Highlights d BALF cell transcriptome indicates robust innate immune responses in COVID-19 patients d COVID-19 patients exhibit chemokine-dominant hypercytokinemia d ISGs are highly expressed in COVID-19 patients and exhibit pathogenic potential

An elevated level of viral diversity was found in some SARS-CoV-2 infected patients, indicating the risk of rapid evolution of the virus. Although no evidence for the transmission of intra-host variants was found, the risk should not be overlooked. Abstract:Background A novel coronavirus (SARS-CoV-2) has infected more than 75,000 individuals and spread to over 20 countries. It is still unclear how fast the virus evolved and how the virus interacts with other microorganisms in the lung. MethodsWe have conducted metatranscriptome sequencing for the bronchoalveolar lavage fluid of eight SARS-CoV-2 patients, 25 community-acquired pneumonia (CAP) patients, and 20 healthy controls. ResultsThe median number of intra-host variants was 1-4 in SARS-CoV-2 infected patients, which ranged between 0 and 51 in different samples. The distribution of variants on genes was similar to those observed in the population data (110 sequences).However, very few intra-host variants were observed in the population as polymorphism, implying either a bottleneck or purifying selection involved in the transmission of the virus, or a consequence of the limited diversity represented in the current polymorphism data. Although current evidence did not support the transmission of intra-host variants in a person-to-person spread, the risk should not be overlooked.The microbiota in SARS-CoV-2 infected patients was similar to those in CAP, either dominated by the pathogens or with elevated levels of oral and upper respiratory commensal bacteria.Conclusion SARS-CoV-2 evolves in vivo after infection, which may affect its virulence, infectivity, and transmissibility. Although how the intra-host variant spreads in the population is still elusive, it is necessary to strengthen the surveillance of the viral Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciaa203/5780800 by guest on 16 March 2020 4 evolution in the population and associated clinical changes.

Purpose The mechanisms accounting for anticancer activity of AZD9291 (osimertinib or TAGRISSO™), an approved third generation EGFR inhibitor, in EGFR-mutant non-small cell lung cancer (NSCLC) cells and particularly for the subsequent development of acquired resistance are unclear and thus are the focus of this study. Experimental design AZD9219-resistant cell lines were established by exposing sensitive cell lines to AZD9291. Protein alterations were detected with Western blotting. Apoptosis was measured with annexin V/flow cytomentry. Growth-inhibitory effects of tested drugs were evaluated in vitro with cell number estimation and colony formation assay and in vivo with mouse xenogtaft models. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. Gene knockdown were achieved with siRNA or shRNA. Results AZD9291 potently induced apoptosis in EGFR-mutant NSCLC cell lines, in which ERK phosphorylation was suppressed accompanied with Bim elevation and Mcl-1 reduction likely due to enhanced Mcl-1 degradation and increased Bim stability. Blocking Bim elevation by gene knockdown or enforcing Mcl-1 expression attenuated or abolished AZD9291-induced apoptosis. Moreover, AZD9291 lost its ability to modulate Bim and Mcl-1 levels in AZD9291-resistant cell lines. The combination of a MEK inhibitor with AZD9291 restores the sensitivity of AZD9291-resistant cells including those with C797S mutation to undergo apoptosis and growth regression in vitro and in vivo. Conclusions Modulation of MEK/ERK-dependent Bim and Mcl-1 degradation critically mediates sensitivity and resistance of EGFR-mutant NSCLC cells to AZD9291 and hence is an effective strategy to overcome acquired resistance to AZD9291.

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Bladder cancer is one of the most common malignancies worldwide. Long non-coding RNAs (lncRNAs) are a class of non-coding RNAs that play crucial roles in diverse biological processes. The pseudogene-expressed lncRNA is one major type of lncRNA family. Small ubiquitin-like modifier (SUMO) 1 pseudogene 3, (SUMO1P3) is a novel indentified lncRNA that was previously reported to be up-regulated in gastric cancer. However, we know nothing about the biological function and underlying mechanism of SUMO1P3 in tumor. Furthermore, the relationship between SUMO1P3 and bladder cancer is completely unknown. We hypothesized that SUMO1P3 also have roles in bladder cancer.In this study, we found that SUMO1P3 was significantly up-regulated in bladder cancer tissues compared with paired-adjacent nontumorous tissues in a cohort of 55 bladder cancer patients. Moreover, up-regulated SUMO1P3 expression was positively correlated with greater histological grade (P<0.05) and advanced TNM stage (P<0.05). Furthermore, we found cell proliferation / migration inhibition and apoptosis induction were also observed in SUMO1P3 siRNA-transfected bladder cancer cells. Our data suggest that SUMO1P3 plays oncogenic roles in bladder cancer and can be used as a potential prognostic and therapeutic target.