52 research outputs found

    Three-year trends in out-of-hospital cardiac arrest across the world : second report from the International Liaison Committee on Resuscitation (ILCOR)

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    Background The International Liaison Committee on Resuscitation (ILCOR) Research and Registries Working Group previously reported data on systems of care and outcomes of out-of-hospital cardiac arrest (OHCA) in 2015 from 16 national and regional registries. To describe the temporal trends with updated data on OHCA, we report the characteristics of OHCA from 2015 through 2017. Methods We invited national and regional population-based OHCA registries for voluntary participation and included emergency medical services (EMS)-treated OHCA. We collected descriptive summary data of core elements of the latest Utstein style recommendation during 2016 and 2017 at each registry. For registries that participated in the previous 2015 report, we also extracted the 2015 data. Results Eleven national registries in North America, Europe, Asia, and Oceania, and 4 regional registries in Europe were included in this report. Across registries, the estimated annual incidence of EMS-treated OHCA was 30.0‚Äď97.1 individuals per 100,000 population in 2015, 36.4‚Äď97.3 in 2016, and 40.8‚Äď100.2 in 2017. The provision of bystander cardiopulmonary resuscitation (CPR) varied from 37.2% to 79.0% in 2015, from 2.9% to 78.4% in 2016, and from 4.1% to 80.3% in 2017. Survival to hospital discharge or 30-day survival for EMS-treated OHCA ranged from 5.2% to 15.7% in 2015, from 6.2% to 15.8% in 2016, and from 4.6% to 16.4% in 2017. Conclusion We observed an upward temporal trend in provision of bystander CPR in most registries. Although some registries showed favourable temporal trends in survival, less than half of registries in our study demonstrated such a trend

    The Expanding Universe of the Study of Sound Change

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    HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer

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    Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3ő≤) a key regulator of glycolysis. Pharmacological inhibition of GSK3ő≤ results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3ő≤ inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC. Brunton et al. demonstrate that differential chromatin accessibility can predict responsiveness and tolerance to GSK3ő≤ inhibitors in the squamous subtype of PDAC. This study provides an important proof of concept that chromatin accessibility can be used to identify additional PDAC subgroups with potential therapeutic utility.</p

    Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

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    Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P &lt; 0.001) and PARP inhibitor therapy (P &lt; 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P &lt; 0.018) and WEE1 inhibitor (P &lt; 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P &lt; 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

    Lovastatin enhances adenovirus-mediated TRAIL induced apoptosis by depleting cholesterol of lipid rafts and affecting CAR and death receptor expression of prostate cancer cells

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    Oncolytic adenovirus and apoptosis inducer TRAIL are promising cancer therapies. Their antitumor efficacy, when used as single agents, is limited. Oncolytic adenoviruses have low infection activity, and cancer cells develop resistance to TRAIL-induced apoptosis. Here, we explored combining prostate-restricted replication competent adenovirus-mediated TRAIL (PRRA-TRAIL) with lovastatin, a commonly used cholesterol-lowering drug, as a potential therapy for advanced prostate cancer (PCa). Lovastatin significantly enhanced the efficacy of PRRA-TRAIL by promoting the in vivo tumor suppression, and the in vitro cell killing and apoptosis induction, via integration of multiple molecular mechanisms. Lovastatin enhanced PRRA replication and virus-delivered transgene expression by increasing the expression levels of CAR and integrins, which are critical for adenovirus 5 binding and internalization. Lovastatin enhanced TRAIL-induced apoptosis by increasing death receptor DR4 expression. These multiple effects of lovastatin on CAR, integrins and DR4 expression were closely associated with cholesterol-depletion in lipid rafts. These studies, for the first time, show correlations between cholesterol/lipid rafts, oncolytic adenovirus infection efficiency and the antitumor efficacy of TRAIL at the cellular level. This work enhances our understanding of the molecular mechanisms that support use of lovastatin, in combination with PRRA-TRAIL, as a candidate strategy to treat human refractory prostate cancer in the future
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