Immune checkpoint proteins (PD-L1 and CTLA-4) in endometrial carcinoma: prognostic role and correlation with CD4+/CD8+ tumor infiltrating lymphocytes (TILs) ratio.

Developing the prognostic aspects of endometrial carcinoma through shedding light on immune check point proteins (PD-L1 and CTLA-4) together with Tumor-Infiltrating Lymphocytes (TILs) may help finding new targets for immunotherapy, especially for advanced cases. This study aimed to study the immunohistochemical expression of PD-L1 and CTLA-4 in correlation with tumor infiltrating lymphocytes (TILs) in series of endometrial carcinomas. CTLA-4 showed notably higher frequency of expression in the studied cases than PD-L1. However, both showed significant association across different histopathological subtypes. PD-L1 immunohistochemical expression in studied endometrial carcinomas was significantly associated with low CD4+/CD8+ratio, high tumor grades, presence of lymph node metastasis and higher tumor stage. CTLA-4 immunohistochemical expression in studied endometrial carcinomas was significantly associated with low CD4+/CD8+ ratio and high tumor grades but not with tumor stage. Both PD-L1 & CTLA-4 are expressed in subset of endometrial carcinomas with more prevalence of the latter. Both immune checkpoint proteins have significant correlation with different prognostic clinicopathological parameters together with TILs (CD4 & CD8 and their ratio). Increased activated cytotoxic T lymphocytes and PD-L1 expression in endometrial carcinomas may suggest identification of patients' subset of tumors that can be candidates for treatment with immunotherapy.

Bone marrow mononuclear cells enhance anti-inflammatory effects of pravastatin against isoproterenol-induced myocardial infarction in rats.

The current study investigated the combinatorial effect of pravastatin (PRAV) and bone marrow mononuclear cells (BM-MNC) on acute myocardial infarction (AMI) induced experimentally in rats. After induction of MI, rats were given oral PRAV (20 mg/kg/day) for 28 days or a bolus intravenous injection (via lateral vein) of a total of 14 × 10(6) autologous BM-MNC or a combination of both. Serum brain natriuretic peptide (BNP) and histologic changes in cardiac tissues were assessed. Cardiac contents of lipid peroxides, superoxide dismutase (SOD) and inflammatory biomarkers including tumor necrosis factor (TNF)-α and interleukin (IL)-1ß as well as vascular endothelial growth factor (VEGF) and nitric oxide (NO) were also measured. Combined PRAV and BM-MNC treatment significantly suppressed serum BNP. Cardiac cell apoptosis and inflammatory cell infiltration in heart tissue decreased significantly in both the PRAV and the PRAV + BM-MNC groups. Cardiac lipid peroxides along with TNFα and IL-1ß levels were significantly reduced in both the PRAV and PRAV + BM-MNC hosts with an increase in SOD levels. However, the combined treatment increased cardiac NO levels and did not modify cardiac VEGF levels. The current results indicated that administration of BM-MNC improved the therapeutic efficacy of PRAV treatment by improving the morphology of infarcted hearts as well as decreasing inflammation in a host, but did not do so by inducing therapeutic angiogenesis.

Discoidin domain receptor-1 as a player in impairment of melanocytes adhesion process in vitiligo.

BACKGROUND: The aim of this paper was to study immunohistochemical expression of discoidin domain receptor 1 (DDR1) in lesional and non-lesional skin of vitiligo patients in comparison to controls, to explore its possible implication vitiligo pathogenesis. METHODS: Twenty patients with non-segmental vitiligo (NSV) were subjected to punch biopsy from lesional and non-lesional vitiligo skin, in addition to punch biopsy from ten healthy subjects. All specimens were examined by H&E staining and by immunohistochemistry for DDR1 expression. RESULTS: Significantly decreased expression of DDR1 in lesional vitiligo skin in comparison to non-lesional skin was observed. In addition, decreased lesional and non-lesional DDR1 expression in vitiligo skin in comparison to controls was found. CONCLUSIONS: Reduced DDR1 expression may be implicated in impaired melanocyte adhesion process involved in vitiligo pathogenesis.

Histamine protects against the acute phase of experimentally-induced hepatic ischemia/re-perfusion.

Histamine, involved in many inflammatory reactions and immune responses, is reported to suppress--via H4R stimulation--injury concomitant with the late phase of warm hepatic ischemia/re-perfusion (I/R). The current study investigated the possible effects of histamine on the acute phase of hepatic I/R injury, and the possible underlying mechanisms like oxidative stress and release of inflammatory cytokines (e.g., tumor necrosis factor (TNF)-α nd interleukin [IL]-12). Rats were divided into naïve, sham-operated, and I/R groups. The I/R group was divided into sub-groups and pre-treated with histaminergic ligands before induction of ischemia. Anesthetized rats were subjected to warm ischemia for 30 min by occlusion of the portal vein and hepatic artery, then re-perfused for 90 min. Rats in the control I/R group showed significant increases in hepatic malondialdehyde (MDA), TNFα, and IL-12 contents, and in plasma alanine transaminase (ALT) and aspartate transaminase (AST) levels, along with significant decreases in hepatic reduced glutathione (GSH) content and marked diffuse histopathologic damage. Pre-treatment with histamine resulted in significant mitigation of each of these end-points. The protective effect of histamine was not antagonized by pre-treatment with mepyramine (H1R antagonist) or ranitidine (H2R antagonist) and completely reversed by pre-treatment with thioperamide (H3R and H4R antagonist). In addition, the histamine protective effect was mimicked by pre-treatment of rats with clozapine (H4R agonist). These observations strongly suggested that histamine has a protective effect against hepatic I/R-mediated tissue injury during the acute phase, and this effect was mediated through an H4R stimulation that led to a decrease in IL-12 and TNFα production--outcomes that consequently decreased localized oxidative stress and afforded hepatic protection in general.