NKT sejt szubpopulációk és aktiválódás sclerosis multiplexben = NKT cell subsets and activation in patients with multiple sclerosis

A vese- és agydaganatokban az NKT, valamint egy új, NKT sejtekhez hasonló T sejt, a MAIT sejtek invariáns receptora kimutatható, vagyis a sclerosis multiplex plakkokban észlelt NKT sejt deficiencia nem a központi idegrendszeri immunszabályozásssal függ össze, hanem a sclerosis multiplexre jellemző. A daganatokat infiltráló MAIT és NKT sejtek aktivált, döntően CD8+ sejtek, és CD56 molekulát nem expresszálnak, annak ellenére, hogy a perifériás vérben CD56+ csoportban is kimutathatók. A MAIT sejtek gyulladáskeltő citokin környezetben fordulnak elő a daganatokban, vagyis az NKT sejtekhez hasonlóan funkcionálisan heterogének. A MAIT és NKT sejteket tartalmazó CD56+ T sejtek sclerosis multiplex betegek vérében aktiváltak, és citotoxikus molekulákat expresszálnak. SSCP klonalitás módszerrel e sejtek klonális expanzióját mutattuk ki SM-ben. Jelen vannak e sejtek a liquorban is, és NK sejtekhez hasonlóan CD11c molekulát expresszálnak, mely a citokinválasszal összefügghet. Ugyanakkor e sejtek deficienciája mutatható ki órákon belül akut stroke-ban, a gyulladáskeltő citokinválasz és a citotoxicitás szuppressziójával. E korai, csak a gyulladáskeltő választ érintő deficiencia mellett a leukocyták aktivációja jellemzi az akut stroke-ot. A limfocita szuppresszió normalizálódásának elmaradása, illetve a korai leukocyta aktiváció deficitje a stroke-ot követő infekciókra hajlamosít, és a stroke kimenetelét szignifikánsan rontja. | The invariant T cell receptors of NKT cells and MAIT, a novel T cell subset with similar functions to NKT cell in mice, were shown in brain and kidney tumors. Thus, the previously observed deficiency of NKT cells in MS plaques is not related to the immunoregulation of the CNS, rather, it is connected to MS. The infiltrating T cells containing NKT and MAIT are activated, express CD8 but not CD56, although the MAIT TCR can be shown in the peripheral CD56+ T cell subset. The presence of pro-inflammatory cytokines in tumors, while anti-inflammatory cytokines are absent, indicates the functional heterogeneity of human MAIT similarly to NKT cells. We also showed that CD56+ T cells are activated and clonally expanded in the peripheral blood of MS, and express cytotoxic molecules. These cells are present in the CSF and express CD1c, which can be related to cytokine production. In contrast, the deficiency of these CD56+ T cells characterizes the acute phase of ischemic stroke: the pro-inflammatory cytokine production and cytotoxicity is suppressed within hours. Besides the early deficient lymphocyte responses, leukocytes are activated within hours in stroke. The delayed normalization of suppressed lymphocyte functions along with the deficiency of early leukocyte activation predispose to post-stroke infections and significantly worsen outcome

Expression Levels of GHRH-Receptor, pAkt and Hsp90 Predict 10-Year Overall Survival in Patients with Locally Advanced Rectal Cancer

Rectal cancer constitutes nearly one-third of all colorectal cancer diagnoses, and certain clinical and molecular markers have been studied as potential prognosticators of patient survival. The main objective of our study was to investigate the relationship between the expression intensities of certain proteins, including growth-hormone-releasing hormone receptor (GHRH-R), Hsp90, Hsp16.2, p-Akt and SOUL, in specimens of locally advanced rectal cancer patients, as well as the time to metastasis and 10-year overall survival (OS) rates. We also investigated whether these outcome measures were associated with the presence of other clinical parameters.In total, 109 patients were investigated retrospectively. Samples of pretreatment tumors were stained for the proteins GHRH-R, Hsp90, Hsp16.2, p-Akt and SOUL using immunhistochemistry methods. Kaplan-Meier curves were used to show the relationships between the intensity of expression of biomarkers, clinical parameters, the time to metastasis and the 10-year OS rate.High levels of p-Akt, GHRH-R and Hsp90 were associated with a significantly decreased 10-year OS rate (p = 0.001, p = 0.000, p = 0.004, respectively) and high expression levels of p-Akt and GHRH-R were correlated with a significantly shorter time to metastasis. Tumors localized in the lower third of the rectum were linked to both a significantly longer time to metastasis and an improved 10-year OS rate.Hsp 90, pAkt and GHRH-R as well as the lower-third localization of the tumor were predictive of the 10-year OS rate in locally advanced rectal cancer patients. The GHRH-R and Hsp90 expression levels were independent prognosticators of OS. Our results imply that GHRH-R could play a particularly important role both as a molecular biomarker and as a target for the anticancer treatment of advanced rectal cancer

Identification of New, Translatable ProtectomiRs against Myocardial Ischemia/Reperfusion Injury and Oxidative Stress: The Role of MMP/Biglycan Signaling Pathways

Introduction: Ischemic conditionings (ICon) were intensively investigated and several protective signaling pathways were identified. Previously, we have shown the role of matrix metalloproteinases (MMP) in myocardial ischemia/reperfusion injury (MIRI) and the cardioprotective role of biglycan (BGN), a small leucine-rich proteoglycan in vitro. Here, we hypothesized that cardiac MMP and BGN signaling are involved in the protective effects of ICon. Methods: A reverse target-microRNA prediction was performed by using the miRNAtarget™ 2.0 software to identify human microRNAs with a possible regulatory effect on MMP and BGN, such as on related genes. To validate the identified 1289 miRNAs in the predicted network, we compared them to two cardioprotective miRNA omics datasets derived from pig and rat models of MIRI in the presence of ICons. Results: Among the experimentally measured miRNAs, we found 100% sequence identity to human predicted regulatory miRNAs in the case of 37 porcine and 24 rat miRNAs. Upon further analysis, 42 miRNAs were identified as MIRI-associated miRNAs, from which 24 miRNAs were counter-regulated due to ICons. Conclusions: Our findings highlight 24 miRNAs that potentially regulate cardioprotective therapeutic targets associated with MMPs and BGN in a highly translatable porcine model of acute myocardial infarction

Concurrent hypermethylation of DNMT1, MGMT and EGFR genes in progression of gliomas

<p>Abstract</p> <p>Background</p> <p>Gliomas are the most common neoplasm of the brain. High-grade gliomas often resist treatment even with aggressive surgical resection and adjuvant radiation and chemotherapy. Despite the combined treatment, they frequently recur with the same or higher-grade histology. Genetic instability is commonly associated with inactivation of the normal DNA repair function and tumour suppressor genes as well as activation of oncogenes resulting from alterations of promoter hypermethylation, but the molecular mechanisms of the histological and clinical progression of gliomas are still poorly understood.</p> <p>Methods</p> <p>This study involved longitudinal analysis samples of primary and recurrent gliomas to determine whether the progression of low- and high-grade gliomas is associated with the promoter methylation of the DNMT1, MGMT and EGFR genes by PCR-based restriction enzyme assay. Epigenetic inactivation of these three important glioma-associated genes was analyzed in paired biopsy samples from 18 patients with tumour recurrence.</p> <p>Results</p> <p>The methylation analysis of the CpG sites in the DNA methyltransferase (DNMT1) promoter revealed a total of 6 hypermethylations (6/18), the methylguanine-DNA methyltransferase (MGMT) promoter revealed a total of 10 hypermethylations (10/18) and the epithelial grow factor receptor (EGFR) promoter revealed a total of 12 (12/18) hypermethylations respectively in recurrent gliomas. The results demonstrated that DNMT1 promoter hypermethylation does not occur in low-grade gliomas, it was mainly observed in secondary glioblastomas. Additionally, the MGMT and EGFR promoter was hypermethylated in both low-and high-grade GLs and their corresponding histological transformed GLs.</p> <p>Conclusion</p> <p>This study has provided further evidence that the histological transformation and progression of gliomas may be associated with the inactivation of the EGFR and MGMT genes. It seems that EGFR and MGMT promoter hypermethylations are early events in the clonal evolution of gliomas and this gene inactivation has proved to be stable even in tumour recurrence. However, the DNMT hypermethylation is a late part of glioma progression.</p> <p>Virtual slides</p> <p>The virtual slide(s) for this article can be found here: <url>http://www.diagnosticpathology.diagnomx.eu/vs/1935054011612460</url></p

Kis- és középvállalkozások problematikája, kérdésköre

BaBibliogr.: fol. 62v