Metamodelling in the information field

The article studies metamodelling in the information field. Specifics of metamodelling are described. Three basic interpretations of metamodelling are shown. The features of metamodelling in information technologies and information field are presented. A functional difference between the information space and the information field is specified. The article studies metarelations in the information field. Three information situations characterizing metarelations are considered: sequence, transformation, and generalization. The differences in metarelations between an object and a metamodel and between a model and a metamodel are described. The article shows the relation scheme in the system "object – model – metamodel". The scheme of metatheory formation is presented. The principles of metamodelling in the information field are revealed. The article proves that a metamodel in the information field is a model of information construction. A new concept of information metamodelling is introduced

The role of c-FLIP splice variants in urothelial tumours

Deregulation of apoptosis is common in cancer and is often caused by overexpression of anti-apoptotic proteins in tumour cells. One important regulator of apoptosis is the cellular FLICE-inhibitory protein (c-FLIP), which is overexpressed, for example, in melanoma and Hodgkin's lymphoma cells. Here, we addressed the question whether deregulated c-FLIP expression in urothelial carcinoma impinges on the ability of death ligands to induce apoptosis. In particular, we investigated the role of the c-FLIP splice variants c-FLIPlong (c-FLIPL) and c-FLIPshort (c-FLIPS), which can have opposing functions. We observed diminished expression of the c-FLIPL isoform in urothelial carcinoma tissues as well as in established carcinoma cell lines compared with normal urothelial tissues and cells, whereas c-FLIPS was unchanged. Overexpression and RNA interference studies in urothelial cell lines nevertheless demonstrated that c-FLIP remained a crucial factor conferring resistance towards induction of apoptosis by death ligands CD95L and TRAIL. Isoform-specific RNA interference showed c-FLIPL to be of particular importance. Thus, urothelial carcinoma cells appear to fine-tune c-FLIP expression to a level sufficient for protection against activation of apoptosis by the extrinsic pathway. Therefore, targeting c-FLIP, and especially the c-FLIPL isoform, may facilitate apoptosis-based therapies of bladder cancer in otherwise resistant tumours

Systems analysis of apoptosis protein expression allows the case-specific prediction of cell death responsiveness of melanoma cells.

Many cancer entities and their associated cell line models are highly heterogeneous in their responsiveness to apoptosis inducers and, despite a detailed understanding of the underlying signaling networks, cell death susceptibility currently cannot be predicted reliably from protein expression profiles. Here, we demonstrate that an integration of quantitative apoptosis protein expression data with pathway knowledge can predict the cell death responsiveness of melanoma cell lines. By a total of 612 measurements, we determined the absolute expression (nM) of 17 core apoptosis regulators in a panel of 11 melanoma cell lines, and enriched these data with systems-level information on apoptosis pathway topology. By applying multivariate statistical analysis and multi-dimensional pattern recognition algorithms, the responsiveness of individual cell lines to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or dacarbazine (DTIC) could be predicted with very high accuracy (91 and 82% correct predictions), and the most effective treatment option for individual cell lines could be pre-determined in silico. In contrast, cell death responsiveness was poorly predicted when not taking knowledge on protein-protein interactions into account (55 and 36% correct predictions). We also generated mathematical predictions on whether anti-apoptotic Bcl-2 family members or x-linked inhibitor of apoptosis protein (XIAP) can be targeted to enhance TRAIL responsiveness in individual cell lines. Subsequent experiments, making use of pharmacological Bcl-2/Bcl-xL inhibition or siRNA-based XIAP depletion, confirmed the accuracy of these predictions. We therefore demonstrate that cell death responsiveness to TRAIL or DTIC can be predicted reliably in a large number of melanoma cell lines when investigating expression patterns of apoptosis regulators in the context of their network-level interplay. The capacity to predict responsiveness at the cellular level may contribute to personalizing anti-cancer treatments in the future

ДВЕ ПРОГРАММЫ ХИМИОТЕРАПИИ В КОМБИНАЦИИ С БЕВАЦИЗУМАБОМ В ЛЕЧЕНИИ ДИССЕМИНИРОВАННОГО КОЛОРЕКТАЛЬНОГО РАКА

The efficiency of 2 programs of chemotherapy in the treatment of 46 patients with disseminated colorectal cancer. The program of chemo-therapy of oxaliplatin + capecitabine (ОХА/САР), established authors, with bevacizumab (BEV) showed the best results compared with oxaliplatin + 5-fluorouracyl + leukovorin (ОХА/5-FU/LV) with bevacizumab. The overall efficiency OXA/5-FU/LV/BEV amounted to 40.91 ± 8.6 %, 4.54 ± 5.1 % of total regressions. The overall effect of therapy in the OXA/CAP/BEV amounted to 45.83 ± 8.6 %, full regression was achieved in 4 patients, which amounted to 16.66 ± 5.6 %. The median time to progression in the first group of patients was 8.3 months, in the second – 9.8 months. Clinical application of involving bevacizumab in combination with different modes of chemotherapy in patients with disseminated colorectal cancer is acceptable and manageable toxicity that doesn't require reduction of doses.Изучена эффективность 2 программ химиотерапии (ХТ) в лечении 46 больных диссеминированным колоректальным раком. Показано, что программа ХТ оксалиплатин + капецитабин (ОХА/САР), созданная авторами, в комбинации с бевацизумабом (BEV) позволила добиться лучших непосредственных результатов по сравнению с программами оксалиплатин + 5-фторурацил + лейковорин (ОХА/5-FU/LV) в комбинации с бевацизумабом. Общая эффективность программы ОХА/5-FU/LV/BEV составила 40,91 ± 8,6 %, из них 4,54 ± 5,1 % полных регрессий. Общий эффект терапии в группе ОХА/САР/BEV составил 45,83 ± 8,6 %, из них полной регрессии удалось добиться у 4 пациентов, что составило 16,66 ± 5,6 %. Медиана времени до прогрессирования в 1-й группе больных составила 8,3 мес, во 2-й – 9,8 мес. Амбулаторное применение бевацизумаба в комбинации с различными режимами ХТ у больных диссеминированным раком ободочной кишки сопровождается приемлемой и управляемой токсичностью, что не требует редукции доз

eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5'UTR

Background: Regulation of the mRNA life cycle is central to gene expression control and determination of cell fate. miRNAs represent a critical mRNA regulatory mechanism, but despite decades of research, their mode of action is still not fully understood. Results: Here, we show that eIF4A2 is a major effector of the repressive miRNA pathway functioning via the Ccr4-Not complex. We demonstrate that while DDX6 interacts with Ccr4-Not, its effects in the mechanism are not as pronounced. Through its interaction with the Ccr4-Not complex, eIF4A2 represses mRNAs at translation initiation. We show evidence that native eIF4A2 has similar RNA selectivity to chemically inhibited eIF4A1. eIF4A2 exerts its repressive effect by binding purine-rich motifs which are enriched in the 5′UTR of target mRNAs directly upstream of the AUG start codon. Conclusions: Our data support a model whereby purine motifs towards the 3′ end of the 5′UTR are associated with increased ribosome occupancy and possible uORF activation upon eIF4A2 binding

A Global Census of Fission Yeast Deubiquitinating Enzyme Localization and Interaction Networks Reveals Distinct Compartmentalization Profiles and Overlapping Functions in Endocytosis and Polarity

Proteomic, localization, and enzymatic activity screens in fission yeast reveal how deubiquitinating enzyme localization and function are tuned

ОТЕЧЕСТВЕННЫЙ ОПЫТ ПРОФИЛАКТИКИ И ЛЕЧЕНИЯ ПРОЯВЛЕНИЙ КОЖНОЙ ТОКСИЧНОСТИ У ПАЦИЕНТОВ МКРР, ПОЛУЧАЮЩИХ ИНГИБИТОРЫ EGFR, НА ПРИМЕРЕ ПРЕПАРАТА ПАНИТУМУМАБ

The results of the first national experience of skin toxicity correction in patients with metastatic colorectal cancer (mCRC) receiving EGRF-inhibitors shown on the example of using of Panitumumab. The collection and evaluation of the data were produced in the framework of the project of the working group on maintenance therapy of Russian society of clinical oncologists and chemotherapeutists (RUSSCO) to develop recommendations for the prevention and treatment of dermatological toxicity in patients receiving EGFR-inhibitors. The project involved 10 centers in Russia.  In 58 patients receiving Panitumumab, the efficacy of prophylactic medication and symptomatic treatment of clinical manifestations of dermatological toxicity using available remedies was evaluated. The results confirm the effectiveness of preventive therapy. Optimal correction schemes of various manifestations of dermal toxicity were developed depending on the clinical manifestations and severity.Освещены результаты первого отечественного опыта коррекции кожной токсичности у пациентов мКРР, получающих ингибиторы EGRF, на примере препарата Панитумумаб. Сбор и оценка данных произведены в рамках проекта рабочей группы по поддерживающей терапии Профессионального Общества онкологов-химиотерапевтов (RUSSCO) по разработке рекомендаций для профилактики и лечения дерматологической токсичности у пациентов, получающих ингибиторы EGFR. В проекте принимали участие 10 центров РФ. У 58 пациентов, получавших Панитумумаб, оценивалась эффективность профилактической медикаментозной и симптоматической терапии клинических проявлений дерматологической токсичности доступными средствами. Полученные результаты подтверждают эффективность профилактической терапии. Разработаны оптимальные схемы коррекции различных проявлений кожной токсичности в зависимости от клинических проявлений и степени тяжести

Resolution of inflammation: a new therapeutic frontier

Dysregulated inflammation is a central pathological process in diverse disease states. Traditionally, therapeutic approaches have sought to modulate the pro- or anti-inflammatory limbs of inflammation, with mixed success. However, insight into the pathways by which inflammation is resolved has highlighted novel opportunities to pharmacologically manipulate these processes — a strategy that might represent a complementary (and perhaps even superior) therapeutic approach. This Review discusses the state of the art in the biology of resolution of inflammation, highlighting the opportunities and challenges for translational research in this field

Сравнение эффективности и токсичности афлиберцепта и бевацизумаба в комбинации с режимом FOLFIRI во 2‑й линии лечения пациентов с метастатическим раком толстой кишки: ретроспективный анализ многоцентрового исследования

Objective: to compare the efficacy and toxicity of aflibercept and bevacizumab in combination with fOLfIRI in secondline therapy for patients with metastatic colon cancer.Materials and methods. we performed a retrospective analysis of data on patients with metastatic colon cancer treated in 9 clinics in the Russian federation. The inclusion criteria were as follows: metastatic or locally advanced colon cancer; treatment with bevacizumab or aflibercept plus fOLfIRI in the second-line therapy. The primary outcome measure was progression-free survival (PfS). Secondary outcome measures included objective response rate and incidence of adverse events.Results. A total of 271 patients with metastatic colon cancer who received second-line therapy with bevacizumab (n = 81) or aflibercept (n = 190) between 2014 and 2018 were selected for this study. Study groups were matched for main prognostic signs. The objective response rate was 18.1 % in the bevacizumab group and 20.5 % in the aflibercept group (p = 0.7). The median PfS was 5 months (95 % confidence interval 3.8–6.1) in the aflibercept group and 7 months (95 % confidence interval 0.81–2.1) in the bevacizumab group (hazard ratio 1.4; 95 % confidence interval 0.99–2.1; p = 0.04). multivariate regression analysis demonstrated that the type of the targeted drug independently had no effect on PfS (hazard ratio 1.3; 95 % confidence interval 0.9–1.9; p = 0.2). we observed no statistically significant differences in the incidence of complications of any grades between the groups (58 % vs 72 %, p = 0.1). Patients receiving aflibercept were more likely to develop grade III–Iv arterial hypertension (2 % vs 9.5 %) and diarrhea (0 % vs 5.4 %), whereas thrombotic complications were more common in the bevacizumab group (10 % vs 1.8 %).Conclusion. we observed no significant differences in objective response rate and PfS between patients with metastatic colon cancer receiving bevacizumab or aflibercept in combination with fOLfIRI as second-line therapy. The toxicity profiles were different. Our findings can be used for choosing an optimal targeted drug for second-line treatment.Цель исследования – сравнение эффективности и токсичности афлиберцепта и бевацизумаба в комбинации с режимом fOLfIRI во 2-й линии лечения пациентов с метастатическим раком толстой кишки.Материалы и методы. Проведен ретроспективный анализ базы данных пациентов с метастатическим раком толстой кишки в рамках наблюдательного исследования работы 9 клиник РФ. Критерии включения в исследование: больные метастатическим или местно-распространенным раком толстой кишки; проведение терапии с включением бевацизумаба или афлиберцепта в комбинации с режимом fOLfIRI во 2-й линии лечения. Основной критерий эффективности – выживаемость без прогрессирования (ВбП). дополнительные критерии: частота объективных эффектов, частота развития нежелательных явлений.Результаты. Отобран 271 пациент с метастатическим раком толстой кишки, которым в 2014–2018 гг. проводилась 2-я линия терапия с включением бевацизумаба (n = 81) и афлиберцепта (n = 190). группы статически значимо не различались по основным прогностическим признакам. частота объективных эффектов составила 18,1 % в группе бевацизумаба и 20,5 % в группе афлиберцепта (р = 0,7). медиана ВбП составила 5 мес (95 % доверительный интервал 3,8–6,1) в группе афлиберцепта и 7 мес (95 % доверительный интервал 0,81–2,1) в группе бевацизумаба (отношение рисков 1,4; 95 % доверительный интервал 0,99–2,1; р = 0,04). многофакторный регрессионный анализ не подтвердил независимого влияния характера таргетного препарата на ВбП (отношение рисков 1,3; 95 % дИ 0,9–1,9; р = 0,2). Не отмечено статистически значимых различий в частоте развития осложнений всех степеней (58 % против 72 %, р = 0,1); среди негематологических осложнений артериальная гипертензия III–Iv степени (2 % против 9,5 %) и диарея (0 % против 5,4 %) чаще наблюдались в группе афлиберцепта, тромботические осложнения чаще наблюдались в группе бевацизумаба (10 % против 1,8 %).Выводы. Не отмечено статистически значимых различий между бевацизумабом и афлиберцептом в сочетании с режимом fOLfIRI во 2-й линии терапии пациентов с метастатическим раком толстой кишки ни в отношении достижения объективного эффекта, ни в отношении ВбП. Профили токсических реакций были различными. Полученные данные можно учитывать при выборе таргетного препарата во 2-й линии терапии