Reimerabildgaard5913

BACKGROUND Bile acids (BAs) regulate hepatic lipid metabolism and inflammation. Bile salt export pump (BSEP) KO mice are metabolically preconditioned with a hydrophilic BA composition protecting them from cholestasis. We hypothesize that changes in hepatic BA profile and subsequent changes in BA signalling may critically determine the susceptibility to steatohepatitis. METHODS Wild-type (WT) and BSEP KO mice were challenged with methionine choline-deficient (MCD) diet to induce steatohepatitis. Serum biochemistry, lipid profiling as well as intestinal lipid absorption were assessed. Markers of inflammation, fibrosis, lipid and BA metabolism were analysed. Hepatic and faecal BA profile as well as serum levels of the BA synthesis intermediate 7-hydroxy-4-cholesten-3-one (C4) were also investigated. RESULTS Bile salt export pump KO MCD-fed mice developed less steatosis but more inflammation than WT mice. Intestinal neutral lipid levels were reduced in BSEP KO mice at baseline and under MCD conditions. Faecal non-esterified fatty acid concentrations at baseline and under MCD diet were markedly elevated in BSEP KO compared to WT mice. Serum liver enzymes and hepatic expression of inflammatory markers were increased in MCD-fed BSEP KO animals. PPARα protein levels were reduced in BSEP KO mice. Accordingly, PPARα downstream targets Fabp1 and Fatp5 were repressed, while NFκB subunits were increased in MCD-fed BSEP KO mice. Farnesoid X receptor (FXR) protein levels were reduced in MCD-fed BSEP KO vs WT mice. Hepatic BA profile revealed elevated levels of TβMCA, exerting FXR antagonistic action, while concentrations of TCA (FXR agonistic function) were reduced. CONCLUSION Presence of hydroxylated BAs result in increased faecal FA excretion and reduced hepatic lipid accumulation. This aggravates development of MCD diet-induced hepatitis potentially by decreasing FXR and PPARα signalling. © 2020 The Authors. Liver International published by John Wiley & Sons Ltd.Recently, many researches have reported that antibiotic tigecycline has significant effect on cancer treatment. However, biomedical functions and molecular mechanisms of tigecycline in human pancreatic ductal adenocarcinoma (PDAC) remain unclear. TAS-120 manufacturer In the current study, we tried to assess the effect of tigecycline in PDAC cells. AsPC-1 and HPAC cells were treated with indicated concentrations of tigecycline for indicated time, and then, MTT, BrdU and soft agar assay were used to test cell proliferation. The effect of tigecycline on cell cycle and cellular apoptosis was tested by cytometry. Migration and invasion were detected by wound healing assay and transwell migration/invasion assay. Expressions of cell cycle-related and migration/invasion-related protein were determined by using Western blot. The results revealed that tigecycline observably suppressed cell proliferation by inducing cell cycle arrest at G0/G1 phase and blocked cell migration/invasion via holding back the epithelial-mesenchymal transition (EMT) process in PDAC. In addition, tigecycline also remarkably blocked tumorigenecity in vivo. Furthermore, the effects of tigecycline alone or combined with gemcitabine in vitro or on PDAC xenografts were also performed. The results showed that tigecycline enhanced the chemosensitivity of PDAC cells to gemcitabine. Interestingly, we found CCNE2 expression was declined distinctly after tigecycline treatment. Then, CCNE2 was overexpressed to rescue tigecycline-induced effect. The results showed that CCNE2 overexpression significantly rescued tigecycline-inhibited cell proliferation and migration/invasion. Collectively, we showed that tigecycline inhibits cell proliferation, migration and invasion via down-regulating CCNE2, and tigecycline might be used as a potential drug for PDAC treatment alone or combined with gemcitabine. © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.FAM46C, frequently mutated in multiple myeloma (MM), has recently been shown to encode a non-canonical poly(A) polymerase (ncPAP). However, its target mRNAs and its role in MM pathogenesis remain mostly unknown. Using CRISPR-Cas9 technology and gene expression analysis, we found that the inactivation of FAM46C in MM down-regulates immunoglobulins (Igs) and several mRNAs encoding ER-resident proteins, including some involved in unfolded protein response and others that affect glycosylation. Interestingly, we show that FAM46C expression is induced during plasma cell (PC) differentiation and that Ig mRNAs encoding heavy and light chains are substrates of the ncPAP, as revealed by poly(A) tail-length determination assays. The absence of the ncPAP results in Ig mRNA poly(A) tail-shortening, leading to a reduction in mRNA and protein abundance. On the other hand, loss of FAM46C up-regulates metastasis-associated lncRNA MALAT1 and results in a sharp increase in the migration ability. This phenotype depends mainly on the activation of PI3K/Rac1 signalling, which might have significant therapeutic implications. In conclusion, our results identify Ig mRNAs as targets of FAM46C, reveal an important function of this protein during PC maturation to increase antibody production and suggest that its role as a tumour suppressor might be related to the inhibition of myeloma cell migration. © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.BACKGROUND The microbiome is an integral component of many animal species, potentially affecting behavior, physiology, and other biological properties. Despite this importance, bacterial communities remain vastly understudied in many groups of invertebrates, including mites. Quill mites (Acariformes Syringophilidae) are a poorly known group of permanent bird ectoparasites that occupy quills of feathers and feed on bird subcutaneous tissue and fluids. Most of the known species have strongly female-biased sex ratio, and it was hypothesized that this is caused by endosymbiotic bacteria. Previously, Anaplasma phagocytophilum (Foggie) and a high diversity of Wolbachia strains were detected in quill mites via targeted PCR screens. Here, we use an unbiased 16S rRNA gene amplicon sequencing approach to determine other bacteria that potentially impact quill mite biology. RESULTS We performed 16S rRNA gene amplicon sequencing of 126 quill mite individuals from eleven species parasitizing twelve species (four families) herited symbionts) in quill mites. © 2019 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.Robust optimization has been shown to be effective for stabilizing treatment planning in intensity modulated proton therapy (IMPT), but existing algorithms for the optimization process is time-consuming. link2 This paper describes a fast robust optimization tool that takes advantage of the GPU parallel computing technologies. link3 The new robust optimization model is based on nine boundary dose distributions - two for ±range uncertainties, six for ±set-up uncertainties along anteroposterior (A-P), lateral (R-L) and superior-inferior (S-I) directions, and one for nominal situation. The nine boundary influence matrices were calculated using an in-house finite size pencil beam dose engine, while the conjugate gradient method was applied to minimize the objective function. The proton dose calculation algorithm and the conjugate gradient method were tuned for heterogeneous platforms involving the CPU host and GPU device. Three clinical cases - one head and neck cancer case, one lung cancer case, and one prostate cancer case edicine.Autosomal dominant (de novo) mutations in PBX1 are known to cause congenital abnormalities of the kidney and urinary tract (CAKUT), with or without extra-renal abnormalities. Using trio exome sequencing, we identified a PBX1 p.(Arg107Trp) mutation in a deceased one-day-old neonate presenting with CAKUT, asplenia, and severe bilateral diaphragmatic thinning and eventration. Further investigation by droplet digital PCR revealed that the mutation had occurred post-zygotically in the father, with different variant allele frequencies of the mosaic PBX1 mutation in blood (10%) and sperm (20%). Interestingly, the father had subclinical hydronephrosis in childhood. With an expected recurrence risk of one in five, chorionic villus sampling and prenatal diagnosis for the PBX1 mutation identified recurrence in a subsequent pregnancy. The family opted to continue the pregnancy and the second affected sibling was stillborn at 35 weeks, presenting with similar severe bilateral diaphragmatic eventration, microsplenia, and complete sex reversal (46, XY female). This study highlights the importance of follow-up studies for presumed de novo and low-level mosaic variants and broadens the phenotypic spectrum of developmental abnormalities caused by PBX1 mutations. © 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.INTRODUCTION Hemostatic prophylaxis (HP) is recommended for patients with bleeding disorders (PWBD) before invasive procedures. However, evidence-based guidelines are needed to determine optimal HP strategies. AIM To determine outcomes of HP for PWBD undergoing colonoscopy. METHODS We undertook a retrospective cohort study of HP and outcomes of colonoscopy procedures performed between 9 November 1993 and 13 February 2018 for PWBD who received care in the Mayo Clinic Comprehensive Hemophilia Treatment Center. RESULTS During the study period, 73 PWBD (58 with milder phenotypes haemophilia, von Willebrand disease [subtypes 1 and 2; II, VII and XI deficiency]) underwent 141 procedures. Preprocedural HP was given to 61%, and interventions were performed in 47%. Of the 39% without preprocedural HP, postprocedural HP was given for 11%. One major (0.7%; 6 days postprocedure despite HP) and 10 minor (7%) bleeding complications occurred, which tended to be in patients with severe disease and/or after excision of larger polyps. There was no significant difference in the rate of bleeding complications with or without preprocedural HP (8.1% vs 5.5%, respectively; P = .74, Fisher's exact test). CONCLUSION The low bleeding rates in our cohort suggest that preprocedure HP may be withheld for patients with mild bleeding disorders who undergo colonoscopy with a low likelihood of requiring an intervention or who require only low-risk intervention. This strategy may be best used in experienced centres, provided optimal local hemostasis measures are undertaken and postprocedural HP is rapidly available if high-risk intervention is required. Further studies are needed to determine optimal evidence-based HP strategies for PWBD undergoing colonoscopy. © 2020 The Authors. Haemophilia published by John Wiley & Sons Ltd.INTRODUCTION Development of inhibitors is the most serious complication in patients with haemophilia (PWH). The prevalence of inhibitors in patients with severe haemophilia A (HA) is approximately 25%-30%. Inhibitor prevalence differs among populations. Some studies report a prevalence of almost twice in Hispanic as compared to Caucasian patients. Most data available, on the prevalence of inhibitors and their predisposing factors, originate from centres in developed countries. AIM Establish the prevalence of inhibitors of FVIII and FIX in Mexico. METHODS This was an observational, cross-sectional and descriptive study. The records of all patients diagnosed with haemophilia A (HA) or B (HB), with and without inhibitors, were included. Clinical and demographical characteristics of patients with inhibitors were assessed. Statistical analysis was performed using IBM SPSS version 22. The Ethics Committees of the various participating institutions approved this study. RESULTS A total of 1455 patients from the 20 participating centres were recruited, from which 1208 (83.