ATF4 Protects the Heart From Failure by Antagonizing Oxidative Stress.

BACKGROUND: Cellular redox control is maintained by generation of reactive oxygen/nitrogen species balanced by activation of antioxidative pathways. Disruption of redox balance leads to oxidative stress, a central causative event in numerous diseases including heart failure. Redox control in the heart exposed to hemodynamic stress, however, remains to be fully elucidated. METHODS: Pressure overload was triggered by transverse aortic constriction in mice. Transcriptomic and metabolomic regulations were evaluated by RNA-sequencing and metabolomics, respectively. Stable isotope tracer labeling experiments were conducted to determine metabolic flux in vitro. Neonatal rat ventricular myocytes and H9c2 cells were used to examine molecular mechanisms. RESULTS: We show that production of cardiomyocyte NADPH, a key factor in redox regulation, is decreased in pressure overload-induced heart failure. As a consequence, the level of reduced glutathione is downregulated, a change associated with fibrosis and cardiomyopathy. We report that the pentose phosphate pathway and mitochondrial serine/glycine/folate metabolic signaling, 2 NADPH-generating pathways in the cytosol and mitochondria, respectively, are induced by transverse aortic constriction. We identify ATF4 (activating transcription factor 4) as an upstream transcription factor controlling the expression of multiple enzymes in these 2 pathways. Consistently, joint pathway analysis of transcriptomic and metabolomic data reveal that ATF4 preferably controls oxidative stress and redox-related pathways. Overexpression of ATF4 in neonatal rat ventricular myocytes increases NADPH-producing enzymes' whereas silencing of ATF4 decreases their expression. Further, stable isotope tracer experiments reveal that ATF4 overexpression augments metabolic flux within these 2 pathways. In vivo, cardiomyocyte-specific deletion of ATF4 exacerbates cardiomyopathy in the setting of transverse aortic constriction and accelerates heart failure development, attributable, at least in part, to an inability to increase the expression of NADPH-generating enzymes. CONCLUSIONS: Our findings reveal that ATF4 plays a critical role in the heart under conditions of hemodynamic stress by governing both cytosolic and mitochondrial production of NADPH.

Cardiotoxicity as an adverse effect of immunomodulatory drugs and proteasome inhibitors in multiple myeloma: A network meta-analysis of randomized clinical trials.

We aim to determine the cumulative and comparative risk of cardiovascular events associated with different Immunomodulatory Drugs (iMiDs) and Proteasome Inhibitor (PIs) in Multiple Myeloma (MM) patients through pairwise and network meta-analysis. Electronic searches were conducted using Ovid MEDLINE, EMBASE, CINAHL, Web of Science, and Clinical Trial Registry (Clinical Trials.gov) up to May 2021. Phase 3 randomized clinical trials (RCTs) reporting cardiotoxicity in MM patients (newly diagnoses and/or relapsed) treated with iMiD and/or PI. Studies, where iMiD or PI was used alongside the chemotherapy versus placebo or no additional drugs (control) in the other arm were included. The primary outcome was the presence of cardiotoxicity after follow-up. Pairwise meta-analysis and network meta-analysis were performed using the frequentist's approach to estimate the odds ratio (OR). Twenty RCTs with 10,373 MM patients were included in this analysis. Eleven studies compared iMiDs with control, seven studies compared PIs with control, and two studies compared bortezomib against carfilzomib. CTACE high-grade (≥grade 3) cardiotoxic events were increased with iMiDs compared to their control counterpart (OR 2.05; 95% CI 1.30-3.26). Similar high-grade cardiotoxicity was also noted more frequently with PI use when compared to the control group (OR 1.67; 95% CI 1.17-2.40). Among the PIs, carfilzomib was associated with a maximum risk of cardiotoxicity (OR 2.68; 95% CI 1.63-4.40). There was no evidence of publication bias among studies. iMiDs and PIs, particularly carfilzomib, appear to be associated with increased risk of high-grade cardiovascular events in MM patients.

Regulatory B cells in infection, inflammation, and autoimmunity.

Regulatory B (Breg) cells are characterized by differential expression of CD5 and CD1d in mouse and CD24 and CD38 in human immune systems. The Breg family also includes LAG-3+CD138hi plasma cells, CD1d CD5 CD21 CD23 cells, Tim1, PD-L1, PD-L2, CD200- expressing B cells, and CD39hiKi67+ cells originating from the transitional, marginal zone or germinal centre of the spleen. Breg cells produce IL10 and IL35 and to cause immunosuppression. These cells respond to TLR2, TLR4, and TLR9 agonists, CD40 ligands, IL12p35 and heat shock proteins. Emerging evidence suggests that TLR signalling component Myd88 impacts the modulation of Breg cell responses and the host's susceptibility to infection. Breg cells are found to reduce relapsing-remitting experimental autoimmune encephalomyelitis. However, the Breg-mediated mechanism used to control T cell-mediated immune responses is still unclear. Here, we review the existing literature to find gaps in the current knowledge and to build a pathway to further research.

SIRT6 deacetylase transcriptionally regulates glucose metabolism in heart.

Sirtuins are a family of enzymes, which govern a number of cellular processes essential for maintaining physiological balance. SIRT6, a nuclear sirtuin, is implicated in the development of metabolic disorders. The role of SIRT6 in regulation of cardiac metabolism is unexplored. Although glucose is not the primary energy source of heart, defects in glucose oxidation have been linked to heart failure. SIRT6+/- mice hearts exhibit increased inhibitory phosphorylation of PDH subunit E1α. SIRT6 deficiency enhances FoxO1 nuclear localization that results in increased expression of PDK4. We show that SIRT6 transcriptionally regulates the expression of PDK4 by binding to its promoter. SIRT6+/- hearts show accumulation of lactate, indicating compromised mitochondrial oxidation. SIRT6 deficiency results in decreased oxygen consumption rate and concomitantly lesser ATP production. Mechanistically, SIRT6 deficiency leads to increased FoxO1-mediated transcription of PDK4. Our findings establish a novel link between SIRT6 and cardiac metabolism, suggesting a protective role of SIRT6 in maintaining cardiac homeostasis.

Impact of nuclear factor-κB on restoration of neuron growth and differentiation in hippocampus of degenerative brain.

The mode of action of nuclear factor-κB (NF-κB) has been extensively observed in different aspects of cell growth and proliferation. The transcription factor regulates various genes controlling inflammation and anti-inflammatory responses in different tissues. Thus, NF-κB signal gains a therapeutic prospect. The activation of NF-κB requires nuclear localization of its p65 subunit. Research also indicates an impact of phosphorylated p65 on the transcription of genes during cell growth and the immune response. Following the trends in investigations over decades, different observations suggest that NF-κB activation and phosphorylation of p65 regulate neuronal plasticity. Also, inhibition of NF-κB activation is a well-demonstrated way to attenuate inflammation. In addition to anti-inflammatory drugs, recent researches unwind a way to regulate regeneration and repair tissue damage. Thus, keeping a critical view on NF-κB signals, we propose the importance of natural or synthetic NF-κB activators for neurogenesis.

Role of 2-(fluorine-18) Fluoro-2-deoxy-D-glucose Positron Emission Tomography/Computed Tomography in Initial Staging and Bone Marrow Involvement Prediction in Patients with Newly Diagnosed Lymphoma in Correlation with Bone Marrow Study.

Background: Lymphoma is a common malignant proliferative disease in which bone marrow infiltration will upstage the disease and thus affect prognosis of the disease. As of now bone marrow biopsy is considered as a reference standard to find out bone marrow involvement in lymphoma. Performing an invasive and painful intervention in all newly diagnosed lymphoma patients is controversial. PET-CT is a non-invasive technique that gives functional information about the cells using the glucose metabolism. It can detect early bone marrow and extra medullary organ involvement which can lead to restaging of the disease. These advantages make PET-CT a valuable adjunct in diagnosis of lymphoma. Aims and Objectives: Our study aims to evaluate the usefulness of 18 F-FDG PET-CT, a non-invasive, semi quantitative whole body imaging technique for detection of early bone marrow and extra medullary organ involvement in lymphoma patients which in turn can obviate the need for bone marrow study (BMS). The primary objective of study is to categorise FDG uptake in bone marrow as diffuse /unifocal /multifocal / no uptake and to correlate pattern of FDG uptake to bone marrow study. Our study also assesses the role of FDG PET/CT in staging of lymphoma. Materials and Methods: Thirty patients with newly diagnosed lymphoma in the age group 18 to 75 years of both sexes within 3 months of diagnosis and who have not been started on any treatment was included in the study. Marrow uptake on FDG PET/CT has been categorized as diffuse, unifocal, multifocal and no uptake. Agreement between bone marrow study and FDG PET/CT has been assessed by reliability analysis using Cohen's kappa. Sensitivity, specificity, PPV, NPV of PET/CT in detecting marrow involvement have been calculated. Results: The sensitivity, specificity, PPV, NPV and accuracy of 18 F-FDG PET-CT in detecting marrow involvement of lymphoma cases are 86.6%, 77.7%, 68.4%, 91.3% and 80.9% respectively. 18 F-FDG PET-CT detected bone marrow involvement in 86.6% (13 out of 15 total positive cases) cases of lymphoma which included both HL and NHL. Reliability analysis using Cohen's kappa is used to test the agreement between bone marrow study and 18F-FDG PET/CT. k value of 0.6 was obtained which showed a moderate agreement between bone marrow study and 18F-FDG PET/CT in marrow assessment. Conclusion: 18F-FDG PET/CT is a highly sensitive imaging modality which can pick up extra-nodal organ and BMI in patients with lymphoma and can upstage the disease and alter treatment strategies. PET-CT cannot completely replace the bone marrow study. However, being an invasive painful procedure, BMB can be avoided in cases with unifocal or multifocal marrow involvement on PET-CT.

18F-Labeled Fluoro-2-Deoxyglucose Positron Emission Tomography and Computed Tomography Findings in a Case of Atypical Presentation of Adult Cutaneous T-cell Lymphoma.

Adult cutaneous T-cell lymphoma is an uncommon malignancy with poor prognosis and is usually seen in association with human T-cell lymphotropic virus type 1. We present the case of a 25-year-old female who gave a history of extensive whole-body polypoidal cutaneous and bilateral orbital and breast swellings. Biopsy was suggestive of cutaneous T-cell lymphoma and the patient was evaluated with 18F-labeled fluoro-2-deoxyglucose positron emission tomography and computed tomography for initial staging of the disease.

Primary Cutaneous Adenoid Cystic Carcinoma Of The Chest Wall With Axillary Lymph Node Metastases And Its Management: A Case Report.

Primary cutaneous adenoid cystic carcinoma (PCACC) is a rare form of adenoid cystic carcinoma (ACC) arising commonly from the salivary gland. Less often they originate outside the head and neck region, with the scalp being the commonest cutaneous site in 40% of the cases. The presentation on the chest wall is rare, with no reports to date on axillary lymph node metastases. Here we report a case of a 65-year-old female with previously operated PCACC of the chest wall at a different center, showing uptake on positron emission tomography imaging at the site of surgical scar that w as inconclusive on needle biopsy metastasized to the axillary lymph node confirmed by needle biopsy managed with wide local excision, axillary lymph node dissection, and chest wall reconstruction with keystone island flap. The postoperative outcome was uneventful with no recurrence or axillary complications at one year's follow-up. She was advised to receive adjuvant radiotherapy; however, she refused. To conclude, though PCACC is rare, they can have an aggressive presentation, and a multidisciplinary approach is necessary for a better outcome.

18F Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Findings in a Case of Metastatic Eccrine Porocarcinoma - An Extremely Rare Malignant Adnexal Tumor.

Porocarcinoma is a rare malignant neoplasm of eccrine sweat glands representing 0.005 to 0.1% of all cutaneous tumors. As eccrine porocarcinoma carries a high risk of recurrence and metastases, early diagnosis and management are crucial to lower mortality rate. We present the case of porocarcinoma in a 69-years-old woman who underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) for staging the disease. PET/CT showed metabolically active multiple cutaneous lesions and also picked up lymph nodal and distant metastases to lungs and breast accurately. PET/CT is useful for accurate staging of the disease and for treatment planning.

Role of textural analysis parameters derived from FDG PET/CT in differentiating hepatocellular carcinoma and hepatic metastases.

INTRODUCTION: Texture and radiomic analysis characterize the tumor's phenotype and evaluate its microenvironment in quantitative terms. The aim of this study was to investigate the role of textural features of 18F-FDG PET/computed tomography (CT) images in differentiating hepatocellular carcinoma (HCC) and hepatic metastasis in patients with suspected liver tumors. METHODS: This is a retrospective, single-center study of 30 patients who underwent FDG PET/CT for the characterization of liver lesions or for staging a suspected liver tumor. The histological diagnosis of either primary or metastatic tumor was obtained from CT-guided biopsy, ultrasound-guided biopsy, or surgical removal of a liver lesion. The PET/CT images were then processed in commercially available textural analysis software. Region of interest was drawn over the primary tumor with a 40% threshold and was processed further to derive 42 textural and radiomic parameters. These parameters were then compared between HCC group and hepatic metastases group. Receiver-operating characteristic (ROC) curves were used to identify cutoff values for textural features with a P value <0.05 for statistical significance. RESULTS: A retrospective study of 30 patients with suspected liver tumors was done. After undergoing PET/CT, the histological diagnosis of these lesions was confirmed. Among these 30 patients, 15 patients had HCC, and 15 patients had hepatic metastases from various primary sites. Seven textural analysis parameters were significant in differentiating HCC from liver metastasis. Cutoff values were calculated for these parameters according to the ROC curves, standardized uptake value (SUV) Skewness (0.705), SUV Kurtosis (3.65), SUV Excess Kurtosis (0.653), gray-level zone length matrix_long zone emphasis (349.2), gray-level zone length matrix_long zone low gray-level emphasis (1.6), gray-level run length matrix_long run emphasis (1.38) and gray-level co-occurrence matrix_Homogeneity (0.406). CONCLUSION: Textural analysis parameters could successfully differentiate HCC and hepatic metastasis non-invasively. Larger multi-center studies are needed for better clinical prognostication of these parameters.

Role of Textural Analysis of Pretreatment 18F Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Response Prediction in Esophageal Carcinoma Patients.

Introduction: Positron emission tomography/computed tomography (PET/CT) is routinely used for staging, response assessment, and surveillance in esophageal carcinoma patients. The aim of this study was to investigate whether textural features of pretreatment 18F-fluorodeoxyglucose (18F-FDG) PET/CT images can contribute to prognosis prediction in carcinoma oesophagus patients. Materials and Methods: This is a retrospective study of 30 diagnosed carcinoma esophagus patients. These patients underwent pretreatment 18F-FDG PET/CT for staging. The images were processed in a commercially available textural analysis software. Region of interest was drawn over primary tumor with a 40% threshold and was processed further to derive 92 textural and radiomic parameters. These parameters were then compared between progression group and nonprogression group. The original dataset was subject separately to receiver operating curve analysis. Receiver operating characteristic (ROC) curves were used to identify the cutoff values for textural features with a P < 0.05 for statistical significance. Feature selection was done with principal component analysis. The selected features of each evaluator were subject to 4 machine-learning algorithms. The highest area under the curve (AUC) values was selected for 10 features. Results: A retrospective study of 30 primary carcinoma esophagus patients was done. Patients were followed up after chemo-radiotherapy and they underwent follow-up PET/CT. On the basis of their response, patients were divided into progression group and nonprogression group. Among them, 15 patients showed disease progression and 15 patients were in the nonprogression group. Ten textural analysis parameters turned out to be significant in the prediction of disease progression. Cutoff values were calculated for these parameters according to the ROC curves, GLZLM_long zone emphasis (Gray Level Zone Length Matrix)_long zone emphasis (44.9), GLZLM_low gray level zone emphasis (0.006), GLZLM_short zone low gray level emphasis (0.0032), GLZLM_long zone low gray level emphasis (0.185), GLRLM_long run emphasis (Gray Level Run Length Matrix) (1.31), GLRLM_low gray level run emphasis (0.0058), GLRLM_short run low gray level emphasis (0.005496), GLRLM_long run low gray level emphasis (0.00727), NGLDM_Busyness (Neighborhood Gray Level Difference Matrix) (0.75), and gray level co-occurrence matrix_homogeneity (0.37). Feature selection by principal components analysis and feature classification by the K-nearest neighbor machine-learning model using independent training and test samples yielded the overall highest AUC. Conclusions: Textural analysis parameters could provide prognostic information in carcinoma esophagus patients. Larger multicenter studies are needed for better clinical prognostication of these parameters.

Primary Biliary Tuberculosis Masquerading Cholangiocarcinoma in 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography.

Hepatobiliary involvement is a less common manifestation of abdominal tuberculosis. We present the case of a 42-year-old female who presented with fever, abdominal pain, and jaundice of 2 months duration. 18F-fluorodeoxyglucose positron emission tomography/computed tomography done for disease evaluation suggested the likely possibility of cholangiocarcinoma but excision biopsy from periportal lymph node later confirmed a granulomatous etiology and she was successfully treated with antitubercular therapy.

Molecular docking of SARS-COV-2 Spike epitope sequences identifies heterodimeric peptide-protein complex formation with human Zo-1, TLR8 and brain specific glial proteins.

SARS-COV-2 infection causes severe respiratory tract illness leading to asphyxia and death. The onset of infection is associated with loss of smell, blurred vision, headache with bronchopulmonary symptoms. The clinical observations of neurological abnormalities lead us to address the question, does the virus enter into brain and what is the underlying mechanism of brain infection? The working hypothesis is, SARS-COV-2 Spike epitopes modify blood brain barrier and infect glial cells to induce brain inflammation in genetically diverse human population. The hypothesis is tested by determining binding or interacting ability of virus Spike epitope peptides M1Lys60 and Ala240Glu300 with human toll-like receptor 8 (TLR 8), brain targeted Vascular Cell adhesion Molecules (VCAM1) proteins, Zonula Occludens (ZO), glial cell specific protein NDRG2 and Apo- S100B. The molecular dynamic experiments are performed, and root mean square deviation (RMSD) values are determined for interactions between the Spike peptides and selected proteins. The observations demonstrate formation of heterodimeric complex between the epitope peptides and selected protein structures. The viral epitopes have ability to bind with HLA-DRB1 15:01, 07:01 or 03.01 alleles thus found immunogenic in nature. The observations altogether suggest entry of these Spike protein epitopes into human brain causes inflammation.

Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is now the dominant form of heart failure and one for which no efficacious therapies exist. Obesity and lipid mishandling greatly contribute to HFpEF. However, molecular mechanism(s) governing metabolic alterations and perturbations in lipid homeostasis in HFpEF are largely unknown. Here, we report that cardiomyocyte steatosis in HFpEF is coupled with increases in the activity of the transcription factor FoxO1 (Forkhead box protein O1). FoxO1 depletion, as well as over-expression of the Xbp1s (spliced form of the X-box-binding protein 1) arm of the UPR (unfolded protein response) in cardiomyocytes each ameliorates the HFpEF phenotype in mice and reduces myocardial lipid accumulation. Mechanistically, forced expression of Xbp1s in cardiomyocytes triggers ubiquitination and proteasomal degradation of FoxO1 which occurs, in large part, through activation of the E3 ubiquitin ligase STUB1 (STIP1 homology and U-box-containing protein 1) a novel and direct transcriptional target of Xbp1s. Our findings uncover the Xbp1s-FoxO1 axis as a pivotal mechanism in the pathogenesis of cardiometabolic HFpEF and unveil previously unrecognized mechanisms whereby the UPR governs metabolic alterations in cardiomyocytes.

SIRT6 transcriptionally regulates fatty acid transport by suppressing PPARγ.

Pathological lipid accumulation is often associated with enhanced uptake of free fatty acids via specific transporters in cardiomyocytes. Here, we identify SIRT6 as a critical transcriptional regulator of fatty acid transporters in cardiomyocytes. We find that SIRT6 deficiency enhances the expression of fatty acid transporters, leading to enhanced fatty acid uptake and lipid accumulation. Interestingly, the haploinsufficiency of SIRT6 is sufficient to induce the expression of fatty acid transporters and cause lipid accumulation in murine hearts. Mechanistically, SIRT6 depletion enhances the occupancy of the transcription factor PPARγ on the promoters of critical fatty acid transporters without modulating the acetylation of histone 3 at Lys 9 and Lys 56. Notably, the binding of SIRT6 to the DNA-binding domain of PPARγ is critical for regulating the expression of fatty acid transporters in cardiomyocytes. Our data suggest exploiting SIRT6 as a potential therapeutic target for protecting the heart from metabolic diseases.

Non-statin interventions in the prevention of cardiovascular events: Sex-based meta-analysis.

OBJECTIVE: To explore the sex-specific association of non-statin classes of drugs in reducing cardiovascular outcomes. METHODS: Published data search up to November 2019 reporting primary outcomes that approximate with major vascular events (MVEs) after treatment with non-statin group of drugs was performed. The primary outcome was the sex-specific association with MVEs. Random-effects meta-analysis was performed to estimate relative risk (RR) of the individual classes of therapies. RESULTS: Seven Randomized Clinical Trials (RCTs) including 122,164 patients were included in our analysis. Four studies compared the Triglyceride (TG)-lowering group of drugs with placebo and 3 studies compared low-density lipoprotein cholesterol (LDL-c) lowering drugs with placebo. Overall, with non-statin drugs, there was no difference in the risk reduction of cardiovascular (CV) events between men (RR 0.86; 95% CI 0.79-0.94, p-value <0.001) and women (RR 0.88; 95% CI 0.83-0.93, p-value 0.91). However, TG targeting interventions showed no cardiovascular outcome benefits in men (RR 0.85; 95% CI 0.71-1.02, p-value <0.001) while no significant benefit was seen in women (RR 0.87; 95% CI 0.77-0.98, p value = 0.85). No such difference existed in non-statin LDL-c lowering group of drugs in between men (RR 0.88; 95% CI 0.81-0.94, p value = 0.18) and women (RR 0.88; 95% CI 0.82-0.94, p value = 0.46). However, lowering of TG was only associated with a higher risk reduction of CV events (RR 0.86; 95% CI 0.77-0.95, p value = 0.03) in the entire study population. CONCLUSION: Non-statin group of drugs was effective in reducing adverse CV outcomes for both sexes. Lowering TG was associated with higher risk reduction in CV events in general.

IL-12 p40 homodimer, the so-called biologically inactive molecule, induces nitric oxide synthase in microglia via IL-12R beta 1.

Earlier we have demonstrated that IL-12 p40 homodimer (p40(2)) induces the expression of inducible nitric oxide synthase (iNOS) in microglia. This study was undertaken to investigate underlying mechanisms required for IL-12 p40(2)- and IL-12 p70-induced expression of iNOS in microglia. IL-12 p40(2) alone induced the activation of both extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK). Interestingly, the ERK pathway coupled p40(2) to iNOS expression via C/EBP beta, but not NF-kappaB, whereas the p38 pathway relayed the signal from p40(2) to iNOS expression via both NF-kappaB and C/EBP beta. Furthermore, by using microglia from IL-12R beta 1 (-/-) and IL-12R beta 2 (-/-) mice or siRNA against IL-12R beta 1 and IL-12R beta 2, we demonstrate that p40(2) induced the expression of iNOS in microglia via IL-12R beta 1-(ERK+p38)-(NF-kappaB +C/EBP beta) pathway. In contrast, both IL-12R beta 1 and IL-12R beta 2 were involved for IL-12 p70-induced microglial expression of iNOS. Although IL-12R beta 1 coupled p70 to NF-kappaB and C/EBP beta, IL-12R beta 2 was responsible for p70-mediated activation of GAS. This study delineates a new role of IL-12R beta 1 and IL-12R beta 2 for the expression of iNOS and production of NO in microglia that may participate in the pathogenesis of neuroinflammatory diseases.

S-Nitrosylation in Regulation of Inflammation and Cell Damage.

BACKGROUND: Cell signaling through nitric oxide (NO) is a multifaceted mechanism, which regulates metabolic activities and fate in different tissues. The peroxynitrite (ONOO-) formed as reaction product of nitric oxide radical and superoxide interacts with cell membrane phospholipids and proteins causing damage. OBJECTIVE: The reaction kinetics to form nitrotyrosine (ONOO-tyrosine) and/or nitrosylated cysteine (ONOO-cysteine) in protein molecules during posttranslational modification and nitration of lipids are therefore critical in determining cells' signaling mechanism for survival or apoptosis. RESULTS: The nitrosylation was found to modulate GPCRs and activation of guanylate cyclase as well as regulate NF-κB activation. The recent findings have shown the neuroprotective effects of S- nitrosylation, though mechanism is unclear. CONCLUSION: While keeping the background in mind, we address here the biological function of NO derivatives in medicine. We target four known compounds: SNAP, SIN- 1 chloride, SNP and GSNO to understand the effect of NO in different tissues. Here we analyze the existing findings to assess therapeutic relevance of NO-signaling during inflammation, vasodilation and tolerance.

Breast Cancer Research in the Caribbean: Analysis of Reports From 1975 to 2017.

PURPOSE: Breast cancer is among the leading causes of death resulting from cancer in Caribbean women. Studies examining exogenous and genetically predetermined endogenous risk factors are critical to define breast cancer susceptibility in Caribbean women. The purpose of this systematic review is to assess the existing scientific literature in the last 42 years (1975 to 2017) to describe the body of research generated for the population of this region and determine future research directions. METHODS: We selected published research articles using a combination of definite keyword searches in PubMed. Only articles presenting the Caribbean population as the focus of their research objectives were included in this analysis. RESULTS: Studies on breast cancer in the Caribbean are limited. A majority of publications on Caribbean populations were descriptive, focusing on cancer trends and clinicopathologic factors. High incidence and mortality rates for breast cancer are reported for the region, and there seem to be some differences between countries in the frequency of cases according to age at presentation. A limited number of epidemiologic, behavioral, and genetic and molecular studies were conducted in more recent years. CONCLUSION: A regional strategy for cancer registration is needed for the Caribbean to address possible underestimates of breast cancer incidence. Furthermore, behavioral, molecular, genetic, and epidemiologic investigations of breast cancer are critical to address the concerns related to currently described high incidence and mortality rates in the Caribbean.

Antigen presentation for priming T cells in central system.

Generation of myelin antigen-specific T cells is a major event in neuroimmune responses that causes demyelination. The antigen-priming of T cells and its location is important in chronic and acute inflammation. In autoimmune multiple sclerosis, the effector T cells are considered to generate in periphery. However, the reasons for chronic relapsing-remitting events are obscure. Considering mechanisms, a feasible aim of research is to investigate the role of antigen-primed T cells in lupus cerebritis. Last thirty years of investigations emphasize the relevance of microglia and infiltrated dendritic cells/macrophages as antigen presenting cells in the central nervous system. The recent approach towards circulating B-lymphocytes is an important area in the context. Here, we analyze the existing findings on antigen presentation in the central nervous system. The aim is to visualize signaling events of myelin antigen presentation to T cells and lead to the strategy of future goals on immunotherapy research.