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ATP-sensitive potassium channels (K-ATP channels) play a key role in adjusting the membrane potential to the metabolic state of cells. They result from the unique combination of two proteins: the sulfonylurea receptor (SUR), an ATP-binding cassette (ABC) protein, and the inward rectifier K+ channel Kir6.2. Both subunits associate to form a heterooctamer (4 SUR/4 Kir6.2). SUR modulates channel gating in response to the binding of nucleotides or drugs and Kir6.2 conducts potassium ions. The activity of K-ATP channels varies with their localization. In pancreatic β-cells, SUR1/Kir6.2 channels are partly active at rest while in cardiomyocytes SUR2A/Kir6.2 channels are mostly closed. This divergence of function could be related to differences in the interaction of SUR1 and SUR2A with Kir6.2. Three residues (E1305, I1310, L1313) located in the linker region between transmembrane domain 2 and nucleotide-binding domain 2 of SUR2A were previously found to be involved in the activation pathway linking binding of openers onto SUR2A and channel opening. To determine the role of the equivalent residues in the SUR1 isoform, we designed chimeras between SUR1 and the ABC transporter multidrug resistance-associated protein 1 (MRP1), and used patch clamp recordings on Xenopus oocytes to assess the functionality of SUR1/MRP1 chimeric K-ATP channels. Our results reveal that the same residues in SUR1 and SUR2A are involved in the functional association with Kir6.2, but they display unexpected side-chain specificities which could account for the contrasted properties of pancreatic and cardiac K-ATP channels. PMID:26416970
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Survivin, as an anti-apoptotic protein and a cell cycle regulator, is recently gaining importance for its regenerative potential in salvaging injured hypoxic cells of vital organs such as heart. Different strategies are being employed to upregulate survivin expression in dying hypoxic cardiomyocytes. We investigated the cardioprotective potential of a cell permeable survivin mutant protein SurR9C84A, for the management of hypoxia mediated cardiomyocyte apoptosis, in a novel and clinically relevant model employing primary human cardiomyocytes (HCM). The aim of this research work was to study the efficacy and mechanism of SurR9C84A facilitated cardioprotection and regeneration in hypoxic HCM. To mimic hypoxicmore microenvironment in vitro, well characterized HCM were treated with 100 µm (48 h) cobalt chloride to induce hypoxia. Hypoxia induced (HI) HCM were further treated with SurR9C84A (1 µg/mL) in order to analyse its cardioprotective efficacy. Confocal microscopy showed rapid internalization of SurR9C84A and scanning electron microscopy revealed the reinstatement of cytoskeleton projections in HI HCM. SurR9C84A treatment increased cell viability, reduced cell death via, apoptosis (Annexin-V assay), and downregulated free cardiac troponin T and MMP-9 expression. SurR9C84A also upregulated the expression of proliferation markers (PCNA and Ki-67) and downregulated mitochondrial depolarization and ROS levels thereby, impeding cell death. Human Apoptosis Array further revealed that SurR9C84A downregulated expression of pro-apoptotic markers and augmented expression of HSPs and HTRA2/Omi. SurR9C84A treatment led to enhanced levels of survivin, VEGF, PI3K and pAkt. SurR9C84A proved non-toxic to normoxic HCM, as validated through unaltered cell proliferation and other marker levels. Its pre-treatment exhibited lesser susceptibility to hypoxia/damage. SurR9C84A holds a promising clinical potential for human cardiomyocyte survival and proliferation following hypoxic
We analyzed the long-term outcome of patients operated for esophageal cancer and evaluated the new seventh edition of the tumor-node-metastasis classification for cancers of the esophagus. Retrospective analysis and new classification. Data of a single-center cohort of 2920 patients operated for cancers of the esophagus according to the seventh edition are presented. Statistical methods to evaluate survival and the prognostic performance of the staging systems included Kaplan-Meier analyses and time-dependent receiver-operating-characteristic-analysis. Union Internationale Contre le Cancer stage, R-status, histologic tumor type and age were identified as independent prognostic factors for cancers of the esophagus. Grade and tumor site, additional parameters in the new American Joint Cancer Committee prognostic groupings, were not significantly correlated with survival. Esophageal adenocarcinoma showed a significantly better long-term prognosis after resection than squamous cell carcinoma (P
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We have demonstrated recently that the tumor-to-blood standard uptake ratio (SUR) is superior to tumor standardized uptake value (SUV) as a surrogate of the metabolic uptake rate K m of fluorodeoxyglucose (FDG), overcoming several of the known shortcomings of the SUV approach: excellent linear correlation of SUR and K m from Patlak analysis was found using dynamic imaging of liver metastases. However, due to the perfectly standardized uptake period used for SUR determination and the comparatively short uptake period, these results are not automatically valid and applicable for clinical whole-body examinations in which the uptake periods (T) are distinctly longer and can vary considerably. Therefore, the aim of this work was to investigate the correlation between SUR derived from clinical static whole-body scans and K m-surrogate derived from dual time point (DTP) measurements. DTP (18)F-FDG PET/CT was performed in 90 consecutive patients with histologically proven non-small cell lung cancer (NSCLC). In the PET images, the primary tumor was delineated with an adaptive threshold method. For determination of the blood SUV, an aorta region of interest (ROI) was delineated manually in the attenuation CT and transferred to the PET image. Blood SUV was computed as the mean value of the aorta ROI. SUR values were computed as ratio of tumor SUV and blood SUV. SUR values from the early time point of each DTP measurement were scan time corrected to 75 min postinjection (SURtc). As surrogate of K m, we used the SUR(T) slope, K slope, derived from DTP measurements since it is proportional to the latter under the given circumstances. The correlation of SUV and SURtc with K slope was investigated. The prognostic value of SUV, SURtc, and K slope for overall survival (OS) and progression-free survival (PFS) was investigated with univariate Cox regression in a homogeneous subgroup (N=31) treated with primary chemoradiation. Correlation analysis revealed for both, SUV and SURtc, a
Quebec's HIV epidemic persists, particularly among men who have sex with men (MSM) and in Montreal. Increasing access to HIV testing is necessary and community-based rapid testing offers one strategy. This paper examines the clienteles and activities of a rapid HIV testing site in Montreal, the pilot project Actuel sur Rue. Comparative analyses were conducted with 1357 MSM, 147 heterosexual men and 64 women who visited Actuel sur Rue between July 2012 and November 2013 on socio-demographics, health, drug use, sexual practices/infection and HIV testing/prevention. Significant group differences were observed in each category. Actuel sur Rue received 1901 clients, conducted 1417 rapid HIV tests and tested 77 never-tested individuals. Rapid testing produced a high reactive rate (2%). Only 1/28 of those with reactive tests had no previous HIV testing, and 36% had used post-exposure prophylaxis, suggesting missed opportunities for prevention. Findings highlight diverse client vulnerability profiles and the relevance of checkpoints and further prevention efforts. The Author(s) 2016.
L'amelioration des performances des roues de turbines hydrauliques a fait l'objet de plusieurs etudes. Dans ce memoire, on s'est interesse a l'effet de la teneur en carbone du materiau de base de type CA6NM des aubes de turbines sur la microstructure et les proprietes mecaniques en general et en particulier sur le comportement en fatigue propagation. De maniere a bien atteindre cet objectif, on a choisi trois differentes nuances d'acier a faible 0.018% C, moyenne 0.033% C et elevee 0.067% C teneurs en carbone. Le 0.018% C et 0.067% C ont ete fabriques par le meme facturier et ils ont subi des traitements thermiques differents. De meme, le 0.033% C a subi des traitements thermiques differents des deux autres apres avoir ete coule par un autre fabricant. Afin d'effacer l'historique des traitements thermiques prealablement effectues et d'avoir la meme taille de grains parents austenitiques (GPA), on a austenitise les trois nuances d'acier a la meme temperature 1040C, a differentes periodes suivant la teneur en carbone. Apres avoir homogeneise la GPA, on a entame le revenu. Le carbone a une influence sur la microstructure revenue notamment la quantite d'austenite de reversion ainsi que sur sa stabilite thermique et mecanique. Pour mettre en evidence l'effet de la teneur en carbone, on a trouve raisonnable d'isoler les effets relies a la temperature de revenu, en particulier la formation d'austenite de reversion. En effet, on a choisi deux temperatures de revenu. La premiere temperature est a 550C pendant 2h imposee aux trois materiaux afin d'avoir une microstructure sans austenite de reversion. La deuxieme temperature choisie est a 610C pour avoir un maximum et une identique quantite d'austenite de reversion sans presence de martensite fraiche. A la lumiere de ces deux microstructures, nous pouvons etablir une relation entre les proprietes mecaniques du CA6NM et la teneur en carbone, ainsi qu'entre les effets de la presence ou non d'austenite de reversion sur les 2ff7e9595c
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