An evaluation of the reliability of the 8-second Skipping with Hand Clapping (8-s SHC) Test with the use of the retest method

Evaluation of speed ability in students, male and female, studying in Universit

Functional impairment of human resident cardiac stem cells by the cardiotoxic antineoplastic agent trastuzumab

Trastuzumab (TZM), a monoclonal antibody against the ERBB2 protein, increases survival in ERBB2-positive breast cancer patients. Its clinical use, however, is limited by cardiotoxicity. We sought to evaluate whether TZM cardiotoxicity involves inhibition of human adult cardiac-derived stem cells, in addition to previously reported direct adverse effects on cardiomyocytes. To test this idea, we exposed human cardiosphere-derived cells (hCDCs), a natural mixture of cardiac stem cells and supporting cells that has been shown to exert potent regenerative effects, to TZM and tested the effects in vitro and in vivo. We found that ERBB2 mRNA and protein are expressed in hCDCs at levels comparable to those in human myocardium. Although clinically relevant concentrations of TZM had no effect on proliferation, apoptosis, or size of the c-kit-positive hCDC subpopulation, in vitro assays demonstrated diminished potential for cardiogenic differentiation and impaired ability to form microvascular networks in TZM-treated cells. The functional benefit of hCDCs injected into the border zone of acutely infarcted mouse hearts was abrogated by TZM: infarcted animals treated with TZM + hCDCs had a lower ejection fraction, thinner infarct scar, and reduced capillary density in the infarct border zone compared with animals that received hCDCs alone (n = 12 per group). Collectively, these results indicate that TZM inhibits the cardiomyogenic and angiogenic capacities of hCDCs in vitro and abrogates the morphological and functional benefits of hCDC transplantation in vivo. Thus, TZM impairs the function of human resident cardiac stem cells, potentially contributing to TZM cardiotoxicity

Reduction of myocardial infarction by postischemic administration of the calpain inhibitor A-705253 in comparison to the Na(+)/H(+) exchange inhibitor Cariporide (R) in isolated perfused rabbit hearts

The calpain inhibitor A-705253 and the Na(+)/H(+) exchange inhibitor Cariporide (R) were studied in isolated perfused rabbit hearts subjected to 60 min occlusion of the ramus interventricularis of the left coronary artery (below the origin of the first diagonal branch), followed by 120 min of reperfusion. The inhibitors were added to the perfusion fluid solely or in combination at the beginning of reperfusion. Hemodynamic monitoring and biochemical analysis of perfusion fluid from the coronary outflow were performed. Myocardial infarct size and area at risk (transiently not perfused myocardium) were determined from left ventricular slices after a special staining procedure with Evans blue and 2,3,5-triphenyltetrazolium chloride. The infarcted area (dead myocardium) was 72.7 +/- 4.0% of the area at risk in untreated controls, but was significantly smaller in the presence of the inhibitors. The largest effect was observed with 10(-6) M A-705253, which reduced the infarcted area to 49.2 +/- 4.1% of the area at risk, corresponding to a reduction of 33.6%. Cariporide (R) at 10(-6) M reduced the infarct size to the same extent. The combination of both inhibitors, however, did not further improve cardioprotection. No significant difference was observed between the experimental groups in coronary perfusion, left ventricular pressure, heart rate, or in the release of lactate dehydrogenase and creatine kinase from heart muscle

LSD1 cooperates with CTIP2 to promote HIV-1 transcriptional silencing

Microglial cells are the main HIV-1 targets in the central nervous system (CNS) and constitute an important reservoir of latently infected cells. Establishment and persistence of these reservoirs rely on the chromatin structure of the integrated proviruses. We have previously demonstrated that the cellular cofactor CTIP2 forces heterochromatin formation and HIV-1 gene silencing by recruiting HDAC and HMT activities at the integrated viral promoter. In the present work, we report that the histone demethylase LSD1 represses HIV-1 transcription and viral expression in a synergistic manner with CTIP2. We show that recruitment of LSD1 at the HIV-1 proximal promoter is associated with both H3K4me3 and H3K9me3 epigenetic marks. Finally, our data suggest that LSD1-induced H3K4 trimethylation is linked to hSET1 recruitment at the integrated provirus

In Trauma Patients, the Occurrence of Early-Onset Nosocomial Infections is Associated With Increased Plasma Concentrations of Chromogranin A:

In previously healthy persons suffering from acute illnesses, nosocomial infections (NIs) are frequent. Their prevalence suggests the existence of as yet unknown conditions that may promote care-related infection. This study assessed whether the measurement of plasma chromogranin A, a stress-related protein involved in innate defense, is related to NI risk, and whether any chromogranin A-derived fragment included in vasostatin-I displays immunosuppressive activities related to AP-1 or NF-kappa B downregulation. At the clinical level, trauma patients and healthy controls were recruited to be eligible. Clinical histories were recorded, and standard biological tests (including plasma chromogranin A) were performed. For 9 randomly chosen patients and 16 controls, the time-dependent concentrations of chromogranin A (CGA) were assessed twice a day over 66 h. The data show that trauma patients present a higher value of CGA concentration during 66 h in comparison with healthy controls. In addition, patients maintaining this significant increase in CGA readily develop NIs. We therefore studied the effects of chromogranin A-derived peptides on monocytes, focusing on transcription factors that play a central role in inflammation. In vitro assay demonstrated that a chromogranin A-derived fragment (CGA47-70) displays a significant inhibition of NF-kappa B and AP-1 transcriptional activities in these cells. In conclusion, the occurrence of NI in trauma patients is associated with significantly increased plasma CGA concentrations. Downregulation of the two transcription factors by CGA47-70 might induce early acquired immune defect after a serious medical stress

Increased Expression of Bcl11b Leads to Chemoresistance Accompanied by G1 Accumulation

BACKGROUND: The expression of BCL11B was reported in T-cells, neurons and keratinocytes. Aberrations of BCL11B locus leading to abnormal gene transcription were identified in human hematological disorders and corresponding animal models. Recently, the elevated levels of Bcl11b protein have been described in a subset of squameous cell carcinoma cases. Despite the rapidly accumulating knowledge concerning Bcl11b biology, the contribution of this protein to normal or transformed cell homeostasis remains open. METHODOLOGY/PRINCIPAL FINDINGS: Here, by employing an overexpression strategy we revealed formerly unidentified features of Bcl11b. Two different T-cell lines were forced to express BCL11B at levels similar to those observed in primary T-cell leukemias. This resulted in markedly increased resistance to radiomimetic drugs while no influence on death-receptor apoptotic pathway was observed. Apoptosis resistance triggered by BCL11B overexpression was accompanied by a cell cycle delay caused by accumulation of cells at G1. This cell cycle restriction was associated with upregulation of CDKN1C (p57) and CDKN2C (p18) cyclin dependent kinase inhibitors. Moreover, p27 and p130 proteins accumulated and the SKP2 gene encoding a protein of the ubiquitin-binding complex responsible for their degradation was repressed. Furthermore, the expression of the MYCN oncogene was silenced which resulted in significant depletion of the protein in cells expressing high BCL11B levels. Both cell cycle restriction and resistance to DNA-damage-induced apoptosis coincided and required the histone deacetylase binding N-terminal domain of Bcl11b. The sensitivity to genotoxic stress could be restored by the histone deacetylase inhibitor trichostatine A. CONCLUSIONS: The data presented here suggest a potential role of BCL11B in tumor survival and encourage developing Bcl11b-inhibitory approaches as a potential tool to specifically target chemoresistant tumor cells