Witttorp0295

56, CI 0.38-0.84, P = .004) and AML-MRC-H having better OS. Compared to a cohort of 468 patients with AML without MRC, patients with AML-MRC-M/AML-MRC-H had similar outcomes to those with intermediate risk AML by European LeukemiaNet criteria. Intensive therapy was associated with improved OS in patients with AML-MRC-M (HR 0.42, CI 0.19-0.94, P = .036) and with improved EFS in AML-MRC-M and AML-MRC-H (HR 0.26, CI 0.10-0.63, P = .003). This data suggests that not all diagnostic criteria for AML-MRC define high-risk patients and that specific subgroups may benefit from different therapeutic interventions. © 2020 Wiley Periodicals, Inc.OBJECTIVES Programmed death-ligand 1 (PD-L1) is an immune checkpoint protein that may be a useful prognostic biomarker in nasopharyngeal cancer (NPC). The purpose of this systematic review and meta-analysis was to investigate the relationship between PD-L1 expression and survival in NPC. METHODS PubMed, Cochrane, Embase, Scopus, and Web of Science were searched from inception to present. A predefined inclusion and exclusion criteria were used to select articles. Hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled for overall survival (OS), disease-free survival (DFS), and disease metastasis-free survival (DMFS). RESULTS Eleven studies published from 2014 to 2018 were included, with 1,356 total participants. PD-L1 expression was not associated with OS (HR = 1.10, 95% CI 0.79-1.55), DFS (HR = 1.66, 95% CI 0.68-4.03), or DMFS (HR = 1.18, 95% CI 0.44-3.20). CONCLUSIONS The prognostic role of PD-L1 in NPC remains unsubstantiated. Future research is needed. Laryngoscope, 2020. © 2020 The American Laryngological, Rhinological and Otological Society, Inc.OBJECTIVE Genetic variants in STXBP1, which encodes the conserved exocytosis protein Munc18-1, are associated with a variety of infantile epilepsy syndromes. We aimed to develop an in vivo Caenorhabditis elegans model that could be used to test the pathogenicity of such variants in a cost-effective manner. METHODS The CRISPR/Cas9 method was used to introduce a null mutation into the unc-18 gene (the C. elegans orthologue of STXBP1), thereby creating a paralyzed worm strain. We subsequently rescued this strain with transgenes encoding the human STXBP1/Munc18-1 protein (wild-type and eight different epilepsy-associated missense variants). The resulting humanized worm strains were then analyzed via behavioral, electrophysiological, and biochemical approaches. RESULTS Transgenic expression of wild-type human STXBP1 protein fully rescued locomotion in both solid and liquid media to the same level as the standard wild-type worm strain, Bristol N2. Six variant strains (E59K, V84D, C180Y, R292H, L341P, R551C) exhibithput drug screens to identify novel therapeutics. © 2020 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.BACKGROUND The correct treatment and management of scabies is expensive, time consuming and may have negative impacts on patients and their families. AIM We sought to investigate the effects of 5 % permethrin cream on scabies mites, and explore mite survival times outside the human body. METHODS We performed a non-randomised controlled study. Twenty petri dishes were coated with 5 % permethrin cream, each with one scabies mite (treatment group), and twenty plain petri dishes with one scabies mite each (control group) were observed at baseline and 3, 4, 5, 6, 7, 8 and 12 hours from baseline. eFT-508 order In the second part of our study, thirty scabies mites from infested patients were investigated in an observational study in 30 plain petri dishes at days 0, 3 and 4. RESULTS Our data showed that 65% of scabies mites survived after eight hours in the treatment group, when compared with 75% of mites in the control group. After 12 hours, 25% of mites in the treatment group, and 60% in the control group were still alive. Data from the observational survival study showed that one mite survived for three days, but all mites were dead by day four. CONCLUSIONS This study showed no significant effects of mite survival times with 5 % topical permethrin after eight hours, while its efficacy was stronger and significant after 12 hours. We recommend the isolation of all mite-infested items for at least four days. This article is protected by copyright. All rights reserved.Ponatinib is an oral drug for the treatment of chronic myeloid leukemia and acute lymphoblastic leukemia, which has been reported to increase the risk of hepatotoxicity. The aim of this study was to characterize the metabolites of ponatinib in human liver microsomes as well as its reactive metabolites. Ponatinib was incubated with human liver microsomes in the presence of NADPH and trapping agents (glutathione or potassium cyanide). The metabolites were characterized by liquid chromatography in combination with Q-Exactive-Orbitrap-MS. Under the current conditions, six metabolites were detected and structurally identified on the basis of their accurate masses, fragmentation patterns, and retention times. link2 M3 (N-demethylation) was unambiguously identified by matching its retention time and fragment ions with those of its reference standard. N-demethylation and oxygenation were proved to be the predominant metabolic pathways of ponatinib. In addition, two reactive metabolites (cyano adducts) were detected in human liver microsomes in the presence of potassium cyanide and NADPH, suggesting that ponatinib underwent CYP450-mediated metabolic activation, which could be one of the causative mechanisms for its hepatotoxicity. The current study provides new information regarding the metabolic profiles of ponatinib and would be helpful in understanding the effectiveness and toxicity of ponatinib, especially the mechanism of hepatotoxicity. © 2020 John Wiley & Sons, Ltd.BACKGROUND Short-chain fatty acids (SCFAs) are fermented dietary components that regulate immune responses, promote colonic health and suppress mast cell-mediated diseases. However, the effects of SCFAs on human mast cell function, including the underlying mechanisms, remain unclear. Here, we investigated the effects of the SCFAs acetate, propionate and butyrate on mast cell-mediated pathology and human mast cell activation, including the molecular mechanisms involved. METHOD Precision-cut lung slices (PCLS) of allergen-exposed guinea pigs were used to assess the effects of butyrate on allergic airway contraction. Human and mouse mast cells were co-cultured with SCFAs and assessed for degranulation after IgE- or non-IgE-mediated stimulation. link3 The underlying mechanisms involved were investigated using knockout mice, small molecule inhibitors/agonists, and genomics assays. RESULTS Butyrate treatment inhibited allergen-induced histamine release and airway contraction in guinea pig PCLS. Propionate and butyrate, but not acetate, inhibited IgE and non-IgE-mediated human or mouse mast cell degranulation in a concentration-dependent manner. Notably, these effects were independent of the stimulation of SCFA receptors GPR41, GPR43 or PPAR, but instead were associated with inhibition of histone deacetylases. Transcriptome analyses revealed butyrate-induced downregulation of the tyrosine kinases BTK, SYK and LAT, critical transducers of FcεRI-mediated signals that are essential for mast cell activation. Epigenome analyses indicated that butyrate redistributed global histone acetylation in human mast cells, including significantly decreased acetylation at the BTK, SYK and LAT promoter regions. CONCLUSION Known health benefits of SCFAs in allergic disease can, at least in part, be explained by epigenetic suppression of human mast cell activation. This article is protected by copyright. All rights reserved.Folium Camelliae Nitidissimae (jinhuacha in Chinese, JHC) is a kind of caffeine-less tea with antioxidant, antitumor and antibacterial effects. Studies on the chemical profiles and hepatoprotective effects of JHC extracts have not been systematically conducted so far. This study comprehensively investigated the compound profiles of JHC extract by ultrafast liquid chromatography with quadrupole time-of-flight tandem mass spectrometry. We also determined JHC's hepatoprotective effects against CCl4 -induced liver injury in mice. A JHC extract was administered orally to mice at 1.95 and 7.80 g/kg body weight once daily for 14 consecutive days prior to CCl4 treatment. Eighty-four compounds including flavonoids, organic acids, catechins, coumarins, phenylpropanol, amino acids, anthraquinones, saponins and nucleosides in JHC extract were authentically identified or tentatively identified by comparing MS information and retention times with those of authentic standards or available references. JHC administration significantly decreased elevated levels of aspartate aminotransferase and alanine aminotransferase in mouse serum, inhibited hepatic malondialdehyde formation and enhanced glutathione and superoxide dismutase activities in the liver of CCl4 -treated mice. The histological observations also further supported the results. These results demonstrate that JHC contains various chemical compounds and its hepatoprotective effects against CCl4 -induced liver injury correlated with decreasing lipid oxidation are significant. © 2020 John Wiley & Sons, Ltd.Imatinib was the first BCR-ABL inhibitor used in clinical practice to treat chronic myeloid leukemia (CML) and significantly improve the life expectancy of CML patients in the chronic phase. However, a portion of CML patients are resistant to imatinib. This study aimed to determine whether menadione (Vitamin K3) can improve imatinib efficacy in CML and to thoroughly explore the combination regimen mechanism between imatinib and menadione. Menadione improved imatinib efficacy in K562 cells by downregulating ABCB1 expression and increased the intracellular concentration of imatinib, which confirmed that this combination regimen is more effective than imatinib monotherapy. The results demonstrate that menadione and imatinib combination therapy may be a promising approach to refractory CML. This article is protected by copyright. All rights reserved.Increasing temperatures resulting from climate change dramatically impact rice crop production in Asia. Depending on the specific stage of rice development, heat stress reduces tiller/panicle number, decreases grain number per plant and lower grain weight, thus negatively impacting yield formation. Hence improving rice crop tolerance to heat stress in terms of sustaining yield stability under high day temperature (HDT), high night temperature (HNT), or combined high day and night temperature (HDNT) will bolster future food security. In this review article, we highlight the phenological alterations caused by heat and the underlying molecular-physiological and genetic mechanisms operating under different types of heat conditions (HDT, HNT, and HDNT) to understand heat tolerance. Based on our synthesis of HDT, HNT, and HDNT effects on rice yield components, we outline future breeding strategies to contribute to sustained food security under climate change. © 2020 John Wiley & Sons Ltd.Estrogen is an important risk factor for cholesterol gallstone disease because women are twice as likely as men to form gallstones. The classical estrogen receptor α (ERα), but not ERβ, in the liver plays a critical role in the formation of estrogen-induced gallstones in female mice. The molecular mechanisms underlying the lithogenic effect of estrogen on gallstone formation have become more complicated with the identification of the G protein-coupled receptor 30 (GPR30), a novel estrogen receptor. We investigated the biliary and gallstone phenotypes in ovariectomized female GPR30 (-/-), ERα (-/-), and wild-type mice injected intramuscularly with the potent GPR30-selective agonist G-1 at 0 or 1 μg/day and fed a lithogenic diet for 8 weeks. The activation of GPR30 by G-1 enhanced cholelithogenesis by suppressing expression of cholesterol 7α-hydroxylase, the rate-limiting enzyme for the classical pathway of bile salt synthesis. These metabolic abnormalities led to an increase in biliary cholesterol concentrations in company with hepatic hyposecretion of biliary bile salts, thereby inducing cholesterol-supersaturated gallbladder bile and accelerating cholesterol crystallization.