Hepatotoxicity Associated with the Use of Anti-TNF-α Agents

Medications to inhibit the actions of tumour necrosis factor alpha have revolutionized the treatment of several pro-inflammatory autoimmune conditions. Despite their many benefits, several serious side effects exist and adverse reactions do occur from these medications. While many of the medications' potential adverse effects were anticipated and recognized in clinical trials prior to drug approval, several more rare adverse reactions were recorded in the literature as the popularity, availability and distribution of these medications grew. Of these potential adverse reactions, liver injury, although uncommon, has been observed in some patients. As case reports accrued over time and ultimately case series developed, the link became better established between this family of medicines and various patterns of liver injury. Interestingly, it appears that the majority of cases exhibit an autoimmune hepatitis profile both in serological markers of autoimmune liver disease and in classic autoimmune features seen on hepatic histopathology. Despite the growing evidence of this relationship, the pathogenesis of this reaction remains incompletely understood, but it appears to depend on characteristics of the medications and the genetic composition of the patients; it is likely more complicated than a simple medication class effect. Because of this still incomplete understanding and the infrequency of the occurrence, treatments have also been limited, although it is clear that most patients improve with cessation of the offending agent and, in certain cases, glucocorticoid use. However, more needs to be done in the future to unveil the underlying mechanisms of this adverse reaction

Profiles of miRNAs in serum in severe acute drug induced liver injury and their prognostic significance

Background & AimsDrug induced liver injury (DILI) is challenging because of the lack of biomarkers to predict mortality. Our aim was to describe miRNA changes in sera of subjects with acute idiosyncratic DILI and determine if levels of miRNAs were associated with 6 month mortality.MethodsClinical data and sera were collected from subjects enrolled in the Drug Induced Liver Injury Network prospective study. miRNAs were isolated from serum obtained from 78 subjects within 2 weeks of acute DILI and followed up for 6 months or longer. miRNAs were compared to 40 normal controls and 6 month survivors vs non‐survivors.ResultsThe mean age of the DILI cohort was 48 years, and 55% were female. Eleven (14.1%) subjects died, 10 within 6 months of DILI onset, 5 (45%) liver related. Lower levels of miRNAs‐122, ‐4463 and ‐4270 were associated with death within 6 months (P<.05). None of the subjects with miRNA‐122 greater than the median value died within 6 months for a sensitivity of 100% and specificity of 57%. In subjects with a serum albumin <2.8 g/dL and miR‐122<7.89 RFU the sensitivity, specificity, positive and negative predictive values for death within 6 months were 100%, 57%, 38% and 100% respectively.ConclusionsSerum miRNA‐122 combined with albumin accurately identified subjects who died within 6 months of drug induced liver injury. If confirmed prospectively, miRNA‐122 and albumin may be useful in identifying patients at high risk for mortality or liver transplantation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136681/1/liv13312_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136681/2/liv13312.pd

Proteomic Profiling of Enteroid Cultures Skewed Towards Development of Specific Epithelial Lineages

Recently, three‐dimensional small intestinal organoids (enteroids) have been developed from cultures of intestinal stem cells which differentiate in vitro to generate all the differentiated epithelial cell types associated with the intestine and mimic the structural properties of the intestine observed in vivo. Small‐molecule drug treatment can skew organoid epithelial cell differentiation towards particular lineages, and these skewed enteroids may provide useful tools to study specific epithelial cell populations, such as goblet and Paneth cells. However, the extent to which differentiated epithelial cell populations in these skewed enteroids represent their in vivo counterparts is not fully understood. In this study, we have performed label‐free quantitative proteomics to determine whether skewing murine enteroid cultures towards the goblet or Paneth cell lineages results in changes in abundance of proteins associated with these cell lineages in vivo. Our data confirm that skewed enteroids recapitulate important features of the in vivo gut environment, confirming that they can serve as useful models for the investigation of normal and disease processes in the intestine. Furthermore, by comparison of our mass spectrometry data with histology data contained within the Human Protein Atlas, we identify putative novel markers for goblet and Paneth cells

The diagnosis and management of idiosyncratic drug‐induced liver injury

Drug‐induced liver injury (DILI) is an uncommon but important cause of liver disease that can arise after exposure to a multitude of drugs and herbal and dietary supplements. The severity of idiosyncratic DILI varies from mild serum aminotransferase elevations to the development of severe liver injury that can progress to acute liver failure resulting in death or liver transplantation within days of DILI onset. Chronic liver injury that persists for more than 6 months after DILI onset is also becoming increasingly recognized in up to 20% of DILI patients. Host demographic (age, gender, race), clinical and laboratory features at DILI onset have been associated with the severity and outcome of liver injury in DILI patients. In addition to cessation of the suspect drug, other medical interventions including the use of N‐acetylcysteine and corticosteroids in selected patients have shown some clinical benefit, but additional prospective studies are needed. A number of promising diagnostic, prognostic and mechanistic serum and genetic biomarkers may help improve our understanding of the pathogenesis and treatment of idiosyncratic DILI.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147192/1/liv13931.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147192/2/liv13931_am.pd

CD9+ Regulatory B Cells Induce T Cell Apoptosis via IL-10 and Are Reduced in Severe Asthmatic Patients

CD9 was recently identified as a marker of murine IL-10-competent regulatory B cells. Functional impairments or defects in CD9+ IL-10-secreting regulatory B cells are associated with enhanced asthma-like inflammation and airway hyperresponsiveness. In mouse models, all asthma-related features can be abrogated by CD9+ B cell adoptive transfer. We aimed herein to decipher the profiles, features, and molecular mechanisms of the regulatory properties of CD9+ B cells in human and mouse. The profile of CD9+ B cells was analyzed using blood from severe asthmatic patients and normal and asthmatic mice by flow cytometry. The regulatory effects of mouse CD9+ B cells on effector T cell death, cell cycle arrest, apoptosis, and mitochondrial depolarization were determined using yellow dye, propidium iodide, Annexin V, and JC-1 staining. MAPK phosphorylation was analyzed by western blotting. Patients with severe asthma and asthmatic mice both harbored less CD19+CD9+ B cells, although these cells displayed no defect in their capacity to induce T cell apoptosis. Molecular mechanisms of regulation of CD9+ B cells characterized in mouse showed that they induced effector T cell cycle arrest in sub G0/G1, leading to apoptosis in an IL-10-dependent manner. This process occurred through MAPK phosphorylation and activation of both the intrinsic and extrinsic pathways. This study characterizes the molecular mechanisms underlying the regulation of CD9+ B cells to induce effector T cell apoptosis in mice and humans via IL-10 secretion. Defects in CD9+ B cells in blood from patients with severe asthma reveal new insights into the lack of regulation of inflammation in these patients

The Nucleosome (Histone-DNA Complex) Is the TLR9-Specific Immunostimulatory Component of Plasmodium falciparum That Activates DCs

The systemic clinical symptoms of Plasmodium falciparum infection such as fever and chills correspond to the proinflammatory cytokines produced in response to the parasite components released during the synchronized rupture of schizonts. We recently demonstrated that, among the schizont-released products, merozoites are the predominant components that activate dendritic cells (DCs) by TLR9-specific recognition to induce the maturation of cells and to produce proinflammatory cytokines. We also demonstrated that DNA is the active constituent and that formation of a DNA-protein complex is essential for the entry of parasite DNA into cells for recognition by TLR9. However, the nature of endogenous protein-DNA complex in the parasite is not known. In this study, we show that parasite nucleosome constitute the major protein-DNA complex involved in the activation of DCs by parasite nuclear material. The parasite components were fractionated into the nuclear and non-nuclear materials. The nuclear material was further fractionated into chromatin and the proteins loosely bound to chromatin. Polynucleosomes and oligonucleosomes were prepared from the chromatin. These were tested for their ability to activate DCs obtained by the FLT3 ligand differentiation of bone marrow cells from the wild type, and TLR2−/−, TLR9−/− and MyD88−/− mice. DCs stimulated with the nuclear material and polynucleosomes as well as mono- and oligonucleosomes efficiently induced the production of proinflammatory cytokines in a TLR9-dependent manner, demonstrating that nucleosomes (histone-DNA complex) represent the major TLR9-specific DC-immunostimulatory component of the malaria parasite nuclear material. Thus, our data provide a significant insight into the activation of DCs by malaria parasites and have important implications for malaria vaccine development

Transcriptional Analysis of Murine Macrophages Infected with Different Toxoplasma Strains Identifies Novel Regulation of Host Signaling Pathways

Most isolates of Toxoplasma from Europe and North America fall into one of three genetically distinct clonal lineages, the type I, II and III lineages. However, in South America these strains are rarely isolated and instead a great variety of other strains are found. T. gondii strains differ widely in a number of phenotypes in mice, such as virulence, persistence, oral infectivity, migratory capacity, induction of cytokine expression and modulation of host gene expression. The outcome of toxoplasmosis in patients is also variable and we hypothesize that, besides host and environmental factors, the genotype of the parasite strain plays a major role. The molecular basis for these differences in pathogenesis, especially in strains other than the clonal lineages, remains largely unexplored. Macrophages play an essential role in the early immune response against T. gondii and are also the cell type preferentially infected in vivo. To determine if non-canonical Toxoplasma strains have unique interactions with the host cell, we infected murine macrophages with 29 different Toxoplasma strains, representing global diversity, and used RNA-sequencing to determine host and parasite transcriptomes. We identified large differences between strains in the expression level of known parasite effectors and large chromosomal structural variation in some strains. We also identified novel strain-specifically regulated host pathways, including the regulation of the type I interferon response by some atypical strains. IFNβ production by infected cells was associated with parasite killing, independent of interferon gamma activation, and dependent on endosomal Toll-like receptors in macrophages and the cytoplasmic receptor retinoic acid-inducible gene 1 (RIG-I) in fibroblasts.National Institutes of Health (U.S.) (R01-AI080621)New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (Developmental Grant AIO57159)Pew Charitable Trusts (Biomedical Scholars Program)Robert A. Swanson Career Development awardThe Knights Templar Eye Foundation, Inc.Pre-Doctoral Grant in the Biological Sciences (5-T32-GM007287-33)Cleo and Paul Schimmel Foundatio

Premières représentations (5 octobre 1895)

Transcript of PREMIÈRES REPRÉSENTATIONS by Auguste Foureau, appearing in L'INTRANSIGEANT, 5 octobre 1895

Premières représentations (21 janvier 1892)

Transcript of PREMIÈRES REPRÉSENTATIONS by Auguste Foureau, appearing in L'INTRANSIGEANT, 21 janvier 1892

Disrupting the methionine biosynthetic pathway in Candida guilliermondii: characterization of the MET gene as counter-selectable marker

International audienceCandida guilliermondii (teleomorph Meyerozyma guilliermondii) is an ascomycetous species belonging to the fungal CTG clade. This yeast remains actively studied as a result of itsmoderate clinical importance and most of all for its potential uses in biotechnology. The aim of the present study was to establish a convenient transformation system for C. guilliermondii by developing both a methionine auxotroph recipient strain and a functional MET gene as selection marker. We first disrupted the MET2 and MET15 genes encoding homoserine-O-acetyltransferase and O-acetylserine O-acetylhomoserine sulphydrylase, respectively. The met2 mutant was shown to be a methionine auxotroph in contrast to met15 which was not. Interestingly, met2 and met15 mutants formed brown colonies when cultured on lead-containing medium, contrary to the wild-type strain, which develop as white colonies on this medium. The MET2 wild-type allele was successfully used to transfer a yellow fluorescent protein (YFP) gene-expressing vector into the met2 recipient strain. In addition, we showed that the loss of the MET2-containing YFPexpressing plasmid can be easily observed on lead-containing medium. The MET2 wildtype allele, flanked by two short repeated sequences, was then used to disrupt the LYS2 gene (encoding the α-aminoadipate reductase) in the C. guilliermondii met2 recipient strain. The resulting lys2 mutants displayed, as expected, auxotrophy for lysine. Unfortunately, all our attempts to pop-out the MET2 marker (following the recombination of the bordering repeat sequences) from a target lys2 locus were unsuccessful using white/brown colony colour screening. Nevertheless, this MET2 transformation/ disruption system represents a new versatile genetic tool for C. guilliermondii