Acetylation of BMAL1 by TIP60 controls BRD4-P-TEFb recruitment to circadian promoters.

Many physiological processes exhibit circadian rhythms driven by cellular clocks composed of interlinked activating and repressing elements. To investigate temporal regulation in this molecular oscillator, we combined mouse genetic approaches and analyses of interactions of key circadian proteins with each other and with clock gene promoters. We show that transcriptional activators control BRD4-PTEFb recruitment to E-box-containing circadian promoters. During the activating phase of the circadian cycle, the lysine acetyltransferase TIP60 acetylates the transcriptional activator BMAL1 leading to recruitment of BRD4 and the pause release factor P-TEFb, followed by productive elongation of circadian transcripts. We propose that the control of BRD4-P-TEFb recruitment is a novel temporal checkpoint in the circadian clock cycle

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

Research of <i>PNPLA3</i> I148M Gene Polymorphism in Patients with Non-Alcoholic Fatty Liver Disease, with Liver Cirrhosis and with Hepatocellular Carcinoma

Aim: to determine the frequency of PNPLA3 rs738409 C&gt;G gene polymorphism, leading to p.I148M substitution, in patients with non-alcoholic fatty liver disease (NAFLD), and to reveal the association between polymorphism and probable NAFLD outcomes: liver cirrhosis (LC) and hepatocellular carcinoma (HCC).Materials and methods. The study was conducted according to the “case-control” design, three main groups were formed: a group with NAFLD (n = 46), a group with LC (n = 61), a group with HCC (n = 50), as well as a control group (n = 70), for all groups we performed genotyping of the rs738409 polymorphism of the PNPLA3 gene. The relationship between the occurrence of different genotype variants and the diagnosis of patients was evaluated, the odds ratio (OR) of progression of NAFLD and the reliability of intergroup differences were determined.Results. NAFLD patients with PNPLA3 I148M polymorphism have a significantly higher chance of developing LC and HCC. The odds ratio for the GG genotype was 7.94 (95 % Cl: 2.19–28.84; p = 0.030) for LC and 6.51 (95 % Cl: 1.15–4.08; p = 0.039) — for HCC with concomitant LC. The presence of the minor G allele also increases the likelhood of transition from NAFLD to LC (OR = 2.38; 95 % Cl: 1.41–4.02; p = 0.010) and HCC in the presence of cirrhosis (OR = 2.17; 95 % Cl: 1.15–4.08; p = 0.039). Differences in the frequency of PNPLA3 polymorphism between the NAFLD and HCC groups were not significant. Additional risk factors for HCC associated with NAFLD are overweight (OR = 5.14; 95 % Cl: 1.94–13.67; p &lt; 0.001), arterial hypertension (OR = 8.49; 95 % Cl: 3.05–23,62; p &lt; 0.001) and diabetes mellitus (OR = 8.57; 95 % Cl: 1.03–71.48; p = 0.032).Conclusion. The frequency of single nucleotide polymorphism PNPLA3 significantly differs in patients with NAFLD, cirrhosis and HCC compared with the control group of healthy volunteers. The PNPLA3 I148M polymorphism increases the incidence of NAFLD progression to cirrhosis and HCC, but only with concomitant cirrhosis

Treatment for elderly patients with advanced non-small-cell lung cancer

1743 new cases of lung cancer were registered in Sverdlovsk Region in 2009.52.5% of them (915 cases) were patients from 65 till 74 years old and 16.2% - patients elder than 75 years. 71 % of patients have stages III and IV. Adenocarcinoma and bronchoalveolar cancer were diagnosed in 30.7% of cases. These patients with lung cancer stage IIIB and IV received either Vinorelbin or Gefitinib after the progression on platinum based chemotherapy. Median survival (7 month), 1-year (32% and 35% respectively) and 2-year survival (16% and 14%) were almost the same in both groups. The use of Vinorelbin is more frequently accompanied by side effects, including III and IV stages of Neutropenia.В 2009 году в Свердловской области зарегистрировано 1743 новых случая рака легкого (РЛ), из них 915 (52,5%) пришлось на пациентов от 65 до 74 лет, а 282 (16,2%) - на пациентов старше 75 лет. Больные с 3-4 стадиями составили 71%. Аденокарцинома, железистый рак и бронхоальвеолярный рак встречались в 30,7% случаев. Пациентам с данными гистологическими вариантами с IIIB и IV стадиями РЛ после прогрессирования на фоне платиносодержащих режимов назначался Гефитиниб или Винорелбин. В обоих случаях медиана выживаемости (7 месяцев) и показатели 1-годичной (32% и 35% соответственно) и 2-годичной выживаемости (16% и 14%) не отличались. Использование Винорелбина чаще сопровождалось побочными эффектами, в том числе нейтропенией 3-4 степени

The result of the treatment of patients with breast cancer associated brain metastases

The article presents the patients characteristics and long-term results of treatment of women suffered from the breast cancer associated brain metastases. 81 patients received the treatment in Sverdlovsk Regional Oncology Dispensary from 2008 till 2014 were included in the analysis. The influence of age, receptor status and extent of the treatment on the median overall survival was examined.В работе представлена характеристика 81 больной раком молочной железы с метастазами в головной мозг и отдаленные результаты их лечения, которое было проведено в Свердловском областном онкологическом диспансере с 2008 по 2014 год. Рассмотрено влияние возраста пациенток, рецепторного статуса, объема проведенного лечения на медиану общей выживаемости

The experience of treatment of stage III breast cancer among the patients elder than 70 years

The article presents the changes of age adjusted structure of breast cancer morbidity during the last 20 years in Sverdlovsk Region. Stage distribution among the patients elder than 70 years from 1992 till 2012 is given. The results of the treatment of elderly women suffered from the breast cancer III stage and being treated in 2012 in Sverdlovsk Regional Oncology Dispensary are presented.В работе представлены изменения возрастной структуры заболеваемости раком молочной железы за последние 20 лет в Свердловской области. Приведено распределение по стадиям среди пациенток старше 70 лет с 1992 по 2012 гг. Представлены результаты лечения возрастных больных раком молочной железы III стадии, получивших лечение в 2012 году в Свердловском областном онкологическом диспансере

Первичные злокачественные новообразования печени: результаты наблюдения за пациентами, поставленными на учет в Свердловской области в 2016 году

305 patients with primary malignant tumors of liver and bile-ducts (C22 according to ICD) were registered in Sverdlovsk Region in 2016. Only 123 of them (40.3%) got consultation in Sverdlovsk Regional Oncology Dispensary. Autopsy was performed in 251 cases (91.9% of deceased patients). On the one hand the exceeding of mortality over morbidity point out the failure of cases registration, on the other hand patients with another type of tumors were identified among the registered ones (4.3%). The majority of liver primary tumors are presented by hepatocellular carcinoma (81.6%). It is usually diagnosed at the age of 60 and older (78.2%) and stage IV (47.9%). Specialized anticancer treatment is not enough provided (just in 18.4% cases). It gives an opportunity to increase the median survival up to 18 months comparing with 1.5 months on best supportive care.В 2016 г. в Свердловской области на учет было поставлено 305 пациентов с диагнозом ЗН печени и внутрипеченочных желчных протоков (код С22 по МКБ10). При этом в единственное в области специализированное онкологическое учреждение были направлены только 123 пациента (40,3%). Из 273 умерших пациентов 251 (91,9%) было проведено патологоанатомическое исследование. Существует превышение смертности над заболеваемостью, что говорит о недоучете больных. Вместе с тем необходимо отметить, что среди поставленных на учет были пациенты с метастазами других солидных опухолей (4,3%). Гепатоцеллюлярная карцинома составляет большинство ЗН печени (81,6%) и диагностируется чаще в возрасте старше 60 лет (78,2%) и в IV стадии (47,9%). Специализированное противоопухолевое лечение назначается недостаточно (лишь у 18,4%), при этом оно позволяет увеличить медиану общей выживаемости до 18 месяцев и более в сравнении с 1,5 месяцами при проведении только симптоматической терапии

The incidence of skin melanoma in the Urals Federal District

To study the current epidemiological situation of skin melanoma in the Urals Federal District, data on the absolute, coarse and standardized incidence rates of melanoma (C43) in the male and female populations were analyzed. The analyses of specific gravity of melanoma patients detected actively at different stages of the tumor process that died during the first year from the date of diagnosis in 2016 was carried out. Higher rates of melanoma morbidity exceeding the average district rates by 29.41% were registered in the Sverdlovsk region. In the Ural Federal District, the incidence of melanoma among women in rough indicators is 1.4 times higher than the incidence in men. The standardized death rate of the population of the Ural FD from skin melanoma is lower than the average for the Russian Federation. The specific gravity of actively detected melanoma patients in the Sverdlovsk Region is 1.3 times higher than the average indicator. The Urals Federal District, among all the Federal Districts of the Russian Federation, has the greatest proportion of patients identified at the first stage (37.6%). The high rates of neglect and one-year lethality in skin melanoma justify the need to develop and conduct additional preventive measures, the introduction of new non-invasive methods for diagnosing skin lesions into practice, and a program for examining patients, especially with suspected skin melanoma.Для изучения современной эпидемиологической ситуации по меланоме кожи в Уральском ФО проанализированы данные об абсолютных, грубых и стандартизованных показателях заболеваемости меланомой (С43) мужской и женской популяции, проведён анализ удельного веса больных меланомой, выявленных активно, на различных стадиях опухолевого процесса, умерших в течение первого года с момента установления диагноза за 2016 год. Более высокие показатели заболеваемости населения меланомой были зарегистрированы в Свердловской области, превышали среднеокружной на 29,41%. В Уральском ФО уровень заболеваемости меланомой женщин в грубых показателях в 1,4 раза превышает заболеваемость мужчин. Стандартизованный показатель смертности населения Уральского ФО от МК ниже, чем в среднем по РФ. Удельный вес активно выявленных больных меланомой в Свердловской области, в 1,3 раза превышает среднеокружной показатель. В уральском ФО среди всех Федеральных округов РФ наибольший удельный вес больных, выявленных на I стадии (37,6%). Высокие показатели запущенности, одногодичной летальности по меланоме кожи свидетельствуют о необходимости разработки и проведения дополнительных профилактических мероприятий, внедрении новых неинвазивных методов диагностики новообразований кожи в практику и программы обследования пациентов, особенно с подозрением на меланому кожи

The experience of palliative treatment of breast cancer patients with Fulvestrant (Faslodex) in Sverdlovsk Region

The article presents analysis of the first results of use of Fulvestrant in palliative treatment of hormone sensitive breast cancer in Sverdlovsk Regional Oncology Dispensary. From February 2009 till February 2012 therapy with Fulvestrant was performed in 20 patients. The progression of the disease was registered in 9 patients. The median time to progression was 6.7 months (from 2 to 12 months). 11 patients continue treatment with Fulvestrant. The median time of their treatment is 10 months (from 5 to 20 months).В работе представлены первые результаты лечения препаратом Фулвестрант (Фазлодекс) в качестве паллиативной гормонотерапии пациенток с гормонозависимым раком молочной железы в Свердловском областном онкологическом диспансере. С февраля 2009 г по февраль 2012 г терапию Фулвестрантом получали 20 больных. Прогрессирование заболевания выявлено у 9. Среднее время до прогрессирования было 6,7 месяцев (от 2 до 12 месяцев). 11 пациенток продолжают получать инъекции Фулвестранта. Длительность их лечения в среднем составляет 10 месяцев (от 5 до 20 месяцев)