Анализ системы управления качеством на региональном уровне

Постоянное совершенствование системы управления качеством и повышения качества продукции является важным условием поддержания высокой конкурентоспособности предприятия. Таким образом, качество выступает главным фактором конкурентоспособности, определяет прямую взаимосвязь между качеством и эффективностью производства.Continuous improvement of the quality management system and product quality improvement is an important condition for maintaining high competitiveness of the enterprise. Thus, quality is the main factor of competitiveness and determines the direct relationship between quality and production efficiency

Alcohol and Obesity: A Dangerous Association for Fatty Liver Disease

Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the most frequent chronic liver disorders, and their advanced forms - alcoholic steatohepatitis and nonalcoholic steatohepatitis - are the most frequent conditions leading to liver cirrhosis and hepatocellular carcinoma worldwide. NAFLD is considered as the hepatic manifestation of the metabolic syndrome. With the pandemic rise of obesity, the incidence of NAFLD is also further increasing, and considering the life style in modern societies, there is a significant overlap of (risk factors causing) NAFLD and (alcohol consumption predisposing for) ALD at least in Western countries. Epidemiological studies propose a causative link between chronic alcohol consumption and progressive liver disease in obese individuals. Furthermore, experimental studies indicate combined pathological effects of alcohol and obesity or fatty acid levels, respectively, on hepatocellular lipid accumulation and injury as well as hepatic inflammation, fibrosis and cancerogenesis. Notably, these combined pathological effects are in part additive but partly even synergistic. And importantly, alcohol does already exhibit synergistic pathological effects with obesity at moderate doses. This indicates significant differences in the dose threshold for hepatotoxic alcohol effects in lean and obese subjects and herewith also has important implications for recommendations for 'safe' alcohol consumption. The purpose of this brief review is to update the knowledge on the combined effects of alcohol and obesity on the development and progression of liver disease. Undoubtedly, alcohol and the metabolic syndrome appear as a dangerous mix, and there are important interactive effects of either condition with regard to crucial triggers of liver injury. (C) 2016 S. Karger AG, Base

Obesity and Fatty Liver Are 'Grease' for the Machinery of Hepatic Fibrosis

Nonalcoholic fatty liver disease (NAFLD) starts with hepatic steatosis, which can progress with inflammation to nonalcoholic steatohepatitis, and a subset of patients develop progressive fibrosis and ultimately cirrhosis. In the majority of cases, NAFLD is associated with (components of) the metabolic syndrome. Obesity, diabetes and hepatic steatosis are also independent risk factors for hepatic fibrosis in different chronic liver diseases. However, the question is whether it is actually nonalcoholic steatohepatitis and not ‘simple’ steatosis that promotes fibrosis progression based on hepatocellular injury. In this review, the concept will be put forward that (1) hepatic steatosis per se is profibrogenic, and (2) that in NAFLD development and progression of hepatic fibrosis is not simply determined by (the degree of) hepatic inflammation. In addition to the liver, this view is expanded to other organs affected by the metabolic syndrome, which affects hepatic injury and fibrosis also via extrahepatic pathophysiological alterations. In conclusion, fatty liver and the metabolic syndrome, respectively, have to be recognized as significant lubricants of hepatic fibrosis, and simple hepatic steatosis cannot be considered as benign

Cylindromatosis gene CYLD regulates hepatocyte growth factor expression in hepatic stellate cells through interaction with histone deacetylase 7

Hepatic fibrosis is considered as a physiological wound‐healing response to liver injury. The process involves several factors, such as hepatocyte growth factor (HGF), which restrains hepatic injury and facilitates reversibility of fibrotic reaction in response to an acute insult. Chronic liver injury and sustained inflammation cause progressive fibrosis and, ultimately, organ dysfunction. The mechanisms tipping the balance from restoration to progressive liver tissue scarring are not well understood. In the present study, we identify a mechanism in which the tumor‐suppressor gene, cylindromatosis (CYLD), confers protection from hepatocellular injury and fibrosis. Mice lacking CYLD (CYLD−/−) were highly susceptible to hepatocellular damage, inflammation, and fibrosis and revealed significantly lower hepatic HGF levels, compared to wild‐type (WT) animals. Exogenous application of HGF rescued the liver injury phenotype of CYLD−/− mice. In the absence of CYLD, gene transcription of HGF in hepatic stellate cells was repressed through binding of histone deacetylase 7 (HDAC7) to the promoter of HGF. In WT cells, CYLD removed HDAC7 from the HGF promoter and induced HGF expression. Of note, this interaction occurred independently of the deubiquitinating activity of CYLD. Conclusions: Our findings highlight a novel link between CYLD and HDAC7, offering mechanistic insight into the contribution of these proteins to progression of liver disease. Thus, through regulation of HGF level, CYLD ameliorates hepatocellular damage and liver fibrogenesis

Histone Deacetylase Expressions in Hepatocellular Carcinoma and Functional Effects of Histone Deacetylase Inhibitors on Liver Cancer Cells In Vitro

Hepatocellular carcinoma (HCC) is a leading cause for deaths worldwide. Histone deacetylase (HDAC) inhibition (HDACi) is emerging as a promising therapeutic strategy. However, most pharmacological HDACi unselectively block different HDAC classes and their molecular mechanisms of action are only incompletely understood. The aim of this study was to systematically analyze expressions of different HDAC classes in HCC cells and tissues and to functionally analyze the effect of the HDACi suberanilohydroxamic acid (SAHA) and trichostatin A (TSA) on the tumorigenicity of HCC cells. The gene expression of all HDAC classes was significantly increased in human HCC cell lines (Hep3B, HepG2, PLC, HuH7) compared to primary human hepatocytes (PHH). The analysis of HCC patient data showed the increased expression of several HDACs in HCC tissues compared to non-tumorous liver. However, there was no unified picture of regulation in three different HCC patient datasets and we observed a strong variation in the gene expression of different HDACs in tumorous as well as non-tumorous liver. Still, there was a strong correlation in the expression of HDAC class IIa (HDAC4, 5, 7, 9) as well as HDAC2 and 8 (class I) and HDAC10 (class IIb) and HDAC11 (class IV) in HCC tissues of individual patients. This might indicate a common mechanism of the regulation of these HDACs in HCC. The Cancer Genome Atlas (TCGA) dataset analysis revealed that HDAC4, HDAC7 and HDAC9 as well as HDAC class I members HDAC1 and HDAC2 is significantly correlated with patient survival. Furthermore, we observed that SAHA and TSA reduced the proliferation, clonogenicity and migratory potential of HCC cells. SAHA but not TSA induced features of senescence in HCC cells. Additionally, HDACi enhanced the efficacy of sorafenib in killing sorafenib-susceptible cells. Moreover, HDACi reestablished sorafenib sensitivity in resistant HCC cells. In summary, HDACs are significantly but differently increased in HCC, which may be exploited to develop more targeted therapeutic approaches. HDACi affect different facets of the tumorigenicity of HCC cells and appears to be a promising therapeutic approach alone or in combination with sorafenib

Complex Formation with Monomeric α-Tubulin and Importin 13 Fosters c-Jun Protein Stability and Is Required for c-Jun’s Nuclear Translocation and Activity

Microtubules are highly dynamic structures, which consist of α- and β-tubulin heterodimers. They are essential for a number of cellular processes, including intracellular trafficking and mitosis. Tubulin-binding chemotherapeutics are used to treat different types of tumors, including malignant melanoma. The transcription factor c-Jun is a central driver of melanoma development and progression. Here, we identify the microtubule network as a main regulator of c-Jun activity. Monomeric α-tubulin fosters c-Jun protein stability by protein–protein interaction. In addition, this complex formation is necessary for c-Jun’s nuclear localization sequence binding to importin 13, and consequent nuclear import and activity of c-Jun. A reduction in monomeric α-tubulin levels by treatment with the chemotherapeutic paclitaxel resulted in a decline in the nuclear accumulation of c-Jun in melanoma cells in an experimental murine model and in patients’ tissues. These findings add important knowledge to the mechanism of the action of microtubule-targeting drugs and indicate the newly discovered regulation of c-Jun by the microtubule cytoskeleton as a novel therapeutic target for melanoma and potentially also other types of cancer