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Heat shock protein taken part in oxidative stress-mediated inflammatory damage via NF-κB process too much manganese-treated hen livers.
These findings suggest that docosanol could effectively reduce the biofilm phenotype and virulence production thus becomes a promising candidate to treat MRSA infections. V.PURPOSE To develop robust normal tissue complication probability (NTCP) models for hepatocellular carcinoma (HCC) patients treated with radiation therapy (RT) using Child-Pugh (CP) score and Albumin-Bilirubin (ALBI) grade increase as endpoints for hepatic toxicity. learn more METHODS AND MATERIALS Data from 108 HCC patients treated with RT between 2008 and 2017 were evaluated, 47 (44%) of which were treated with proton RT. Of these patients, 29 received stereotactic body RT and 79 received moderately hypofractionated RT to median physical tumor doses of 43 Gy in 5 fractions and 59 Gy in 15 fractions, respectively. A generalized Lyman-Kutcher-Berman (LKB) model was used to model the NTCP using two clinical endpoints, both evaluated at 3 months post-RT CP score increase of two or more and ALBI grade increase of one or more from pre-RT baseline. Confidence intervals on LKB fit parameters were determined using bootstrap resampling. RESULTS Compared to previous NTCP models, this study found a stronger correlation between normal liver volume receiving low doses of radiation (5-10 Gy) and CP/ALBI increase. CP score increase exhibited a stronger correlation to normal liver volume irradiated than ALBI grade increase. LKB models for CP increase found values for the volume-effect parameter of a=0.06 for all patients and 0.02/0.09 when fit to photon/proton patients separately. Subset analyses for patients with superior initial liver function showed consistent dose-volume effects (a=0.1) and consistent dose-response relationships. CONCLUSIONS This study presents an update of liver NTCP models in the era of modern RT techniques using relevant endpoints of hepatic toxicity, CP score and ALBI grade increase. Results show a stronger influence of low-dose bath on hepatic toxicity than those found in previous studies, indicating that RT techniques which minimize the low-dose bath may be beneficial for patients. Meticillin-resistant Staphylococcus aureus (MRSA) is prevalent in extended-care facilities. We conducted a quasi-experimental before-after study in a 100-bed rehabilitation hospital, Jan 2013 to Jun 2019. Universal chlorhexidine bathing was implemented throughout the period, with intranasal octenidine for MRSA-colonizers added from Sept 2017. Interrupted time-series with segmented regression analysis revealed that after adjusting for at-admission MRSA-colonization and hand-hygiene compliance, a constant trend was observed pre-implementation of intranasal octenidine(adjusted mean coefficient 0.012 [95%CI -0.037 to 0.06]), with an immediate drop with implementation(-2.145 [95%CI -0.248 to -0.002], P=0.033), followed by a significant reduction in MRSA acquisition post-implementation(-0.125 [95%CI -0.248 to -0.002], P= 0.047). Functional CRISPR-Cas systems provide many bacteria and most archaea with adaptive immunity against invading DNA elements. CRISPR arrays store DNA fragments of previous infections while products of cas genes provide immunity by integrating new DNA fragments and using this information to recognize and destroy invading DNA. Escherichia coli contains the CRISPR-Cas type I-E system in which foreign DNA targets are recognized by Cascade, a crRNA-guided complex comprising five proteins (CasA, CasB, CasC, CasD, CasE), and degraded by Cas3. In E. coli the CRISPR-Cas type I-E system is repressed by the histone-like nucleoid-structuring protein H-NS. H-NS repression can be relieved either by inactivation of the hns gene or by elevated levels of the H-NS antagonist LeuO, which induces higher transcript levels of cas genes than was observed for Δhns cells. This suggests that derepression in Δhns cells is incomplete and that an additional repressor could be involved in the silencing. One such candidate is the H-NS paralog protein StpA, which has DNA binding preferences similar to those of H-NS. Here we show that overexpression of StpA in Δhns cells containing anti-lambda spacers abolishes resistance to λvir infection and reduces transcription of the casA gene. link2 In cells lacking hns and stpA genes, the transcript levels of the casA gene are higher than Δhns and similar to wt cells overexpressing LeuO. Taken together, these results suggest that Cascade genes in E. coli are repressed by the StpA protein when H-NS is absent. Physico-chemical properties of HspB6 S10F and P20L mutants with abrogated cardioprotective activity and associated with different forms of cardiomyopathy were analyzed. Under normal conditions both the wild-type HspB6 and its mutants formed small size oligomers (dimers) with apparent molecular weight of 50-60 kDa. Under crowding conditions (0.5 M trimethylamine N-oxide, TMAO) the wild-type HspB6 remained predominantly dimeric or formed small molecular weight complexes, whereas both mutants tended to form high molecular weight complexes. Catalytic subunit of cAMP-dependent protein kinase phosphorylated the wild-type HspB6 and its S10F mutant with comparable rate. The rate of P20L mutant phosphorylation was higher than that of the wild-type HspB6. S10F and P20L mutations did not affect interaction of phosphorylated HspB6 with universal adapter proteins 14-3-3. The wild-type HspB6 was resistant to heat-induced denaturation and aggregation, whereas both its mutants were denatured and started to aggregate at temperature much lower than its wild-type counterpart. Titration with fluorescent probe bis-ANS was accompanied by larger increase of fluorescence in the case of both mutants than in the case of the wild-type HspB6. Both mutants possessed higher chaperone-like activity than the wild-type protein. It is concluded that both S10F and P20L mutations are accompanied by increase of hydrophobicity of the very N-terminal region of HspB6 leading to increased aggregation at elevated temperature, formation of large complexes under crowding conditions and increased chaperone-like activity measured in vitro. Increased hydrophobicity and self-association can affect substrate specificity and interaction with certain target proteins thus leading to decrease or complete abrogation of cardioprotective activity. The presence of flavors is one of the commonly cited reasons for use of e-cigarettes by youth; however, the potential harms from inhaling these chemicals and byproducts have not been extensively studied. One mechanism of interest is DNA adduct formation, which may lead to carcinogenesis. We identified two chemical classes of flavors found in tobacco products and byproducts, alkenylbenzenes and aldehydes, documented to form DNA adducts. Using in silico toxicology approaches, we identified structural analogs to these chemicals without DNA adduct information. We conducted a structural similarity analysis and also generated in silico model predictions of these chemicals for genotoxicity, mutagenicity, carcinogenicity, and skin sensitization. The empirical and in silico data were compared, and we identified strengths and limitations of these models. Good concordance (80-100%) was observed between DNA adduct formation and models predicting mammalian mutagenicity (mouse lymphoma sassy L5178Y) and skin sensitization for both chemical classes. On the other hand, different prediction profiles were observed for the two chemical classes for the modeled endpoints, unscheduled DNA synthesis and bacterial mutagenicity. These results are likely due to the different mode of action between the two chemical classes, as aldehydes are direct acting agents, while alkenylbenzenes require bioactivation to form electrophilic intermediates, which form DNA adducts. The results of this study suggest that an in silico prediction for the mouse lymphoma assay L5178Y, may serve as a surrogate endpoint to help predict DNA adduct formation for chemicals found in tobacco products such as flavors and byproducts. Published by Elsevier Inc.Significant attention has been given to the potential of environmental chemicals to disrupt lipid homeostasis at the cellular level. These chemicals, classified as obesogens, are abundantly used in a wide variety of consumer products. However, there is a significant lack of information regarding the mechanisms by which environmental exposure can contribute to the onset of obesity and non-alcoholic fatty liver disease (NAFLD). Several studies have described the interaction of potential obesogens with lipid-related peroxisome proliferator-activated receptors (PPAR). However, no studies have quantified the degree of modification to lipidomic profiles in relevant human models, making it difficult to directly link PPAR agonists to the onset of lipid-related diseases. A quantitative metabolomic approach was used to examine the dysregulation of lipid metabolism in human liver cells upon exposure to potential obesogenic compounds. The chemicals rosiglitazone, perfluorooctanoic acid, di-2-ethylexylphthalate, and tributyltin significantly increased total lipids in liver cells, being diglycerides, triglycerides and phosphatidylcholines the most prominent. Contrarily, perfluorooctane sulfonic acid and the pharmaceutical fenofibrate appeared to lower total lipid concentrations, especially those belonging to the acylcarnitine, ceramide, triglyceride, and phosphatidylcholine groups. Fluorescence microscopy analysis for cellular neutral lipids revealed significant lipid bioaccumulation upon exposure to obesogens at environmentally relevant concentrations. This integrated omics analysis provides unique mechanistic insight into the potential of these environmental pollutants to promote diseases like obesity and NAFLD. Furthermore, this study provides a significant contribution to advance the understanding of molecular signatures related to obesogenic chemicals and to the development of alternatives to in vivo experimentation. Human adenoviruses (HAdVs) often cause mild respiratory infections. These infections, however, can potentially become fatal in immunosuppressive patients. Unfortunately, there has been no specific anti-HAdV drug approved for treatment of HAdV infections. In this study, a time-course transcriptome of HAdV-infected human lung epithelial cells (A549 cells) was performed and compared with perturbation datasets of 890 drug-treated A549 cells from the library of integrated network-based cellular signatures (LINCS) database to predict previously unknown therapeutic drug-HAdV relationships using a characteristic direction (CD) algorithm. We performed experiments to validate a prediction for the anti-diabetic drug rosiglitazone as a candidate drug for treatment of anti-HAdV both in vivo and in vitro. The Type I interferon (IFNs) signaling pathway was negatively regulated during the course of HAdV infection and rosiglitazone increased STAT1 phosphorylation for antiviral IFN response induction. Taken together, this study confirmed the prospect for re-exploitation of this FDA-approved drug as a potential therapeutic for HAdV infections. PURPOSE To determine if female hormonal therapy (FHT) increases the incidence of non-infectious uveitis. DESIGN Retrospective cohort study PARTICIPANTS FHT-exposed women and matched unexposed women enrolled in a national insurance plan. METHODS Estimation of non-infectious uveitis incidence used multivariable Cox proportional hazards regression. link3 To account for differences between the exposed and unexposed cohorts, a propensity score for being prescribed FHT was created using logistic regression, and inverse probability of treatment weighting was performed. MAIN OUTCOME MEASURES Incidence of non-infectious uveitis. For the primary outcome, incident non-infectious uveitis was defined as a new diagnosis code for non-infectious uveitis followed by a second instance of a non-infectious uveitis code within 120 days. For the alternative outcome definition, a corticosteroid prescription or code for an ocular corticosteroid injection within 120 days of the uveitis diagnosis code was used instead of the second uveitis diagnosis code.
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