A User-centric Framework for Accessing Biological Sources and Tools

Biologists face two problems in interpreting their experiments: the integration of their data with information from multiple heterogeneous sources and data analysis with bioinformatics tools. It is difficult for scientists to choose between the numerous sources and tools without assistance. Following a thorough analysis of scientists’ needs during the querying process, we found that biologists express preferences concerning the sources to be queried and the tools to be used. Interviews also showed that the querying process itself – the strategy followed – differs between scientists. In response to these findings, we have introduced a user-centric framework allowing to specify various querying processes. Then we have developed the BioGuide system which helps the scientists to choose suitable sources and tools, find complementary information in sources, and deal with divergent data. It is generic in that it can be adapted by each user to provide answers respecting his/her preferences, and obtained following his/her strategies

Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia

Bromodomains (BRDs) have emerged as compelling targets for cancer therapy. The development of selective and potent BET (bromo and extra-terminal) inhibitors and their significant activity in diverse tumor models have rapidly translated into clinical studies and have motivated drug development efforts targeting non-BET BRDs. However, the complex multidomain/subunit architecture of BRD protein complexes complicates predictions of the consequences of their pharmacological targeting. To address this issue, we developed a promiscuous BRD inhibitor [bromosporine (BSP)] that broadly targets BRDs (including BETs) with nanomolar affinity, creating a tool for the identification of cellular processes and diseases where BRDs have a regulatory function. As a proof of principle, we studied the effects of BSP on leukemic cell lines known to be sensitive to BET inhibition and found, as expected, strong antiproliferative activity. Comparison of the modulation of transcriptional profiles by BSP after a short exposure to the inhibitor resulted in a BET inhibitor signature but no significant additional changes in transcription that could account for inhibition of other BRDs. Thus, nonselective targeting of BRDs identified BETs, but not other BRDs, as master regulators of context-dependent primary transcription response.The Structural Genomics Consortium is a registered charity (no. 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) (ULTRA-DD grant 115766), Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation (FAPESP), Takeda, and Wellcome Trust (092809/Z/10/Z). P.F., S.P., and C.-Y.W. were supported by a Wellcome Career Development Fellowship (095751/Z/11/Z). A.-C.G. is the Canada Research Chair in Functional Proteomics and the Lea Reichmann Chair in Cancer Proteomics and was supported by the Canadian Institutes of Health Research (foundation grant FDN143301). J.-P.L. was supported by a Cancer Research Society (Canada) Scholarship for the Next Generation of Scientists

Маркеры ранних стадий рака легкого у ликвидаторов Чернобыльской аварии

Persons exposed to inhaled radionuclides are at high risk for lung cancer, primarily, due to lung fibrosis development. This work studied lung fibrotic changes and lung cancer genetic markers in liquidators of the Chernobyl accident consequences. The study involved 33 men worked at the Chernobyl station area in 1986-1987, aged from 37 to 65 years (average 45.45±0.95; M±m), and 10 control group men comparable on the age, hazards, social and occupational status, lung pathology, but had never exposed to radiation.Lung function tests, fibreoptic bronchoscopy, histological examination of lung and bronchi tissues biopsy specimens, and lung computed tomography were performed. Oncogene c-myc, Ki-67 proliferation marker, and a deletion in the short arm of the chromosome 3 were investigated in the bronchial epithelium.The lung fibrosis was detected in 13 (42.4%) liquidators and in no-one of the control group. The liquidators also had more bronchial epithelium dysregenerative changes with significant prevalence of basement cell hyperplasia (0.58±.09 and 0.2±0.13 cases in the groups accordingly, p<0.05). Meanwhile the control group had no mild dysplasia at all and demonstrated severe dysplasia rather more frequently (0.2±0.13 vs 0.06±0.04 in the liquidators, p<0.05). The liquidators showed the 3p deletion in the bronchial epithelium cells more often (0.21±0.07 and 0.1±0.1 accordingly, p<0.05) and tended to show other genetic lung cancer markers quite more frequent either.The correlation was found between the lung fibrosis and 3p deletion presence (r=0.45, p<0.05) and also between a pneumonia number anamnestically and Ki-67 expression in the liquidators’ group (r=0.46, p<0.05). The second patients’ group did not demonstrated such the correlaions.Thus, chronic respiratory pathology liquidators develop lung fibrosis earlier than other patients with the similar lung pathology. Basement cell hyperplasia and some oncogenes (3p deletion, c-myc) encounter considerably more often in liquidators that likely to be poor prognostic signs for lung cancer occurrence. Therefore, the Chernobyl accident liquidators are at higher risk for lung cancer compared to the similar lung pathology patients without radiation exposureЛица, ингалировавшие радионуклиды в результате профессиональных воздействий либо неблагоприятной экологической обстановки, имеют высокий риск заболевания раком легкого, в первую очередь, за счет развития пневмофиброза. В данной работе исследовались фиброзные изменения легочной ткани и ряд генетических маркеров рака легкого у ликвидаторов последствий Чернобыльской аварии. В исследование вошли 33 ликвидатора (все мужчины) в возрасте от 37 до 65 лет (в среднем 45,4±0,95 года; М±т) и 10 мужчин группы сравнения, сравнимые с “ликвидаторами” по возрасту, вредным привычкам, социально-бытовым и профессиональным условиям, характеру и длительности бронхолегочной патологии, но не контактировавшие с радиацией.Пациентам проводились исследования легочной функции, фибробронхоскопия с биопсией и последующим гистологическим исследованием ткани бронхов и легких, компьютерная томография легких. В биоптатах определяли онкоген c-myc и маркер пролиферации Ki-67, делецию в коротком плече 3-й хромосомы.Среди ликвидаторов пневмофиброз был выявлен у 13 (42,4%) человек, в группе сравнения не выявлен ни у кого. Также у ликвидаторов чаще, чем в группе сравнения, встречались дисрегенераторные изменения бронхиального эпителия с достоверным преобладанием базальноклеточной гиперплазии (0,58±0,09 и 0,2±0,13 случаев соответственно по группам, р<0,05). Вместе с тем в группе сравнения совсем не обнаруживалась дисплазия 1 ст. и несколько чаще встречалась дисплазия 3 ст. (0,2±0,13 в группе сравнения и 0,06±0,04 у ликвидаторов, р<0,05). Делеция Зр в клетках бронхиального эпителия у ликвидаторов определялась достоверно чаще, чем в группе сравнения (0,21±0,07 и 0,1±0,1 соответственно, р<0,05). Имеется тенденция к более частому обнаружению в группе ликвидаторов и других генетических маркеров.Корреляционный анализ показал достоверную связь между наличием пневмофиброза и делеции в коротком плече 3-й хромосомы (r=0,45, р<0,05), а также между числом перенесенных пневмоний и экспрессией Ki-67 в группе ликвидаторов (r=0,46, р<0,05). В группе сравнения такой зависимости не получено.Таким образом, у ликвидаторов с ХОБЛ фиброз легочной ткани развивается значительно раньше, чем у обычных больных ХОБЛ. У ликвидаторов достоверно чаще обнаруживаются базальноклеточная гиперплазия и генетические маркеры рака легкого (делеция Зр, с-тус), что является прогностически неблагоприятным фактором в развитии этого заболевания. В результате ликвидаторы имеют больший риск заболевания раком легкого по сравнению с обычными больными ХОБЛ.

Сравнительный анализ применения тоцилизумаба при тяжелых COVID-19-ассоциированных пневмониях у пациентов разных возрастных групп

According to accumulated clinical data, one of the causes of severe damage to lung epithelial cells associated with SARS-CoV-2 (2019-nCoV) is an acute, timely underestimated "cytokine storm" (cytokine cascade, hypercytokinaemia) with characteristic signs of an expressed hyper-inflammatory syndrome with subsequent polyorganic failure. The study presents the results of the analysis of the effectiveness of tocilizumab therapy (TCZ) in patients (n = 181) of different age groups with developed pneumonia caused by SARS-CoV-2. The aim of the study was to evaluate the effectiveness of TCZ therapy in patients of different age groups with developed pneumonia in the frame of COVID-19. Methods. Patients (n = 181) with community-acquired pneumonia caused by coronavirus SARS-CoV-2 are included in a one-center, non-randomized, prospective study to evaluate the effectiveness of TCZ therapy conducted at the State Public Health Institution "City Clinical Hospital No.52" of the Moscow City Health Department. Patients were divided into 3 age subgroups – up to 50 years, 50–70 years and over 70 years. Patients with community-acquired SARS-CoV-2-induced pneumonia receiving non-invasive oxygen support and patients who had artificial lung ventilation (ALV) were given a single dose of 400 mg of TCZ in addition to basic therapy. Results. There are no significant differences between age groups in the severity of pneumonia according to the data of the computed tomography (CT), however, a more severe condition and a higher mortality rate (p < 0.001) were reliably observed in patients over 70 age compared to the other age groups. After TCZ treatment in patients of each age group, the severity of the condition assessed on the National Early Warning Score (NEWS2) has been significantly reduced compared to the baseline. Conclusion. According to the data of the pilot study the efficacy and safety of TCZ in patients of all presented age groups with COVID-associated pulmonary tissue lesion and signs of "cytokine storm" was demonstrated. At the same time, patients up to 50 years after the therapy of TCZ managed to achieve greater clinical efficiency compared to patients in other groups. According to the severity of the state and laboratory criteria, the lowest clinical efficacy of TCZ therapy was observed in patients over 70 years of age; as a consequence, the highest mortality rate was observed in the same group. At the same time, the TCZ therapy has not had a positive impact on the change of laboratory values and the severity of the disease in case of unfavorable outcome. Согласно накопленным клиническим данным, одной из причин тяжелых повреждений клеток эпителия легких, ассоциированных с SARS-CoV-2 (2019-nCoV), является острый, вовремя недооцененный синдром «цитокинового шторма» (цитокиновый каскад, гиперцитокинемия) с характерными признаками выраженного гипервоспалительного синдрома с последующей полиорганной недоста - точностью. В работе представлены результаты анализа эффективности терапии тоцилизумабом (ТЦЗ) у пациентов (n = 181) разных возрастных групп с развившейся пневмонией в рамках COVID-19. Целью исследования явилась оценка эффективности терапии ТЦЗ у пациентов разных возрастных групп с развившейся пневмонией, вызванной SARS-CoV-2. Материалы и методы. В одноцентровом нерандомизированном проспективном исследовании оценки эффективности терапии ТЦЗ, проведенном на базе Государственного бюд жетного учреждения здравоохранения «Городская клиническая больница № 52» Департамента здравоохранения города Мос - квы, приняли участие пациенты (n = 181) с внебольничной пневмонией, вызванной коронавирусом SARS-CoV-2. Больные были распределены в 3 возрастные подгруппы: до 50 лет, 50–70 лет, старше 70 лет. Пациентам с внебольничной пневмонией, вызванной SARS-CoV-2, получающим неинвазивную кислородную поддержку, и больным, у которых проводилась искусственная вентиляция легких (ИВЛ), в до полнение к основной терапии назначен ТЦЗ однократно в дозе 400 мг. Результаты. Достоверных различий между возрастными группами по тяжести пневмонии по данным компьютерной томографии (КТ) не выявлено, однако отмечено достоверно более тяжелое состояние и более высокий уровень смертности (p < 0,001) у больных старше 70 лет по сравнению с остальными возрастными группами. После терапии ТЦЗ у больных каждой из возрастных групп тяжесть состояния, оцененная по шкале National Early Warning Score (NEWS2), достоверно снизилась по сравнению с исходными показателями. Заключение. По данным пилотного исследования продемонстрирована эффективность и безопасность применения ТЦЗ у пациентов всех представленных возрастных групп с COVID-ассоциированным повреждением легочной ткани и признаками «цитокинового шторма». При этом у пациентов до 50 лет после терапии ТЦЗ удалось добиться бόльшей клинической эффективности по сравнению с больными остальных групп. По степени тяжести состояния и лабораторным критериям самая низкая клиническая эффективность терапии ТЦЗ отмечена у пациентов старше 70 лет; как следствие, в этой же группе отмечен самый высокий уровень смертности. При этом в случае неблагоприятного исхода терапия ТЦЗ не оказывала положительного влияния на изменение лабораторных показателей и степень тяжести заболевания.

A Scoping Review of Quality of Life Questionnaires in Glaucoma Patients

PRECIS: Multiple questionnaires exist to measure glaucoma's impact on quality of life (QoL). Selecting the right questionnaire for the research question is essential, as is patients' acceptability of the questionnaire to enable collection of relevant patient-reported outcomes. PURPOSE: QoL relating to a disease and its treatment is an important dimension to capture. This scoping review sought to identify the questionnaires most appropriate for capturing the impact of glaucoma on QoL. METHODS: A literature search of QoL questionnaires used in glaucoma, including patient-reported outcomes measures, was conducted and the identified questionnaires were analyzed using a developed quality criteria assessment. RESULTS: Forty-one QoL questionnaires were found which were analyzed with the detailed quality criteria assessment leading to a summary score. This identified the top 10 scoring QoL questionnaires rated by a synthesis of the quality criteria grid, considering aspects such as reliability and reproducibility, and the authors' expert clinical opinion. The results were ratified in consultation with an international panel of ophthalmologists (N=49) from the Educational Club of Ocular Surface and Glaucoma representing 23 countries. CONCLUSIONS: Wide variability among questionnaires used to determine vision related QoL in glaucoma and in the responses elicited was identified. In conclusion, no single existing QoL questionnaire design is suitable for all purposes in glaucoma research, rather we have identified the top 10 from which the questionnaire most appropriate to the study objective may be selected. Development of a new questionnaire that could better distinguish between treatments in terms of vision and treatment-related QoL would be useful that includes the patient perspective of treatment effects as well as meeting requirements of regulatory and health authorities. Future work could involve development of a formal weighting system with which to comprehensively assess the quality of QoL questionnaires used in glaucoma

Comparative analysis of the transcriptome across distant species

The transcriptome is the readout of the genome. Identifying common features in it across distant species can reveal fundamental principles. To this end, the ENCODE and modENCODE consortia have generated large amounts of matched RNA-sequencing data for human, worm and fly. Uniform processing and comprehensive annotation of these data allow comparison across metazoan phyla, extending beyond earlier within-phylum transcriptome comparisons and revealing ancient, conserved features. Specifically, we discover co-expression modules shared across animals, many of which are enriched in developmental genes. Moreover, we use expression patterns to align the stages in worm and fly development and find a novel pairing between worm embryo and fly pupae, in addition to the embryo-to-embryo and larvae-to-larvae pairings. Furthermore, we find that the extent of non-canonical, non-coding transcription is similar in each organism, per base pair. Finally, we find in all three organisms that the gene-expression levels, both coding and non-coding, can be quantitatively predicted from chromatin features at the promoter using a 'universal model' based on a single set of organism-independent parameters

Organization of medical abilitation for extremely premature infants with perinatal central-nervous-system lesions

Health status of infants with extremely low and very low birth weight is a challenge for today's healthcare. Ivanovo Research Institute of Maternity and Childhood named after V.N. Gorodkov has established the system of medical care to extremely premature infants with perinatal lesions of the central nervous system. Abilitation for extremely premature infants with perinatal lesions of the central nervous system should involve territorial and inter-territorial level organizations, interaction algorithms, a complex of forecasting methods, early diagnosis of health disorders, a series of initiatives for the ultimate recovery of defective functions, prevention of disability and development of new therapies, particularly, application of neuropeptide Semax in children with hypoxic-ischemic disorder