BackgroundAtrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all‐cause mortality may guide interventions.Methods and ResultsIn the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose‐adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all‐cause mortality in the 14 171 participants in the intention‐to‐treat population. The median age was 73 years, and the mean CHADS 2 score was 3.5. Over 1.9 years of median follow‐up, 1214 (8.6%) patients died. Kaplan–Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all‐cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33–1.70, P<0.0001) and age ≥75 years (hazard ratio 1.69, 95% CI 1.51–1.90, P<0.0001) were associated with higher all‐cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C‐index 0.677).ConclusionsIn a large population of patients anticoagulated for nonvalvular atrial fibrillation, ≈7 in 10 deaths were cardiovascular, whereas <1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival.Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00403767.

The RAS proteins are the most frequently mutated oncogenes in cancer, with highest frequency found in pancreatic, lung, and colon tumors. Moreover, the activity of RAS is required for the proliferation and/or survival of these tumor cells and thus represents a high-value target for therapeutic development. Direct targeting of RAS has proven challenging for multiple reasons stemming from the biology of the protein, the complexity of downstream effector pathways and upstream regulatory networks. Thus, significant efforts have been directed at identifying downstream targets on which RAS is dependent. These efforts have proven challenging, in part due to confounding factors such as reliance on two-dimensional adherent monolayer cell cultures that inadequately recapitulate the physiologic context to which cells are exposed in vivo.  To overcome these issues, we implemented a High Throughput Screening (HTS) approach using a spheroid-based 3-dimensional culture format, thought to more closely reflect conditions experienced by cells in vivo. Using isogenic cell pairs, differing in the status of KRAS, we identified Proscillaridin A as a selective inhibitor of cells harboring the oncogenic KRasG12V allele. Significantly, the identification of Proscillaridin A was facilitated by the 3D screening platform and would not have been discovered employing standard 2D culturing methods.

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Цель: изучить показатели системы матриксные металлопротеиназы (ММП)/ингибиторы при инфильтративном туберкулезе легких (ИТЛ) в динамике интенсивной фазы лечения для разработки статистической модели прогноза характера репаративных изменений� Материалы и методы. В сыворотке крови 35 больных с верифицированным диагнозом ИТЛ с разным характером репаративных изменений в ходе интенсивной фазы терапии оценивали содержание проММП-1, ММП-8,-9, ТИMП-1 и α 2-макроглобулина методом ELISA (Bender MedSystems, USA)� Рассчитывали объемы инфильтративных изменений легочной ткани (ИЛТ) (Vitrea, Nodule Analysis)� Использовали программу Statistica 10, ANOVA Repeated Measures и мультидискриминантный анализ� Результаты. ИТЛ характеризуется нарушением баланса в системе ММП/ингибиторы независимо от характера репаративных изменений: повышением уровня ММП-9 и сохранением референтного уровня ТИМП-1 и α 2-макроглобулина� Уровень ММП-9 значимо снижается, но не нормализуется при всех вариантах инволюции процесса� Сохранение высоких значений ММП-8 снижает вероятность закрытия зон распада, тогда как повышение уровня ММП-1 способствует их рассасыванию� В оценке прогноза характера репаративных изменений по окончании фазы продолжения терапии при ИТЛ наиболее информативно сочетание уровней ММП/ингибиторы с ИЛТ в ходе интенсивной фазы терапии�

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