Nevirapine- and efavirenz-associated hepatotoxicity under programmatic conditions in Kenya and Mozambique.

To describe the frequency, risk factors, and clinical signs and symptoms associated with hepatotoxicity (HT) in patients on nevirapine- or efavirenz-based antiretroviral therapy (ART), we conducted a retrospective cohort analysis of patients attending the ART clinic in Kibera, Kenya, from April 2003 to December 2006 and in Mavalane, Mozambique, from December 2002 to March 2007. Data were collected on 5832 HIV-positive individuals who had initiated nevirapine- or efavirenz-based ART. Median baseline CD4+ count was 125 cells/μL (interquartile range [IQR] 55-196). Over a median follow-up time of 426 (IQR 147-693) days, 124 (2.4%) patients developed HT. Forty-one (54.7%) of 75 patients with grade 3 HT compared with 21 (80.8%) of 26 with grade 4 had associated clinical signs or symptoms (P = 0.018). Four (5.7%) of 124 patients with HT died in the first six months compared with 271 (5.3%) of 5159 patients who did not develop HT (P = 0.315). The proportion of patients developing HT was low and HT was not associated with increased mortality. Clinical signs and symptoms identified 50% of grade 3 HT and most cases of grade 4 HT. This suggests that in settings where alanine aminotransferase measurement is not feasible, nevirapine- and efavirenz-based ART may be given safely without laboratory monitoring

Functional Cellular Anti-Tumor Mechanisms are Augmented by Genetic Proteoglycan Targeting.

While recent research points to the importance of glycans in cancer immunity, knowledge on functional mechanisms is lacking. In lung carcinoma among other tumors, anti-tumor immunity is suppressed; and while some recent therapies boost T-cell mediated immunity by targeting immune-checkpoint pathways, robust responses are uncommon. Augmenting tumor antigen-specific immune responses by endogenous dendritic cells (DCs) is appealing from a specificity standpoint, but challenging. Here, we show that restricting a heparan sulfate (HS) loss-of-function mutation in the HS sulfating enzyme Ndst1 to predominantly conventional DCs (Ndst1f/f CD11cCre+ mutation) results in marked inhibition of Lewis lung carcinoma growth along with increased tumor-associated CD8+ T cells. In mice deficient in a major DC HS proteoglycan (syndecan-4), splenic CD8+ T cells showed increased anti-tumor cytotoxic responses relative to controls. Studies examining Ndst1f/f CD11cCre + mutants revealed that mutation was associated with an increase in anti-tumor cytolysis using either splenic CD8+ T cells or tumor-infiltrating (TIL) CD8+ T cells purified ex-vivo, and tested in pooled effector-to-target cytolytic assays against tumor cells from respective animals. On glycan compositional analysis, HS purified from Ndst1f/f CD11cCre + mutant DCs had reduced overall sulfation, including reduced sulfation of a tri-sulfated disaccharide species that was intriguingly abundant on wildtype DC HS. Interestingly, antigen presentation in the context of major histocompatibility complex class-I (MHC-I) was enhanced in mutant DCs, with more striking effects in the setting of HS under-sulfation, pointing to a likely regulatory role by sulfated glycans at the antigen/MHC-I - T-cell interface; and possibly future opportunities to improve antigen-specific T cell responses by immunologic targeting of HS proteoglycans in cancer

Rheology of distorted nematic liquid crystals

We use lattice Boltzmann simulations of the Beris--Edwards formulation of nematodynamics to probe the response of a nematic liquid crystal with conflicting anchoring at the boundaries under shear and Poiseuille flow. The geometry we focus on is that of the hybrid aligned nematic (HAN) cell, common in devices. In the nematic phase, backflow effects resulting from the elastic distortion in the director field render the velocity profile strongly non-Newtonian and asymmetric. As the transition to the isotropic phase is approached, these effects become progressively weaker. If the fluid is heated just above the transition point, however, another asymmetry appears, in the dynamics of shear band formation.Comment: 7 pages, 4 figures. Accepted for publication in Europhys. Let

Control of RelB during dendritic cell activation integrates canonical and noncanonical NF-κB pathways.

The NF-κB protein RelB controls dendritic cell (DC) maturation and may be targeted therapeutically to manipulate T cell responses in disease. Here we report that RelB promoted DC activation not as the expected RelB-p52 effector of the noncanonical NF-κB pathway, but as a RelB-p50 dimer regulated by canonical IκBs, IκBα and IκBɛ. IκB control of RelB minimized spontaneous maturation but enabled rapid pathogen-responsive maturation. Computational modeling of the NF-κB signaling module identified control points of this unexpected cell type-specific regulation. Fibroblasts that we engineered accordingly showed DC-like RelB control. Canonical pathway control of RelB regulated pathogen-responsive gene expression programs. This work illustrates the potential utility of systems analyses in guiding the development of combination therapeutics for modulating DC-dependent T cell responses

Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8(+) Cytolytic T Cell Responses.

Despite the importance of the co-receptor PD-1 in T cell immunity, the upstream signaling pathway that regulates PD-1 expression has not been defined. Glycogen synthase kinase 3 (GSK-3, isoforms α and β) is a serine-threonine kinase implicated in cellular processes. Here, we identified GSK-3 as a key upstream kinase that regulated PD-1 expression in CD8(+) T cells. GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8(+) cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8(+) CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8(+) OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy.C.E.R. was supported by Wellcome Trust 092627/Z/10/Z, J.A.H. by an Irvington Institute Postdoctoral Fellowship from the Cancer Research Institute (New York), and E.I.Z. by a Leukemia and Lymphoma Society Scholar Award and a grant from the NIH AI081923. We thank Dr. Graham Lord (King’s College London) for the kind gift of the Ifng CNS-12 promoter.This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.immuni.2016.01.01

Adoptive immunotherapy induces CNS dendritic cell recruitment and antigen presentation during clearance of a persistent viral infection

Given the global impact of persistent infections on the human population, it is of the utmost importance to devise strategies to noncytopathically purge tissues of infectious agents. The central nervous system (CNS) poses a unique challenge when considering such strategies, as it is an immunologically specialized compartment that contains a nonreplicative cell population. Administration of exogenously derived pathogen-specific memory T cells (referred to as adoptive immunotherapy) to mice burdened with a persistent lymphocytic choriomeningitis virus (LCMV) infection from birth results in eradication of the pathogen from all tissues, including the CNS. In this study, we sought mechanistic insights into this highly successful therapeutic approach. By monitoring the migration of traceable LCMV-specific memory CD8+ T cells after immunotherapy, it was revealed that cytotoxic T lymphocytes (CTLs) distributed widely throughout the CNS compartment early after immunotherapy, which resulted in a dramatic elevation in the activity of CNS antigen-presenting cells (APCs). Immunotherapy induced microglia activation as well as the recruitment of macrophages and dendritic cells (DCs) into the brain parenchyma. However, DCs emerged as the only CNS APC population capable of inducing memory CTLs to preferentially produce the antiviral cytokine tumor necrosis factor-α, a cytokine demonstrated to be required for successful immunotherapeutic clearance. DCs were also found to be an essential element of the immunotherapeutic process because in their absence, memory T cells failed to undergo secondary expansion, and viral clearance was not attained in the CNS. These experiments underscore the importance of DCs in the immunotherapeutic clearance of a persistent viral infection and suggest that strategies to elevate the activation/migration of DCs (especially within the CNS) may facilitate pathogen clearance

Shape resonances in nested diffraction gratings

The diffraction problem of a plane wave impinging on a grating formed by nested cavities is solved by means of the modal method, for $s$ and $p$ polarization modes. The cavities are formed by perfectly conducting sheets that describe rectangular profiles. The electromagnetic response of the grating is analyzed, paying particular attention to the generation of resonances within the structure. The dependence of the resonances on the geometrical parameters of the grating is studied, and results of far and near field are shown. The results are checked and compared with those available in the literature for certain limit cases.Comment: 18 pages, 8 figure