The malignant phenotype in breast cancer is driven by eIF4A1-mediated changes in the translational landscape

Human mRNA DeXD/H-box helicases are ubiquitous molecular motors that are required for the majority of cellular processes that involve RNA metabolism. One of the most abundant is eIF4A, which is required during the initiation phase of protein synthesis to unwind regions of highly structured mRNA that would otherwise impede the scanning ribosome. Dysregulation of protein synthesis is associated with tumorigenesis, but little is known about the detailed relationships between RNA helicase function and the malignant phenotype in solid malignancies. Therefore, immunohistochemical analysis was performed on over 3000 breast tumors to investigate the relationship among expression of eIF4A1, the helicase-modulating proteins eIF4B, eIF4E and PDCD4, and clinical outcome. We found eIF4A1, eIF4B and eIF4E to be independent predictors of poor outcome in ER-negative disease, while in contrast, the eIF4A1 inhibitor PDCD4 was related to improved outcome in ER-positive breast cancer. Consistent with these data, modulation of eIF4A1, eIF4B and PCDC4 expression in cultured MCF7 cells all restricted breast cancer cell growth and cycling. The eIF4A1-dependent translatome of MCF7 cells was defined by polysome profiling, and was shown to be highly enriched for several classes of oncogenic genes, including G-protein constituents, cyclins and protein kinases, and for mRNAs with G/C-rich 5′UTRs with potential to form G-quadruplexes and with 3′UTRs containing microRNA target sites. Overall, our data show that dysregulation of mRNA unwinding contributes to the malignant phenotype in breast cancer via preferential translation of a class of genes involved in pro-oncogenic signaling at numerous levels. Furthermore, immunohistochemical tests are promising biomarkers for tumors sensitive to anti-helicase therapies

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

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

Implementation of the Far Eastern Hectare Program: Effect of Incentives to Its Agents

The article examines large-scale privatisation of land resources in the Russian Far East under the Far Eastern hectare program. This program transforms the institution of property in the region by transferring land to private ownership. The study explores mechanisms for implementing the program, as well as its effects. New institutional economics is applied to explain the differences in the program implementation rates across regions and municipalities and assess the correlation between reform results and incentives and performance of its agents (mostly municipal authorities). We analysed 155 observations of hectares, a survey of 200 participants of the Far Eastern hectare program, more than 20 interviews with developers, agents and program participants, comparative cases of receiving and not receiving land, participation and non-participation in the program, as well as quantitative statistics on 157,016 granted and non-granted applications for land plots submitted before May 31, 2020. The research revealed an uneven distribution of total applications for land, as well as that of rejections, ranging from 18 % to 56 % per region, with even greater disparity across municipalities. Correlation analysis identified key indicators affecting the share of rejection, including economic indicators of municipalities, as well as indicators of local revenue structure. Regression analysis showed that it is more difficult to get a hectare in economically developed regions, and that the share of granted hectares depends on current or potential benefits of their use for municipalities. It was concluded that economic incentives of municipalities contradict the goals of the Far Eastern hectare program, greatly hindering its successful implementation.В статье представлены результаты исследования приватизации земель на российском Дальнем Востоке в рамках программы «Дальневосточный гектар». Программа трансформирует институт собственности в регионе, перераспределяя землю в частное владение населения. Исследование касается механизмов реализации программы и ее эффектов. Авторы используют положения новой институциональной экономической теории, чтобы объяснить обнаруженные различия в показателях реализации программы по регионам и муниципальным образованиям, а также ответить на вопрос, каким образом результаты проекта зависят от стимулов и качества работы непосредственных исполнителей на местах в лице представителей муниципальных властей. Эмпирической базой исследования являются 155 фактических наблюдений «гектаров», опрос 200 участников программы, более 20 интервью с разработчиками, исполнителями и участниками программы, сравнительные кейсы получения и неполучения земли, участия и неучастия в программе, а также количественные статистические данные о 157 016 заявок на выданные и невыданные земельные участки по программе, поданных до 31 мая 2020 г. Анализ эмпирических данных выявил неравномерность не только в общем числе заявок на получение земельных участков, но и в доле отказов, варьирующейся от 18 % до 56 % по регионам, и с еще большим разрывом по муниципальным образованиям. С помощью корреляционного анализа выявлены ключевые показатели, связанные с вариацией доли отказов. Среди них экономические показатели муниципальных образований и те, которые характеризуют структуру доходов местного бюджета. Регрессионный анализ позволил принять гипотезы о том, что, во-первых, «гектар» сложнее получить в более экономически развитых территориях, во-вторых, доля выданных «гектаров» зависит от текущих или потенциальных выгод от их использования муниципальным образованием. Авторы делают вывод, что формируемые экономические стимулы муниципалитетов противоречат целям программы, что является существенным препятствием на пути к ее успешной реализации.Acknowledgments: The article has been prepared with the support of the Center for Post-Institutional Studies (PIS-center) as part of the implementation of the donation agreement dated 19.05.2022 No. D-156-22 of the FEFU Endowment Fund for financing winning projects of the open competition for the support of research and applied projects for the period from 07.02.2022 to 31.12.2024 of the FEFU School of Economics and Management from the income from endowment fiduciary management “Strategic projects of FEFU” (Purpose donation from PJSC Sberbank)

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

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

Programmed cell death and its role in inflammation

Cell death plays an important role in the regulation of inflammation and may be the result of inflammation. The maintenance of tissue homeostasis necessitates both the recognition and removal of invading microbial pathogens as well as the clearance of dying cells. In the past few decades, emerging knowledge on cell death and inflammation has enriched our molecular understanding of the signaling pathways that mediate various programs of cell death and multiple types of inflammatory responses. This review provides an overview of the major types of cell death related to inflammation. Modification of cell death pathways is likely to be a logical therapeutic target for inflammatory diseases

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