An emerging role for NAADP-mediated Ca2+ signaling in the pancreatic beta-cell

Several recent reports, including one in this journal, have reignited the debate about whether the calcium-mobilizing messenger, nicotinic adenine nucleotide diphosphate (NAADP) plays a central role in the regulation of calcium signalling in pancreatic β-cell. These studies have highlighted a role for NAADP-induced Ca(2+) mobilization not only in mediating the effects of the incretin, GLP-1 and the autocrine proliferative effects of insulin, but also possibly a fundamental role in glucose-mediated insulin secretion in the pancreatic β-cell

The Role of the Transcription Factor SIM2 in Prostate Cancer

Background: Recent reports have suggested a possible involvement of Single-minded homolog 2 (SIM2) in human solid cancers, including prostate cancer. However, the exact role of SIM2 in cancer in general, and in prostate cancer in particular, remains largely unknown. This study was designed to elucidate the role of SIM2 in prostate cancer using a shRNA-based approach in the PC3 prostate cancer cell line. Methods: Lentiviral shRNAs were used to inhibit SIM2 gene and protein levels in PC3 cells. Quantitative RT-PCR and branched DNA were performed to evaluate transcript expression. SIM2 protein expression level was measured by western blot. Profiling of gene expression spanning the whole genome, as well as polar metabolomics of several major metabolic pathways was performed to identify major pathway dysregulations. Results: SIM2 gene and protein products were significantly downregulated by lenti-shRNA in PC3 cell line. This low expression of SIM2 affected gene expression profile, revealing significant changes in major signaling pathways, networks and functions. In addition, major metabolic pathways were affected. Conclusion: Taken together, our results suggest an involvement of SIM2 in key traits of prostate tumor cell biology an

Immunization with a Peptide Containing MHC Class I and II Epitopes Derived from the Tumor Antigen SIM2 Induces an Effective CD4 and CD8 T-Cell Response

Here, we sought to determine whether peptide vaccines designed harbor both class I as well as class II restricted antigenic motifs could concurrently induce CD4 and CD8 T cell activation against autologous tumor antigens. Based on our prior genome-wide interrogation of human prostate cancer tissues to identify genes over-expressed in cancer and absent in the periphery, we targeted SIM2 as a prototype autologous tumor antigen for these studies. Using humanized transgenic mice we found that the 9aa HLA-A*0201 epitope, SIM2237–245, was effective at inducing an antigen specific response against SIM2-expressing prostate cancer cell line, PC3. Immunization with a multi-epitope peptide harboring both MHC-I and MHC-II restricted epitopes induced an IFN-γ response in CD8 T cells to the HLA-A*0201-restricted SIM2237–245 epitope, and an IL-2 response by CD4 T cells to the SIM2240–254 epitope. This peptide was also effective at inducing CD8+ T-cells that responded specifically to SIM2-expressing tumor cells. Collectively, the data presented in this study suggest that a single peptide containing multiple SIM2 epitopes can be used to induce both a CD4 and CD8 T cell response, providing a peptide-based vaccine formulation for potential use in immunotherapy of various cancers

The triglyceride glucose-waist-to-height ratio outperforms obesity and other triglyceride-related parameters in detecting prediabetes in normal-weight Qatari adults: A cross-sectional study

IntroductionThe triglyceride-glucose (TyG)-driven indices, incorporating obesity indices, have been proposed as reliable markers of insulin resistance and related comorbidities such as diabetes. This study evaluated the effectiveness of these indices in detecting prediabetes in normal-weight individuals from a Middle Eastern population.MethodsUsing the data of 5,996 adult Qatari participants from the Qatar Biobank cohort, we employed adjusted logistic regression to assess the ability of various obesity and triglyceride-related indices to detect prediabetes in normal-weight (18.5 ≤ BMI <25 kg/m2) adults (≥18 years).ResultsOf the normal-weight adults, 13.62% had prediabetes. TyG-waist-to-height ratio (TyG-WHTR) was significantly associated with prediabetes among normal-weight men [OR per 1-SD 2.68; 95% CI (1.67–4.32)] and women [OR per 1-SD 2.82; 95% CI (1.61–4.94)]. Compared with other indices, TyG-WHTR had the highest area under the curve (AUC) value for prediabetes in men [AUC: 0.76, 95% CI (0.70–0.81)] and women [AUC: 0.73, 95% CI (0.66–0.80)], and performed significantly higher than other indices (p < 0.05) in detecting prediabetes in men. Tyg-WHTR shared similar diagnostic values as fasting plasma glucose (FPG).DiscussionOur findings suggest that the TyG-WHTR index could be a better indicator of prediabetes for general clinical usage in normal weight Qatari adult men than other obesity and TyG-related indices. TyG-WHTR can help identify a person’s risk for developing prediabetes in both men and women when combined with FPG results

The Scavenger Receptor MARCO Modulates TLR-Induced Responses in Dendritic Cells

The scavenger receptor MARCO mediates macrophage recognition and clearance of pathogens and their polyanionic ligands. However, recent studies demonstrate MARCO expression and function in dendritic cells, suggesting MARCO might serve to bridge innate and adaptive immunity. To gain additional insight into the role of MARCO in dendritic cell activation and function, we profiled transcriptomes of mouse splenic dendritic cells obtained from MARCO deficient mice and their wild type counterparts under resting and activating conditions. In silico analysis uncovered major alterations in gene expression in MARCO deficient dendritic cells resulting in dramatic alterations in key dendritic cell-specific pathways and functions. Specifically, changes in CD209, FCGR4 and Complement factors can have major consequences on DC-mediated innate responses. Notably, these perturbations were magnified following activation with the TLR-4 agonist lipopolysaccharide. To validate our in silico data, we challenged DC‘s with various agonists that recognize all mouse TLRs and assessed expression of a set of immune and inflammatory marker genes. This approach identified a differential contribution of MARCO to TLR activation and validated a major role for MARCO in mounting an inflammatory response. Together, our data demonstrate that MARCO differentially affects TLR-induced DC activation and suggest targeting of MARCO could lead to different outcomes that depend on the inflammatory context encountered by DC

The Serums Tool-Chain:Ensuring Security and Privacy of Medical Data in Smart Patient-Centric Healthcare Systems

Digital technology is permeating all aspects of human society and life. This leads to humans becoming highly dependent on digital devices, including upon digital: assistance, intelligence, and decisions. A major concern of this digital dependence is the lack of human oversight or intervention in many of the ways humans use this technology. This dependence and reliance on digital technology raises concerns in how humans trust such systems, and how to ensure digital technology behaves appropriately. This works considers recent developments and projects that combine digital technology and artificial intelligence with human society. The focus is on critical scenarios where failure of digital technology can lead to significant harm or even death. We explore how to build trust for users of digital technology in such scenarios and considering many different challenges for digital technology. The approaches applied and proposed here address user trust along many dimensions and aim to build collaborative and empowering use of digital technologies in critical aspects of human society

A safety-modified SV40 Tag developed for human cancer immunotherapy

Simian virus 40 (SV40)-like DNA sequences have been found in a variety of human tumors, raising the possibility that strategies targeting SV40 may provide a potential avenue for immunotherapy directed against SV40 large T Antigen (Tag)-expressing tumors. We generated a recombinant vaccinia (vac-mTag) expressing mTag and herein assessed the ability of mTag to transform cells and to interact with anti-oncoproteins, as well as screened for the presence of potential HLA-A2.1-restricted epitopes within mTag. We found that transfection of cells with mTag did not lead to their transformation. Also, we demonstrated that mTag protein is degraded rapidly in cells. In addition, our work revealed that mTag did not physically interact with certain anti-oncoproteins. Finally, two potential HLA-A2.1-restricted functional epitopes within mTag sequence were identified. Our results show that mTag lacks the oncogenecity of full-length Tag and harbors potential HLA-A2.1-restricted immunogenic epitopes, hence suggesting the safety of vac-mTag for use in cancer immunotherapy

Inositol 1,4,5-Trisphosphate Receptors in Hypertension.

Chronic hypertension remains a major cause of global mortality and morbidity. It is a complex disease that is the clinical manifestation of multiple genetic, environmental, nutritional, hormonal, and aging-related disorders. Evidence supports a role for vascular aging in the development of hypertension involving an impairment in endothelial function together with an alteration in vascular smooth muscle cells (VSMCs) calcium homeostasis leading to increased myogenic tone. Changes in free intracellular calcium levels ([Ca] ) are mediated either by the influx of Ca from the extracellular space or release of Ca from intracellular stores, mainly the sarcoplasmic reticulum (SR). The influx of extracellular Ca occurs primarily through voltage-gated Ca channels (VGCCs), store-operated Ca channels (SOC), and Ca release-activated channels (CRAC), whereas SR-Ca release occurs through inositol trisphosphate receptor (IPR) and ryanodine receptors (RyRs). IPR-mediated SR-Ca release, in the form of Ca waves, not only contributes to VSMC contraction and regulates VGCC function but is also intimately involved in structural remodeling of resistance arteries in hypertension. This involves a phenotypic switch of VSMCs as well as an alteration of cytoplasmic Ca signaling machinery, a phenomena tightly related to the aging process. Several lines of evidence implicate changes in expression/function levels of IPR isoforms in the development of hypertension, VSMC phenotypic switch, and vascular aging. The present review discusses the current knowledge of these mechanisms in an integrative approach and further suggests potential new targets for hypertension management and treatment.This publication was made possible by an MPP fund (#320133) from the American University of Beirut to AE