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Objectives: Programmed death-ligand 1 (PD-L1) expression is a biomarker for cancer immunotherapy. Diabetes mellitus type-2 is a comorbid disease associated with adverse outcomes in Non-Small Cell Lung Cancer (NSCLC). We aimed to investigate the differences in PD-L1 expression in diabetics., Methods: A matched case-control cohort of surgically-resected NSCLC was assembled from an early multicenter study (PMID: 19152440). PD-L1 immunohistochemistry (Clone 22C3) was graded by a tumor positive score (TPS) system (TPS0: no staining; TPS1: <1%; TPS2: 1-49%; TPS3: ≥50%). Variables showing significance at univariate survival analysis were fit in a Cox regression survival model., Results: Diabetics (n=40) and nondiabetics (n=39) showed no differences in age, gender, cancer stage, and follow-up. NSCLCs were more likely PD-L1 positive in diabetics but with tumor positivity <50% (TPS0: 7.5 vs. 20.5%, TPS1: 35 vs. 25.6%, TPS2: 45 vs.23.1%, TPS3: 12.5 vs. 30.8%, respectively; P<0.05). In diabetics, squamous cell carcinomas (SCC) and adenocarcinomas were mainly TPS2 (65% vs. 20%) and TPS1 (50% vs. 26%), respectively. Peritumoral inflammation correlated with TPS (r=0.228), a relationship accentuated in diabetics (r=0.377, P<0.05) but diminished and non-significant in nondiabetics (r=0.136, P≥0.05). This association was stronger in SCC (r=0.424). Diabetes was associated with increased tumor recurrence (HR: 3.08; 95%CI: 1.027-9.23)., Conclusion: Diabetes is associated with an increase in peritumoral inflammation, PD-L1 positivity, and recurrence in NSCLC, more pronounced in SCC, suggesting the possibility of metabolic reprogramming and upregulation of PD-L1 by inducible pathways., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Aim: To evaluate the epicardial adipose tissue (EAT) transcriptome in comparison to subcutaneous fat (SAT) in coronary artery disease (CAD) and type 2 diabetes (T2DM)., Methods and Results: SAT and EAT samples were obtained from subjects with T2DM and CAD (n = 5) and those without CAD with or without T2DM (=3) undergoing elective cardiac surgery. RNA-sequencing analysis was performed in both EAT and SAT. Gene enrichment analysis was conducted to identify pathways affected by the differentially expressed genes. Changes of top genes were verified by quantitative RT-PCR (qRT-PCR), western blot, and immunofluorescence. A total of 592 genes were differentially expressed in diabetic EAT, whereas there was no obvious changes in SAT transcriptome between diabetics and non-diabetics. Diabetic EAT was mainly enriched in inflammatory genes, such as Colony Stimulating Factor 3 (CSF3), Interleukin-1b (IL-1b), IL-6. KEGG pathway analysis confirmed that upregulated genes were involved in inflammatory pathways, such as Tumor Necrosis Factor (TNF), Nuclear Factor-κB (NF-κB) and advanced glycation end-products-receptor advanced glycation end products (AGE-RAGE). The overexpression of inflammatory genes in diabetic EAT was largely correlated with upregulated transcription factors such as NF-κB and FOS., Conclusions: Diabetic EAT transcriptome is significantly different when compared to diabetic SAT and highly enriched with genes involved in innate immune response and endothelium, like Pentraxin3 (PTX3) and Endothelial lipase G (LIPG). EAT inflammatory genes expression could be induced by upregulated transcription factors, mainly NF-kB and FOSL, primarily activated by the overexpressed AGE-RAGE signaling. This suggests a unique and novel atherogenic pathway in diabetes., (Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Binge drinking (BD) is a harmful pattern of alcohol use. This study describes this pattern of drinking and the sociodemographic variables associated with it in a representative sample of Brazilians., Methods: A cross-sectional survey of 3007 individuals using a multistage probabilistic sample was conducted in 143 Brazilian municipalities. The frequency of BD in the year preceding the study was assessed. BD was defined as the consumption of four drinks of alcohol within a two-hour period for women and five drinks in two hours for men. Weighted-ordered logit regression was used to assess the relationship between sociodemographic factors and BD., Results: Most respondents had not engaged in binge drinking (69.7%; 95% confidence interval (CI) 67.0-72.2%). Binge drinking was more common among participants who were male (odds ratio (OR) 2.9; 95% CI 2.3-3.6) or single (OR 1.5; 95% CI 1.1-2.1) or had higher family income (OR 2.3; 95% CI 1.3-3.8). Individuals between 18 and 44 years of age were four times more likely to engage in binge drinking than adolescents (OR 4.7; 95% CI 3.3-6.8). Evangelicals/Protestants were less likely to engage in binge drinking (OR 0.7; 95% CI 0.2-0.5)., Conclusions: Our study, which is the first representative survey of BD in Brazil, showed that the age range of adults who engaged in BD is wider than the age range observed in other countries. These individuals are at increased risk for the adverse consequences of binge drinking, including addiction, car accidents, involvement in crime, absenteeism, and family violence., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The mice born to female mice infected with LP-BM5 MuLV, the etiologic agent for lymphoproliferative disease and nursed for 4-6 weeks by them were less susceptible upon reinfection by i.v. transfusion of blood or plasma from infected donors with fully developed disease. Sera of 7 week or older perinatally exposed mice were capable of a complete in vitro neutralization of virus in plasma or blood from mice with fully developed disease. In contrast, sera from 3-week old perinatally exposed mice were ineffective. The neutralizing ability of the sera was drastically reduced or abrogated after their absorption with anti-mouse IgM. These observations are consistent with the notion that perinatally exposure results ina moderate form of the disease of the offspring. This perinatal infection is followed by a production of neutralizing antibodies of predominantly the IgM class that significantly alters the course of the lymphoproliferative disease and, in some instances, even prevents its development.

C57BL/6Kh mice were infected with a single i.p. injection of 1 x 10(5) FFU of LP-BM5 MuLV. The development and progress of the virus-induced lymphoproliferative disease was followed for 12 weeks after infection. As anticipated, progressive splenomegaly and lymphadenopathy, as well as almost total abrogation of immune responsiveness ensued. In contrast to previous reports, there was a dramatic increase in the frequency of CD4+ cells in spleens among which over 20% expressed V beta 5 TCR, as compared with fewer than 3% in spleens of normal mice. Spleen cells from infected mice retained their in vitro ability to proliferate upon stimulation with IL-2 and anti-CD3, but were unable to respond when stimulated with phorbol ester and either a low dose of IL-2 or calcium ionophore (ionomycin). A similar pattern of in vitro proliferative responses was obtained when normal spleen cells were treated with K252a compound, a known inhibitor of protein kinase C activity. Together with the observations that viral infection impaired down-regulation of the phorbol-induced kinase activity and that the kinase inhibitor only marginally enhanced suppression of virus-infected cells proliferation, this finding suggests that disturbances of protein kinase C activity may underly the pathological effects seen after viral infection. However, since no apparent quantitative and qualitative changes in protein kinase C itself and its translocation were observed, it is more likely that the virus may interfere with either the substrate or product of kinase activity.

To determine the kinetics of the ontogeny of polygenically controlled proliferative responses, spleen cells from 5, 10 and 20 day-old mice, previously identified as high (B10.PL-Thy-1a, AKR.M) and low (C3H.A) responders were tested. Cells (10(5)) were simulated in vitro with human recombinant IL-2 (35 U), a mixture of either IL-2 (0.7 U) and 13-myristate 12-acetate phorbol (5 ng) or phorbol and calcium ionophore A23187 (5 ng). Two parameters were assessed; proliferation measured by 3H-thymidine incorporation and the synergistic effect expressed as a synergism coefficient (SC): the ratio of proliferation induced by a mixture to the sum of proliferations induced by each component alone. At the age of 5 days, all three strains, regardless of stimulation, produced similar proliferation and showed no synergistic effect (SC = 1.0). At the age of 10 days, proliferation of high responder cells was 3-5 times higher than that of the low responder, but only high responders displayed marginal synergistic effect (2 greater than SC greater than 1.5). At the age of 20 days, proliferative responses of the high responders increased somewhat and a definitive synergistic effect became clearly demonstrable (SC greater than 3.0). This effect increased further after the age of 20 days to reach the level of SC greater than 5.0 in adult high responders. The delay in expression of synergistic effect was due to a substantial proliferation induced by phorbol alone in 10 day-old animals. The available data allow the conclusion that phenotypic strain variation in proliferative responses is first detectable at the age of 10 days and becomes fully developed only after attaining the age of 20 days or more. Since the magnitude of proliferative responses was not associated with frequencies of IL-2R alpha + cells it seems that differences in responsiveness can not be attributed to the induction of IL-2R alpha chain, and they may reflect intrinsic abilities of cells to proliferate.

Proliferative responses of normal (not immunized intentionally) spleen cells from inbred strains of mice to co-stimulation with phorbol ester (PMA) and calcium ionophore A23187 were studied. Striking differences in the magnitude of the responses of spleen cells and splenic T cells from various strains were observed. It appeared that these differences reflected mainly differences in the inducibility of the expression of the gene for the alpha chain of the IL2 receptor (IL2R) by phorbol ester. Formal genetic analysis suggested that the differences in response to phorbol ester and calcium ionophore are controlled by two independent genes with the alleles controlling good response being dominant. The differences in the inducibility of the IL2R gene seemed to be controlled by alleles of a single gene. At least one of the putative genes may be a regulatory element affecting the gene for the alpha chain of IL 2R. The results may have a practical significance for devising more efficient procedure(s) to generate LAK cells used for tumor immunotherapy.