Notes

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Adaptive resistance is a major limitation in the use of targeted therapies for cancer. Using real time biomass tracking, we demonstrate the isolation and identification of rare (1% fraction) diffuse large B cell lymphoma cells resistant to the PI3K inhibitor idelalisib, from an otherwise sensitive population. This technique allows direct study of these rare, drug tolerant cells.The P2/O3 layered oxide system is thought to benefit from a synergistic enhancement, resulting from the presence of both phases, which makes it a promising cathode material for Na-ion battery applications. Here, biphasic P2/O3-Na2/3Li0.18Mn0.8Fe0.2O2 is investigated via a combination of neutron and X-ray scattering techniques. Neutron diffraction data indicates that the O3 alkali metal site is fully occupied by Li. Real time operando X-ray diffraction data shows the structural evolution of the composite electrode - at the charged state there is no evidence of O2, OP4 or Z phases. The results presented herein provide new insight into site preference of Li in biphasic materials and highlights the value of utilizing multiple phases to achieve high performance layered cathode materials for sodium battery applications.Overexpression/amplification of erb-b2 receptor tyrosine kinase 2 (ERBB2) is a major prognostic factor in gastroesophageal cancers; it is currently the only biomarker established for the selection of targeted therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). Current standard procedure for determining ERBB2 status in such patients is immunohistochemistry (IHC), followed by in situ hybridization (ISH), when IHC result is equivocal. Insufficient knowledge regarding the utilities of chromosomal microarray (CMA) has hindered its use as an adjunct tool in ERBB2 analysis. Here, we performed CMA on 7 formalin-fixed paraffin-embedded (FFPE) GEA specimens previously tested by ERBB2 fluorescence in situ hybridization (FISH) and evaluated the concordance and performance of CMA. CMA identified 4 (57.1%) samples with amplification of ERBB2, compared to 3 (42.9%) by FISH. CMA also detected several additional DNA copy number variants in these samples, which may have prognostic and therapeutic indications. Further case studies and clinical trials may provide evidence for the utility of CMA-based genomic studies in the management of patients with suspected ERBB2-positive gastroesophageal adenocarcinoma.In our recent publication [1], we have explored at the molecular level the consequences of reovirus administration to patients with KRAS mutated colorectal cancer (CRC). This was the first reported study where transcriptome assay was performed on KRAS mutated CRC patients receiving reovirus (pelareorep) therapy. Using peripheral mononuclear cells as a tumor surrogate, we have identified several hundred genes that were significantly altered in a transcriptome assay of patients receiving pelareorep serving as their own controls (pre and post reovirus administration) and compared to untreated controls [2]. We focused primarily on 884 immune related genes and published the data for genes with significance probability of 0.001 (1 in thousand for a perfect random occurrence). Samples were collected at 48 hours, day 8 and day 15 post reovirus administration and compared for dynamic gene expression alterations over time. Using PBMC we also performed flow cytometry, cytokine ELISA, immunohistochemistry, and determination of the expression level of CRC specific microRNA miR-29a-3p. Our data supports the therapeutic competence of reovirus and identifies the four major ways by which it exerts its antitumor effects.Caspase-6 was discovered decades ago, but its roles in biological processes remain largely unknown. Recently, we have demonstrated that caspase-6 plays a critical role in influenza A virus (IAV)-induced cell death and innate immune responses. During IAV infection, Z-DNA binding protein 1 (ZBP1) initiates ZBP1-PANoptosome assembly to drive inflammasome activation and cell death, and we showed that caspase-6 interacts with RIPK3 to enhance the interaction between RIPK3 and ZBP1, thus promoting PANoptosome assembly. Moreover, the caspase activity of caspase-6 is not required for tins process, suggesting a caspase-independent function of caspase-6 during IAV infection. Additionally, we found that caspase-6 is required for the alternative activation of alveolar macrophages in response to IAV infection. Our findings provide an opportunity to reconsider the physiological role of caspase-6.The symptoms of the COVID-19 range from asymptomatic or mild disease to severe disease that results in acute respiratory distress syndrome (ARDS) and eventually death. Understanding the molecular mechanisms responsible for the progression from mild to severe disease is the key to decreasing the mortality of COVID-19. Compared to mild cases, severe cases of the COVID-19 have decreased interferon (IFN) α, β, λ production. Type I (IFN α/β) and III IFNs (λ) work coordinately to induce inhibition of viral reproduction through the stimulation of interferon stimulated genes (ISGs). Failure to mount an IFN response leads to suboptimal activation of adaptive immune response and increased viral load. The increased viral load causes severe tissue damage, inducing a late wave of IFNs and an exacerbated inflammatory response. There are two known risk factors associated with severe disease- obesity and aging. Both lead to the activation of inflammasome NLRP3, which stimulates transcription factor NFκB and the production of inflammatory cytokines. Type I IFNs inhibit activation of NRLP3. Etrumadenant antagonist Taken together, an early deficient IFN response and the following hyperinflammatory state are the hallmarks of severe COVID-19. This suggests that both type I and III IFNs could potentially be beneficial as prophylaxis and treatment of COVID-19 at the early stage of infection. Indeed, clinical studies have shown benefit of IFN Is, and there are ongoing trials testing type III IFNs for the treatment of COVID-19. Another strategy is to use hydroxychloroquine (HCQ) to inhibit the viral entry into the cells. Our reanalysis of the results from two randomized clinical trials (RCTs) has concluded that use of HCQ is beneficial in postexposure prophylaxis. These two strategies can have great potential in the current pandemic of COVID-19.
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