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Leblanc Fournier posted an update 6 months ago
W10 was an essential amino acid in the activity of peptide 4-2.PARP inhibitor monotherapy (olaparib) was recently FDA approved for the treatment of BRCA1/2-mutant, homologous recombination (HR) repair-deficient pancreatic cancer. Most pancreatic cancers, however, are HR proficient and thus resistant to PARP inhibitor monotherapy. We tested the hypothesis that combined therapy with radiation and ataxia telangiectasia and Rad3-related (ATR) inhibitor (AZD6738) would extend the therapeutic indication of olaparib to HR-proficient pancreatic cancers. We show that olaparib combined with AZD6738 significantly reduced radiation survival relative to either agent alone, regardless of HR status. Whereas catalytic inhibition of PARP with low concentrations of olaparib radiosensitized HR-deficient models, maximal sensitization in HR-proficient models required concentrations of olaparib that induce formation of PARP1-DNA complexes. Furthermore, CRISPR-Cas9-mediated PARP1 deletion failed to recapitulate the effects of olaparib on radiosensitivity and negated the combinatorial efficacy of olaparib and AZD6738 on radiosensitization, suggesting that PARP1-DNA complexes, rather than PARP catalytic inhibition, were responsible for radiosensitization. see more Mechanistically, therapeutic concentrations of olaparib in combination with radiation and AZD6738 increased DNA double-strand breaks. DNA fiber combing revealed that high concentrations of olaparib did not stall replication forks but instead accelerated replication fork progression in association with an ATR-mediated replication stress response that was antagonized by AZD6738. Finally, in HR-proficient tumor xenografts, the combination of olaparib, radiation, and AZD6738 significantly delayed tumor growth compared with all other treatments. These findings suggest that PARP1-DNA complexes are required for the therapeutic activity of olaparib combined with radiation and ATR inhibitor in HR-proficient pancreatic cancer and support the clinical development of this combination for tumors intrinsically resistant to PARP inhibitors.The gut microbiota of autism spectrum disorder (ASD) children differs from that of children without ASD. The maternal gut microbiota impacts offspring gut microbiota. However, the relationship between the development of ASD and gut bacteria shared between children and their mothers remains elusive. Our study recruited 76 children with ASD and 47 age- and gender-matched children with typical development (TD), as well as the mothers of both groups, and investigated their gut microbiota using amplicon sequence variants (ASVs). The gut microbiota of ASD children was altered compared with that of children with TD, while no significant alterations were found in their mothers. We established 30 gut bacterial coabundance groups (CAGs) and found the relative abundances of CAG15 and CAG16 significantly decreased in ASD children. CAG15 showed a positive correlation with developmental level. The proportion of ASD children who shared either one of the two Lachnospiraceae ASVs from CAG15 with their mothers was significantlclinical symptoms of autism spectrum disorder and the gut bacteria shared between children and their mothers is not yet known. In our study, the gut microbiota of children with autism spectrum disorder differed from that of children with typical development, but there were no differences in the gut microbiota of their mothers. More importantly, gut bacteria shared between children with autism spectrum disorder and their mothers were related to developmental disabilities and social deficits. Thus, our study suggests that these shared gut bacteria may play an important role in the development of autism spectrum disorder. This provides a new direction for future studies aiming to explore the role of the gut microbiota in autism spectrum disorder.While Epstein-Barr virus (EBV) is the major cause of nasopharyngeal carcinoma (NPC), the value of the humoral immune response to EBV glycoproteins and NPC development remains unclear. Correlation between antiglycoprotein antibody levels, neutralization of EBV infectivity, and the risk of NPC requires systematic study. Here, we applied a cytometry-based method and enzyme-linked immunosorbent assay to measure neutralization of infectivity and antibody response to EBV glycoproteins (gH/gL, gB, gp350, and gp42) of plasma samples from 20 NPC cases and 20 high-risk and 20 low-risk healthy controls nested within a screening cohort in Sihui, southern China. We found that NPC cases have similar plasma neutralizing activity in both B cells and epithelial cells and EBV glycoprotein-specific IgA and IgG antibody levels compared with those of healthy controls. Significant correlations were observed between gH/gL IgG and gB IgG and the neutralizing ability against EBV infection of epithelial cells and B cells. These resulttematically assessed the correlation between antiglycoprotein antibody levels, neutralization of EBV infectivity, and the risk of NPC development. These results provide valuable information that will contribute to designing effective prevention and treatment strategies for EBV-related diseases such as NPC.Understanding the environmental and behavioral factors that influence how organisms maintain energy balance can inform us about their potential resiliency to rapid environmental changes. Flexibility in maintaining energy balance is particularly important to long-lived, central-place foraging seabirds that are constrained when locating food for offspring in a dynamic ocean environment. To understand the role of environmental interactions, behavioral flexibility and morphological constraints on energy balance, we used doubly labeled water to measure the at-sea daily energy expenditure (DEE) of two sympatrically breeding seabirds, Campbell (Thalassarche impavida) and grey-headed (Thalassarchechrysostoma) albatrosses. We found that species and sexes had similar foraging costs, but DEE varied between years for both species and sexes during early chick rearing in two consecutive seasons. For both species, greater DEE was positively associated with larger proportional mass gain, lower mean wind speeds during water take-offs, greater proportions of strong tailwinds (>12 m s-1), and younger chick age.
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