучения и проведения профилактических мероприяти

Неоперабельный гепатоцеллюлярный рак — перспективы лекарственной терапии ленватинибом

There is a number of unresolved issues regarding the systemic therapy administration for hepatocellular carcinoma (HCC). Their solution is facilitated by accumulating real‑world study results. Lenvatinib therapy is a recognized drug with a good efficacy and safety profile for the treatment of HCC. Subanalyses of the REFLECT study showed that the absence of stratification by baseline AFP and baseline liver function, as well as the lack of options for subsequent drug therapy after lenvatinib, also affects the outcomes. Once these factors are taken into account, the hypothesis of superiority of lenvatinib to sorafenib and other drugs can be tested. Real‑world clinical studies have demonstrated positive results of lenvatinib therapy in patients with Child‑Pugh class B liver function, provided recommendations on the sequence of systemic therapy after lenvatinib and on the use of lenvatinib in patients with BCLC stage B, along with considering the possibility of lenvatinib monotherapy and the prospects for its use in patients with nHCC. Further real‑world studies of lenvatinib for HCC in the Russian population are required.В подходах к назначению лекарственной терапии гепатоцеллюлярного рака (ГЦР) есть ряд еще нерешенных вопросов. Их решению способствует накопление результатов исследований в реальной клинической практике. Методом медикаментозной терапии ГЦР с хорошим профилем эффективности и безопасности признана терапия ленватинибом. В субанализах исследования REFLECT показано, что отсутствие стратификации по исходному уровню альфа-фетопротеина и оценке исходной функции печени, а также дефицит опций последующей после назначения ленватиниба медикаментозной терапии оказывают влияние на результаты. Учет этих факторов даст возможность проверить гипотезу превосходства терапии ленватинибом в сравнении с сорафенибом и другими препаратами. В исследованиях реальной клинической практики продемонстрированы положительные результаты применения ленватиниба у пациентов с нарушением функции печени класса B по шкале Чайлд-Пью, даны рекомендации по последовательности системной терапии после ленватиниба, применению ленватиниба у пациентов стадии BCLC B, а также рассмотрены возможности монотерапии ленватинибом и перспективы его применения у пациентов с нГЦК. Необходимы дальнейшие исследования ленватиниба при ГЦР в реальной клинической практике на российской популяции

The Ionizing Radiation-Induced Bystander Effect: Evidence, Mechanism, and Significance

It has long been considered that the important biological effects of ionizing radiation are a direct consequence of unrepaired or misrepaired DNA damage occurring in the irradiated cells. It was presumed that no effect would occur in cells in the population that receive no direct radiation exposure. However, in vitro evidence generated over the past two decades has indicated that non-targeted cells in irradiated cell cultures also experience significant biochemical and phenotypic changes that are often similar to those observed in the targeted cells. Further, nontargeted tissues in partial body-irradiated rodents also experienced stressful effects, including oxidative and oncogenic effects. This phenomenon, termed the “bystander response,” has been postulated to impact both the estimation of health risks of exposure to low doses/low fluences of ionizing radiation and the induction of second primary cancers following radiotherapy. Several mechanisms involving secreted soluble factors, oxidative metabolism, gap-junction intercellular communication, and DNA repair, have been proposed to regulate radiation-induced bystander effects. The latter mechanisms are major mediators of the system responses to ionizing radiation exposure, and our knowledge of the biochemical and molecular events involved in these processes is reviewed in this chapter

Brain regions showing white matter loss in Huntington's Disease are enriched for synaptic and metabolic genes

Background The earliest white matter changes in Huntington’s disease are seen before disease onset in the premanifest stage around the striatum, within the corpus callosum, and in posterior white matter tracts. While experimental evidence suggests that these changes may be related to abnormal gene transcription, we lack an understanding of the biological processes driving this regional vulnerability. Methods Here, we investigate the relationship between regional transcription in the healthy brain, using the Allen Institute for Brain Science transcriptome atlas, and regional white matter connectivity loss at three time points over 24 months in subjects with premanifest Huntington’s disease relative to control participants. The baseline cohort included 72 premanifest Huntington’s disease participants and 85 healthy control participants. Results We show that loss of corticostriatal, interhemispheric, and intrahemispheric white matter connections at baseline and over 24 months in premanifest Huntington’s disease is associated with gene expression profiles enriched for synaptic genes and metabolic genes. Corticostriatal gene expression profiles are predominately associated with motor, parietal, and occipital regions, while interhemispheric expression profiles are associated with frontotemporal regions. We also show that genes with known abnormal transcription in human Huntington’s disease and animal models are overrepresented in synaptic gene expression profiles, but not in metabolic gene expression profiles. Conclusions These findings suggest a dual mechanism of white matter vulnerability in Huntington’s disease, in which abnormal transcription of synaptic genes and metabolic disturbance not related to transcription may drive white matter loss