Background An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab — which blocks cytotoxic T-lymphocyte–associated antigen 4 to potentiate an antitumor T-cell response — administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. Methods A total of 676 HLA-A*0201–positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. Results The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P = 0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P = 0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Conclusions Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

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Improved Survival with Ipilimumab in Patients with Metastatic Melanoma.

The selective degradation of many short-lived proteins in eukaryotic cells is carried out by the ubiquitin system. In this pathway, proteins are targeted for degradation by covalent ligation to ubiquitin, a highly conserved small protein. Ubiquitin-mediated degradation of regulatory proteins plays important roles in the control of numerous processes, including cell-cycle progression, signal transduction, transcriptional regulation, receptor down-regulation, and endocytosis. The ubiquitin system has been implicated in the immune response, development, and programmed cell death. Abnormalities in ubiquitin-mediated processes have been shown to cause pathological conditions, including malignant transformation. In this review we discuss recent information on functions and mechanisms of the ubiquitin system. Since the selectivity of protein degradation is determined mainly at the stage of ligation to ubiquitin, special attention is focused on what we know, and would like to know, about the mode of action of ubiquitin-protein ligation systems and about signals in proteins recognized by these systems.

The Ubiquitin System

The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.

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The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

Dendritic cells (DCs) are antigen-presenting cells with a unique ability to induce primary immune responses. DCs capture and transfer information from the outside world to the cells of the adaptive immune system. DCs are not only critical for the induction of primary immune responses, but may also be important for the induction of immunological tolerance, as well as for the regulation of the type of T cell-mediated immune response. Although our understanding of DC biology is still in its infancy, we are now beginning to use DC-based immunotherapy protocols to elicit immunity against cancer and infectious diseases.

Immunobiology of Dendritic Cells

Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.

https://science.sciencemag.org/content/sci/early/2015/03/11/science.aaa1348.full.pdf

Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer

L'invention concerne une famille de vaccins qui contient des complexes proteines de stress-peptides. Lorsqu'ils sont administres a un mammifere ces complexes induisent une reponse des lymphocytes T cytotoxique contre les cellules infectees par un agent pathogene intracellulaires preselectionne. L'invention concerne egalement des methodologies pour la preparation et l'administration de vaccins contenant lesdits complexes proteines de stress-peptides.

Complexes proteines de stress-peptides utilises en tant que vaccins prophylactiques et therapeutiques contre les agents pathogenes intracellulaires

The Large Volume Plasma device(LVPD), a cylindrically shaped, linear plasma device of dimension( $\phi =2m $, $ L =3m $) have successfully demonstrated the excitation of Electron Temperature Gradient(ETG) turbulence[ Mattoo et al.,[1]]. The observed ETG turbulence shows significant power between $\omega \sim (25-90 krad/s )> \Omega_{ci}(= 8 krad/s )$, corresponding to the wavenumber, $ k_y \rho_e ~ (0.1- 0.2)$ where, $ \Omega_{ci}$ and $\rho_e(=5 mm ) $, ion cyclotron frequency and electron Larmor radius, respectively. The observed frequency and wave number matches well with theoretical estimates corresponding to Whistler-ETG mode. We investigated electromagnetic (EM) fluctuations induced plasma transport in high beta ( $ \beta \sim 0.01 - 0.4 $ ) ETG mode suitable plasma in LVPD. The radial electromagnetic (EM) electron (ion) flux ( $ \Gamma^{e,i}_{em} $) results primarily from the correlation between fluctuations of parallel electron current ($\delta J_{\parallel ,e,i}$ ) and radial magnetic field ($ \delta B_r $ ). The electromagnetic particle flux is observed to be much smaller than the electrostatic particle flux,$ \Gamma_{em}\approx 10^{-5} \Gamma_{es} $ .The EM flux is small but finite contrary to the conventional slab ETG model. The electromagnetic flux is non-ambipolar. A theoretical model is obtained for the EM particle flux in straight homogeneous magnetic field geometry. The theoretical estimates are seen to compare well with the experimental observations. Sluggish parallel ion response is identified as the key mechanism for generation of small but finite electromagnetic flux.

Observation of Electromagnetic Fluctuation Induced Particle Transport in ETG Dominated Large Laboratory Plasma

WRF-PDM: prognostic approach for discharge prediction in ungauged catchment.

Development of site-specific time distribution pattern of rainfall for Tarapur, India

https://robots.iopscience.iop.org/article/10.1088/1361-6587/ab0d71/pdf

Pramod K. Srivastava

Papers

Complexes proteines de stress-peptides utilises en tant que vaccins prophylactiques et therapeutiques contre les agents pathogenes intracellulaires

Observation of Electromagnetic Fluctuation Induced Particle Transport in ETG Dominated Large Laboratory Plasma

WRF-PDM: prognostic approach for discharge prediction in ungauged catchment.

Development of site-specific time distribution pattern of rainfall for Tarapur, India

Observation of electromagnetic fluctuation induced particle transport in ETG dominated large laboratory plasma