Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency.

Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34 cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT.

An astrocyte cell line that differentially propagates murine prions.

Prion diseases are fatal infectious neurodegenerative disorders in human and animals caused by misfolding of the cellular prion protein (PrP) into the pathological isoform PrP Elucidating the molecular and cellular mechanisms underlying prion propagation may help to develop disease interventions. Cell culture systems for prion propagation have greatly advanced molecular insights into prion biology, but translation of to findings is often disappointing. A wider range of cell culture systems might help overcome these shortcomings.

Sephin1 Reduces Prion Infection in Prion-Infected Cells and Animal Model.

Prion diseases are fatal infectious neurodegenerative disorders in human and animals caused by misfolding of the cellular prion protein (PrP) into the infectious isoform PrP. These diseases have the potential to transmit within or between species, and no cure is available to date. Targeting the unfolded protein response (UPR) as an anti-prion therapeutic approach has been widely reported for prion diseases.

Metformin reduces prion infection in neuronal cells by enhancing autophagy.

Prion diseases are fatal infectious neurodegenerative disorders in human and animals that are caused by misfolding of the cellular prion protein (PrP) into the infectious isoform PrP. No effective treatment is available for prion diseases. Metformin is a first-line medication for treatment of type 2 diabetes which is known to activate AMPK and induce autophagy through the inhibition of mammalian target of rapamycin (mTOR1) signaling.

Autophagy pathways in the treatment of prion diseases.

Prions use cellular machineries for autocatalytic propagation by conformational conversion of the cellular prion protein into the pathological isoform PrP. Autophagy is a basic cellular degradation and recycling machinery that delivers cargo to lysosomes. Increase of autophagic flux in cells results in enhanced delivery of PrP in late endosomes to lysosomal degradation, providing a therapeutic target for prion diseases.

Circulating microRNA-155 is associated with insulin resistance in chronic hepatitis C patients.

Background And Study Aim: Hepatitis C represents a potential public health problem worldwide. Insulin resistance (IR) and type 2 diabetes (T2D) are among the serious metabolic complications for chronic hepatitis C virus (HCV) infection. MicroRNAs (miRNAs) are a group of small non-coding RNAs which are implicated in the modulation of almost all biological processes.

Inflammasome Genes' Polymorphisms in Egyptian Chronic Hepatitis C Patients: Influence on Vulnerability to Infection and Response to Treatment.

Chronic inflammation is a pivotal contributor to the liver damage mediated by hepatitis C virus (HCV). The NOD-like receptor, pyrin domain-containing 3 (NLRP3) inflammasome is activated by HCV in both hepatocytes and Kupffer cells. The aim of our study was to investigate the association of nine single-nucleotide polymorphisms in four inflammasome genes (NLRP3, CARD8, IL-1, and IL-18) with the susceptibility to HCV infection and outcome of interferon treatment in 201 Egyptian chronic hepatitis C patients and 95 healthy controls.

Recombinant prion protein vaccination of transgenic elk PrP mice and reindeer overcomes self-tolerance and protects mice against chronic wasting disease.

Chronic wasting disease (CWD) is a fatal neurodegenerative disease that affects cervids in North America and now Europe. No effective measures are available to control CWD. We hypothesized that active vaccination with homologous and aggregation-prone recombinant prion protein (PrP) could overcome self-tolerance and induce autoantibody production against the cellular isoform of PrP (PrP), which would be protective against CWD infection from peripheral routes.

Overexpression of quality control proteins reduces prion conversion in prion-infected cells.

Prion diseases are fatal infectious neurodegenerative disorders in humans and other animals and are caused by misfolding of the cellular prion protein (PrP) into the pathological isoform PrP These diseases have the potential to transmit within or between species, including zoonotic transmission to humans. Elucidating the molecular and cellular mechanisms underlying prion propagation and transmission is therefore critical for developing molecular strategies for disease intervention. We have shown previously that impaired quality control mechanisms directly influence prion propagation.

Autophagy regulates exosomal release of prions in neuronal cells.

Prions are protein-based infectious agents that autocatalytically convert the cellular prion protein PrP to its pathological isoform PrP Subsequent aggregation and accumulation of PrP in nervous tissues causes several invariably fatal neurodegenerative diseases in humans and animals. Prions can infect recipient cells when packaged into endosome-derived nanoparticles called exosomes, which are present in biological fluids such as blood, urine, and saliva. Autophagy is a basic cellular degradation and recycling machinery that also affects exosomal processing, but whether autophagy controls release of prions in exosomes is unclear.

The celecoxib derivatives AR-12 and AR-14 induce autophagy and clear prion-infected cells from prions.

Prion diseases are fatal infectious neurodegenerative disorders that affect both humans and animals. The autocatalytic conversion of the cellular prion protein (PrP) into the pathologic isoform PrP is a key feature in prion pathogenesis. AR-12 is an IND-approved derivative of celecoxib that demonstrated preclinical activity against several microbial diseases.

Immunization of cervidized transgenic mice with multimeric deer prion protein induces self-antibodies that antagonize chronic wasting disease infectivity in vitro.

Chronic wasting disease (CWD) is the most contagious prion disease. It is expanding rapidly in North America, was found recently in Europe, and the potential for transmission to humans cannot be excluded yet. We hypothesized that it is possible to prevent peripheral CWD infection and CWD prion shedding by inducing auto-antibodies against the cellular prion protein (PrP) by active vaccination.

Gastric antral webs in adults: A case series characterizing their clinical presentation and management in the modern endoscopic era.

Aim: To investigate the current management of gastric antral webs (GAWs) among adults and identify optimal endoscopic and/or surgical management for these patients.

Methods: We reviewed our endoscopy database seeking to identify patients in whom a GAW was visualized among 24640 esophagogastroduodenoscopies (EGD) over a seven-year period (2006-2013) at a single tertiary care center. The diagnosis of GAW was suspected during EGD if aperture size of the antrum did not vary with peristalsis or if a "double bulb" sign was present on upper gastrointestinal series.

Alterations in serum levels of fetuin A and selenoprotein P in chronic hepatitis C patients with concomitant type 2 diabetes: A case-control study.

Background: Insulin resistance (IR) and type 2 diabetes mellitus (T2DM) are serious extrahepatic manifestations of chronic hepatitis C virus (HCV) infection. However, the mechanism underlying the IR in chronic HCV is obscure. Hepatokines are group of liver-derived protein, which affect the glucose and lipid metabolism in several tissues.

The cooperation between the autophagy machinery and the inflammasome to implement an appropriate innate immune response: do they regulate each other?

Autophagy is originally described as the main catabolic pathway responsible for maintaining intracellular nutritional homeostasis that involves the formation of a unique vacuole, the autophagosome, and the interaction with the endosome-lysosome pathways. This conserved machinery plays a key role in immune-protection against different invaders, including pathogenic bacteria, intracellular parasites, and some viruses like herpes simplex and hepatitis C virus. Importantly, autophagy is linked to a number of human diseases and disorders including neurodegenerative disease, Crohn's disease, type II diabetes, tumorigenesis, cardiomyopathy, and fatty liver disease.

Phoenix dactylifera seeds ameliorate early diabetic complications in streptozotocin-induced diabetic rats.

Context: In Arabic folk medicine, the seeds of Phoenix dactylifera L. (Arecaceae) have been used to manage diabetes for many years. Few studies have reported the antidiabetic effect of P.

The protective effect of Phoenix dactylifera L. seeds against CCl4-induced hepatotoxicity in rats.

Ethnopharmacological Relevance: In traditional Egyptian medicine, Phoenix dactylifera L. (date palm) seeds are listed in folk remedies for the management of diabetes, liver diseases and gastrointestinal disorders. The present study was conducted to investigate the protective effect of Phoenix dactylifera L.

Changes of serum omentin-1 levels and relationship between omentin-1 and insulin resistance in chronic hepatitis C patients.

Objectives: Omentin-1 is a novel adipokine that has a pivotal role in modulating the insulin sensitivity, immunity and inflammation. The current study was conducted to evaluate the serum omentin-1 level in hepatitis C virus (HCV) infected patients, with or without type 2 diabetes, and to investigate its correlation with liver function parameters and insulin resistance.

Methods: Eighty subjects were enrolled in this study divided into four groups: chronic HCV infected patients (n=20), chronic hepatitis C patients with concomitant type 2 diabetes (n=18), type 2 diabetic patients (n=22) and 20 healthy controls.

Caspase-11 promotes the fusion of phagosomes harboring pathogenic bacteria with lysosomes by modulating actin polymerization.

Inflammasomes are multiprotein complexes that include members of the NLR (nucleotide-binding domain leucine-rich repeat containing) family and caspase-1. Once bacterial molecules are sensed within the macrophage, the inflammasome is assembled, mediating the activation of caspase-1. Caspase-11 mediates caspase-1 activation in response to lipopolysaccharide and bacterial toxins, and yet its role during bacterial infection is unknown.

Activation of the pyrin inflammasome by intracellular Burkholderia cenocepacia.

Burkholderia cenocepacia is an opportunistic pathogen that causes chronic infection and induces progressive respiratory inflammation in cystic fibrosis patients. Recognition of bacteria by mononuclear cells generally results in the activation of caspase-1 and processing of IL-1β, a major proinflammatory cytokine. In this study, we report that human pyrin is required to detect intracellular B.

A comparison between two strategies for monitoring hepatic function during antituberculous therapy.

Rationale: The optimum strategy for monitoring liver function during antituberculous therapy is unclear.

Objectives: To assess the value of the American Thoracic Society risk-factor approach for predicting drug-induced liver injury and to compare with a uniform policy of liver function testing in all patients at 2 weeks.

Methods: We conducted an observational study of adult patients undergoing therapy for active tuberculosis at a tertiary center.

Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis.

Cystic fibrosis (CF) is the most common inherited lethal disease of Caucasians which results in multi organ dysfunction. However, 85% of the deaths are due to pulmonary infections. Infection by Burkholderia cenocepacia (B.

Asc-dependent and independent mechanisms contribute to restriction of legionella pneumophila infection in murine macrophages.

The apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc) is an adaptor molecule that mediates inflammatory and apoptotic signals. Legionella pneumophila is an intracellular bacterium and the causative agent of Legionnaire's pneumonia. L.

Burkholderia cenocepacia O polysaccharide chain contributes to caspase-1-dependent IL-1beta production in macrophages.

Burkholderia cenocepacia infections in CF patients involve heightened inflammation, fatal sepsis, and high antibiotic resistance. Proinflammatory IL-1β secretion is important in airway inflammation and tissue damage. However, little is known about this pathway in macrophages upon B.

Apoptosis-associated speck-like protein (ASC) controls Legionella pneumophila infection in human monocytes.

The ability of Legionella pneumophila to cause pneumonia is determined by its capability to evade the immune system and grow within human monocytes and their derived macrophages. Human monocytes efficiently activate caspase-1 in response to Salmonella but not to L. pneumophila.