Zobrazení zdroje stránky Raskwrenn0961

We discuss how the use of rigid tissue culture plastic for cancer drug screening may select agents that lack efficacy in the soft in vivo tissue environment. Tuning of integrin signaling via external mechanical forces in vivo and subsequent effects on growth factor signaling thus has implications for normal cellular physiology and anti-cancer therapies.Microbiota-reactive CD4+ T memory (TM) cells are generated during intestinal infections and inflammation, and can revert to pathogenic CD4+ T effector (TE) cells, resulting in chronicity of inflammatory bowel disease (IBD). Unlike TE cells, TM cells have a low rate of metabolism unless they are activated by reencountering cognate antigen. Here, we show that the combination of cell activation and metabolic checkpoint inhibition (CAMCI), by targeting key metabolic regulators mTORC and AMPK, resulted in cell death and anergy, but enhanced the induction of the regulatory subset. Parenteral application of this treatment with a synthetic peptide containing multiple flagellin T cell epitopes (MEP1) and metabolic inhibition successfully prevented the development of CD4+ T cell-driven colitis. Microbiota-specific CD4+ T cells, especially the pathogenic TE subsets, were decreased 10-fold in the intestinal lamina propria. Furthermore, using the CAMCI strategy, we were able to prevent antigen-specific TM cell formation upon initial antigen encounter, and ablate existing TM cells upon reactivation in mice, leading to an altered transcriptome in the remaining CD4+ T cells after ablation. Microbiota flagellin-specific CD4+ T cells from patients with Crohn's disease were ablated in a similar manner after CAMCI in vitro, with half of the antigen-specific T cells undergoing cell death. These results indicate that parenteral activation of microbiota-specific CD4+ T cells with concomitant metabolic inhibition is an effective way to ablate pathogenic CD4+ TM cells and to induce T regulatory (Treg) cells that provide antigen-specific and bystander suppression, supporting a potential immunotherapy to prevent or ameliorate IBD.Recurrent herpesvirus infections can manifest in different forms of disease, including cold sores, genital herpes, and encephalitis. There is an incomplete understanding of the genetic and immunological factors conferring susceptibility to recurrent herpes simplex virus 2 (HSV2) infection in the central nervous system (CNS). Here, we describe two adult patients with recurrent HSV2 lymphocytic Mollaret's meningitis that each carry a rare monoallelic variant in the autophagy proteins ATG4A or LC3B2. HSV2-activated autophagy was abrogated in patient primary fibroblasts, which also exhibited significantly increased viral replication and enhanced cell death. HSV2 antigen was captured in autophagosomes of infected cells, and genetic inhibition of autophagy by disruption of autophagy genes, including ATG4A and LC3B2, led to enhanced viral replication and cell death in primary fibroblasts and a neuroblastoma cell line. Activation of autophagy by HSV2 was sensitive to ultraviolet (UV) irradiation of the virus and inhibited in the presence of acyclovir, but HSV2-induced autophagy was independent of the DNA-activated STING pathway. Reconstitution of wild-type ATG4A and LC3B2 expression using lentiviral gene delivery or electroporation of in vitro transcribed mRNA into patient cells restored virus-induced autophagy and the ability to control HSV2 replication. This study describes a previously unknown link between defective autophagy and an inborn error of immunity that can lead to increased susceptibility to HSV2 infection, suggesting an important role for autophagy in antiviral immunity in the CNS.<br /><br /> To investigate if in radiographic axial Spondyloarthritis (r-axSpA) low vertebral bone mineral density (BMD) is associated with development of new syndesmophytes at the same vertebral level.<br /><br /> In a post-hoc analysis from the ASSERT trial (infliximab vs placebo), dual-energy X-ray absorptiometry was used to measure baseline BMD (g/cm<br /><br /> ) of the lumbar spine L1 to L4. Syndesmophyte formation was assessed in the same vertebrae on conventional radiographs defined as an increase in modified Stoke Ankylosing Spondylitis Spine Score from 0 or 1 to 2 or 3 after 2 years. Radiographs were scored by two readers. Generalised estimating equations (GEE) adjusted for within-patient correlation across multiple vertebrae, taking potential confounders into account.<br /><br /> We analysed 599 vertebrae in 165r-axSpA patients (78% male, mean (SD) age 38 (10) years, 67% with at least one syndesmophyte anywhere in the spine). In total, 24 to 74 new syndesmophytes developed in 9 (5%) to 30 (18%) patients and 13 (2%) to 39 (7%) vertebrae, if either a syndesmophyte was seen by both or only one of the readers (ie, specific and sensitive definitions) respectively. In multivariable analyses, no association was found between baseline local vertebral BMD and new syndesmophyte formation after 2 years adjOR (95% CI) 0.56 (0.01, 44.45) (specific definition) and 0.26 (0.03, 2.63) (sensitive definition).<br /><br /> In patients with active and established r-axSpA, with an observed low incidence of lumbar spine syndesmophyte formation over 2 years, no relationship was found between baseline BMD and new radiographic syndesmophyte formation at the same vertebra.<br /><br />In patients with active and established r-axSpA, with an observed low incidence of lumbar spine syndesmophyte formation over 2 years, no relationship was found between baseline BMD and new radiographic syndesmophyte formation at the same vertebra.<br /><br /> A decrease in proteinuria has been considered protective from renal damage in lupus nephritis (LN), but a cut-off point has yet to be established. The aim of this study was to identify the predictors of renal damage in patients with LN and to determine the best cut-off point for a decrease in proteinuria.<br /><br /> We included patients with LN defined clinically or histologically. Possible predictors of renal damage at the time of LN diagnosis were examined proteinuria, low complement, anti-double-stranded DNA antibodies, red cell casts, creatinine level, hypertension, renal activity (assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)), prednisone dose, immunosuppressive drugs and antimalarial use. [https://www.selleckchem.com/products/ca-170.html selleckchem] Sociodemographic variables were included at baseline. Proteinuria was assessed at baseline and at 12months, to determine if early response (proteinuria &lt;0.8g/day within 12months since LN diagnosis) is protective of renal damage occurrence. Renal damage was defined as an increase of one or more points in the renal domain of The Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI).