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© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.Trametinib is a MEK1/2 inhibitor and exerts anticancer activity against a variety of cancers. However, the effect of Trametinib on colorectal cancer (CRC) is not well understood. In the current study, our results demonstrate the ability of sub-toxic doses of Trametinib to enhance TRAIL-mediated apoptosis in CRC cells. Our findings also indicate that Trametinib and TRAIL activate caspase-dependent apoptosis in CRC cells. Moreover, Mcl-1 overexpression can reduce apoptosis in CRC cells treated with Trametinib with or without TRAIL. We further demonstrate that Trametinib degrades Mcl-1 through the proteasome pathway. In addition, GSK-3β phosphorylates Mcl-1 at S159 and promotes Mcl-1 degradation. The E3 ligase FBW7, known to polyubiquitinate Mcl-1, is involved in Trametinib-induced Mcl-1 degradation. Taken together, these results provide the first evidence that Trametinib enhances TRAIL-mediated apoptosis through FBW7-dependent Mcl-1 ubiquitination and degradation. © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.During a career, which spanned nearly 60 years, Professor Philip J. DiSaia (1937-2018) trailblazed a path forward in academic medicine, which would become the standard by which Departments of Obstetrics and Gynecology and Gynecologic Oncology Divisions and Cancer Centers would be measured throughout the United States, in Europe and Japan. Following his discovery of fetal warfarin syndrome as a resident, DiSaia would serve in the U.S. Navy and successfully compete for an American Cancer Society Grant that would fund his Fellowship in Gynecologic Oncology under the instruction of Dr Felix N. Rutledge at the MD Anderson Hospital and Tumor Institute in Houston, Texas. Dr DiSaia's goal to establish a traditional academic department was realized at the University of California, Irvine, where he remained active in an unprecedented, uninterrupted 42-year run, training many outstanding obstetrician-gynecologists and gynecologic oncologists, future Division Directors, Cancer Center Directors and Department Chairpersons. His dedication to the field and inexhaustible work ethic fueled his many successes in tumor immunology and the clinical trials of the National Cancer Institute's Gynecologic Oncology Group. © 2020 Japan Society of Obstetrics and Gynecology.Hepatitis Delta Virus (HDV) is the agent responsible for the most severe form of human viral hepatitis. The HDV genome consists of a single stranded circular RNA molecule that encodes for one single protein, the delta antigen. Given its simplicity, HDV must make use of several host cellular proteins to accomplish its life cycle processes, including transcription, replication, post-transcriptional and post-translational modifications. Consequently, identification of the interactions established between HDV components and host proteins assumes a pivotal interest in the search of novel therapeutic targets. Here, we used the yeast three-hybrid system to screen a human liver cDNA library to identify host proteins that interact with the HDV genomic RNA. One of the identified proteins corresponded to the splicing factor SF3B155, a component of the U2snRNP complex that is essential for the early recognition of 3' splice sites in the pre-mRNAs of human genes. We show that the interaction between the HDV genomic RNA and SF3B155 occurs in vivo and that the expression of HDV promotes changes in splicing of human genes whose alternative splicing is SF3B155-dependent. NMS-P937 solubility dmso We further show that expression of HDV triggers alterations in several constitutive and alternative splicing events in the tumor suppressor RBM5 transcript, with consequent reduction of its protein levels. This is the first description that HDV expression promotes changes in the splicing of human genes and we suggest that the HDV-induced alternative splicing changes, through SF3B155 sequester, may contribute for the early progression to hepatocellular carcinoma characteristic of HDV infected patients. This article is protected by copyright. All rights reserved.Loci associated with longevity are likely to harbor genes coding for key players of molecular pathways involved in a lifelong decreased mortality and decreased/compressed morbidity. However, identifying such loci is challenging. One of the most plausible reasons is the uncertainty in defining long-lived cases with the heritable longevity trait among long-living phenocopies. To avoid phenocopies, family selection scores have been constructed, but these have not yet been adopted as state of the art in longevity research. Here, we aim to identify individuals with the heritable longevity trait by using current insights and a novel family score based on these insights. We use a unique dataset connecting living study participants to their deceased ancestors covering 37,825 persons from 1,326 five-generational families, living between 1788 and 2019. Our main finding suggests that longevity is transmitted for at least two subsequent generations only when at least 20% of all relatives are long-lived. This proves the importance of family data to avoid phenocopies in genetic studies. © 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.The thermoresponsive nature of aqueous solutions of poly( N -isopropylacrylamide) (PNIPAAM) star polymers containing 2, 3, 4, and 6 arms has been investigated by turbidity, dynamic light scattering, rheology, and rheo-SALS. Simulations of the thermosensitive nature of the single star polymers have also been conducted. Some of the samples form aggregates even at temperatures significantly below the lower critical solution temperature (LCST) of PNIPAAM. Increasing concentration and number of arms promotes associations at low temperatures. When the temperature is raised, there is a competition between size increase due to enhanced aggregation and a size reduction caused by contraction. Monte Carlo simulations show that the single stars contract with increasing temperature, and that this contraction is more pronounced when the number of arms is increased. Some samples exhibit a minimum in the turbidity data after the initial increase at the cloud point. The combined rheology and rheo-SALS data suggest that this is due to a fragmentation of the aggregates followed by re-aggregation at even higher temperatures.