Notes

Traits of Permeable Aluminum Supplies Made by Important Sea Chloride within their Melts.
Endocrine resistance (EnR) in advanced prostate cancer is fatal. EnR can be mediated by androgen receptor (AR) splice variants, with AR splice variant 7 (AR-V7) arguably the most clinically important variant. In this study, we determined proteins key to generating AR-V7, validated our findings using clinical samples, and studied splicing regulatory mechanisms in prostate cancer models. Triangulation studies identified JMJD6 as a key regulator of AR-V7, as evidenced by its upregulation with in vitro EnR, its downregulation alongside AR-V7 by bromodomain inhibition, and its identification as a top hit of a targeted siRNA screen of spliceosome-related genes. JMJD6 protein levels increased (P less then 0.001) with castration resistance and were associated with higher AR-V7 levels and shorter survival (P = 0.048). JMJD6 knockdown reduced prostate cancer cell growth, AR-V7 levels, and recruitment of U2AF65 to AR pre-mRNA. Mutagenesis studies suggested that JMJD6 activity is key to the generation of AR-V7, with the catalytic machinery residing within a druggable pocket. Taken together, these data highlight the relationship between JMJD6 and AR-V7 in advanced prostate cancer and support further evaluation of JMJD6 as a therapeutic target in this disease. SIGNIFICANCE This study identifies JMJD6 as being critical for the generation of AR-V7 in prostate cancer, where it may serve as a tractable target for therapeutic intervention.Defects in genes crucial for the process of DNA repair by homology-directed DNA repair (HDR), such as BRCA1 and BRCA2, are well-known contributors to cancer pathogenesis as well as an Achilles' heel that can be exploited therapeutically. BRCA1/2-deficient cells are exquisitely sensitive to agents that stall replication forks, such as PARP inhibitors and platinating drugs, presumably due to the inability to repair double-stranded breaks that form as a consequence of replication fork collapse. BRCA1/2 also promote tolerance to DNA replication stress by protecting replication forks from nucleolytic degradation. Both biological endpoints involve the deposition of RAD51 onto single-stranded DNA (ssDNA) for homology searching and strand exchange during HDR repair, as well as protection of newly synthesized DNA from nucleolytic degradation (i.e., replication fork protection). In this issue of Cancer Research, Panzarino and colleagues performed multiple separation-of-function studies and identify the lesion most associated with intolerance to replication stress in BRCA1/2-deficient cells is persistent ssDNA gaps in newly synthesized DNA, resulting from a failure to restrain DNA replication. BAY-218 cell line Mechanisms that suppress gap formation are closely associated with chemoresistance, and the authors' findings challenge the paradigm that lack of HR repair or fork protection underlie the phenotype known as BRCAness.See related article by Panzarino et al., p. 1388.The roles of intronic miRNAs and their functional interaction with host coding genes represent a topic that is poorly explored. The study by Kwok and colleagues in this issue of Cancer Research presents solid evidence that the FTX locus at chromosome Xq13.2 contains multiple noncoding RNAs (ncRNA) with coordinated expression and concordant functional effects in colorectal cancer cells. The long ncRNA, FTX, and its intronic miRNAs, miR-374a, -374b, -421, and -545, are all interconnected in a functional network, including the downstream protein coding targets DHX9, DICER, PTEN, and RIG-I These data prove that multigenic loci in the human genome have a complex functional landscape that modulates key signaling pathways for cancer progression and that much knowledge with potential clinical utility remains to be revealed from the largest, noncoding portion of the genome.See related article by Kwok et al., p. 1308.The death toll and economic loss resulting from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic are stark reminders that we are vulnerable to zoonotic viral threats. Strategies are needed to identify and characterize animal viruses that pose the greatest risk of spillover and spread in humans and inform public health interventions. Using expert opinion and scientific evidence, we identified host, viral, and environmental risk factors contributing to zoonotic virus spillover and spread in humans. We then developed a risk ranking framework and interactive web tool, SpillOver, that estimates a risk score for wildlife-origin viruses, creating a comparative risk assessment of viruses with uncharacterized zoonotic spillover potential alongside those already known to be zoonotic. Using data from testing 509,721 samples from 74,635 animals as part of a virus discovery project and public records of virus detections around the world, we ranked the spillover potential of 887 wildlife viruses. Validating the risk assessment, the top 12 were known zoonotic viruses, including SARS-CoV-2. Several newly detected wildlife viruses ranked higher than known zoonotic viruses. Using a scientifically informed process, we capitalized on the recent wealth of virus discovery data to systematically identify and prioritize targets for investigation. The publicly accessible SpillOver platform can be used by policy makers and health scientists to inform research and public health interventions for prevention and rapid control of disease outbreaks. SpillOver is a living, interactive database that can be refined over time to continue to improve the quality and public availability of information on viral threats to human health.
To investigate the associations between echocardiographic left atrial (LA) size and incident stoke and stroke cause mortality among a rural population in China.

A prospective study.

Based on the Northeast China Rural Cardiovascular Health Study, we selected a total of 10 041 participants aged ≥35 years who agreed to have transthoracic echocardiography at baseline and were successfully followed up for incident stoke and stroke cause mortality.

The outcomes were stroke and stroke cause death according to medical records and death certificates during the follow-up period.

LA enlargement (LAE) group had a higher prevalence of cardiovascular disease than normal LA diameter (LAD) group. After excluding individuals who had a prior stroke, subjects with LAE showed higher incident rates of stroke and its mortality in the overall and specific stratified analyses (all p<0.05). Kaplan-Meier analysis revealed that LAE could predict stroke incidence and stroke-free survival, but the association was no longer observed after the adjustment for potential confounding factors.
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