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A partir de la definición de los estándares de calidad se establece, en correspondencia a las actividades, los indicadores de gestión, evalúan a la calidad de forma general en la prestación de servicios. Lograr una adecuada gestión de los indicadores que evalúen la calidad en los servicios de las empresas en el sector terciario, resulta importante para el fortalecimiento y mejora continua de las organizaciones. Se determino los indicadores claves de calidad presentes en la gestión para la fabricación del servicio en las empresas del sector terciario.Para el estudio se parte de un análisis teórico de la gestión de calidad, estándares e indicadores, su importancia, los instrumentos y modelos principales que se utilizan. Se determinarán los instrumentos que permitan diagnosticar la situación actual, y determinar los indicadores de gestión que evalúen los estándares de calidad en la fabricación de servicios en empresas del sector terciario. Se desarrollará en primer lugar una investigación bibliográfica, que permita el análisis teórico del tema, estudiar las herramientas existentes en la literatura para el desarrollo metodológico de los instrumentos a aplicar; a continuación, a partir de una metodología propuesta, se realizará la propuesta de determinar indicadores claves que evalúen la calidad en la fabricación del servicio en las empresas del sector terciario. Se utiliza como recurso la información disponible en internet, los recursos económicos serán asumidos por parte de la investigadora.

BACKGROUND and AIMSExtra-hepatic biliary atresia (BA) is a pediatric liver disease with no approved medical therapy. Recent studies using human samples and experimental modeling suggest that glutathione redox metabolism and heterogeneity play a role in disease pathogenesis. We sought to dissect the mechanistic basis of liver redox variation and explore how other stress responses affect cholangiocyte injury in BA.METHODSWe performed quantitative in situ hepatic glutathione redox mapping in zebrafish larvae carrying targeted mutations in glutathione metabolism genes and correlated these findings with sensitivity to the plant-derived BA-linked toxin biliatresone. We also determined whether genetic disruption of HSP90 protein quality control pathway genes implicated in human BA altered biliatresone toxicity in zebrafish and human cholangiocytes. An in vivo screen of a known drug library was performed to identify novel modifiers of cholangiocyte injury in the zebrafish experimental BA model with subsequent validation.RESULTSGlutathione metabolism gene mutations caused regionally distinct changes in the redox potential of cholangiocytes that differentially sensitized them to biliatresone. Disruption of human BA-implicated HSP90 pathway genes sensitized zebrafish and human cholangiocytes to biliatresone-induced injury independent of glutathione. Phosphodiesterase-5 inhibitors (PDE5i) and other cGMP signaling activators worked synergistically with the glutathione precursor N- acetylcysteine (NAC) in preventing biliatresone-induced injury in zebrafish and human cholangiocytes. PDE5i enhanced proteasomal degradation and required intact HSP90 chaperone.CONCLUSIONRegional variation in glutathione metabolism underlies sensitivity to the biliary toxin biliatresone, and mirrors recently reported BA risk stratification linked to glutathione metabolism gene expression. Human BA can be causatively linked to genetic modulation of protein quality control. Combined treatment with NAC and cGMP signaling enhancers warrants further investigation as therapy for BA.What You Need to KnowBackground and ContextBiliary atresia (BA) is an obstructive fibrosing cholangiopathy that is the leading indication for liver transplantation in the pediatric population. There are no known treatments to prevent progressive liver injury after surgical restoration of bile flow.New FindingsThe authors identify factors that affect susceptibility of cholangiocytes to oxidative injury using a toxin-induced BA model. This information is used to validate genetic risk factors for human BA and identified PDE5i as a potential treatment for biliary atresia, either on its own or in combination with the anti-oxidant N-acetyl-cysteine.LimitationsThe work done in animal and cell culture models needs further study in human tissue-derived models and a larger cohort of BA patients.ImpactThe findings from this study provide a rationale for identifying new genetic risk factors that predispose to BA and for an interventional study to prevent progressive liver injury in this enigmatic disease.Short SummaryThis study uses zebrafish and human cell culture models to identify novel injury mechanisms, genetic risk factors and new therapies for the pediatric liver disease biliary atresia.

We report the first synthesis of the plant isoflavonoid biliatresone. The convergent synthesis has been applied to the synthesis of several analogs, which have facilitated the first structure-activity relationship study for this environmental toxin that, on ingestion, recapitulates the phenotype of biliary atresia.

In this work, two specific, sensitive, and rapid analytical methods were developed. One of them was for the determination of ketorolac in a hospital wastewater treatment plant where there is no interference with other organic substances; the other one was for the determination of the degradation kinetics in aqueous medium. Ketorolac was extracted from wastewater samples through solid-phase extraction (SPE) cartridges, then it was identified and quantified by high-performance liquid chromatography (HPLC). Ketorolac was detected in concentrations between 0.1376 and 0.2667 μg/L. Photolytic degradation was performed on aqueous solutions of ketorolac tromethamine reference substance, at a concentration of 50 μg/mL. Samples were in direct contact with ultraviolet light in a dark chamber, equipped with two mercury lamps (254 nm) at a radiation source of 15 W. The results of the photolytic degradation were adjusted to a first-order model, obtaining a half-life of 4.8 hrs.

Drugs used for the treatment of castration resistant prostate cancer (CRPC) include Abiraterone acetate (Zytiga®) and Enzalutamide (XTANDI®). However, these drugs provide clinical benefit in metastatic disease for only a brief period before drug resistance emerges. One mechanism of drug resistance involves the overexpression of type 5 17-β-hydroxysteroid dehydrogenase (aldo-keto reductase 1C3 or AKR1C3), a major enzyme responsible for the formation of intratumoral androgens that activate the androgen receptor (AR). 3-((4-Nitronaphthalen-1-yl)amino)benzoic acid 1 is a “first-in-class” AKR1C3 competitive inhibitor and AR antagonist. Compound 1 was compared in a battery of in vitro studies with structurally related N-naphthyl-aminobenzoates, and AKR1C3 targeted therapeutics e.g. GTx-560 and ASP9521, as well as with R-bicalutamide, enzalutamide and abiraterone acetate. Compound 1 was the only naphthyl derivative that was a selective AKR1C3 inhibitor and AR antagonist in direct competitive binding assays and in AR driven reporter gene assays. GTx-560 displayed weak activity as a direct AR antagonist but had high potency in the AR reporter gene assay consistent with its ability to inhibit the co-activator function of AKR1C3. By contrast ASP9521 did not act as either an AR antagonist or block AR reporter gene activity. Compound 1 was the only compound that showed comparable potency to inhibit AKR1C3 and act as a direct AR antagonist. Compound 1 blocked the formation of testosterone in LNCaP-AKR1C3 cells, and the expression of PSA driven by the AKR1C3 substrate (4-androstene-3,17-dione) and by an AR agonist, 5α-dihydrotestosterone consistent with its bifunctional role. Compound 1 blocked the nuclear translocation of the AR at similar concentrations to enzalutamide and caused disappearance of the AR from cell lysates. R-biaclutamide and enzalutamide inhibited AKR1C3 at concentrations 200x greater than compound 1, suggesting that its bifunctionality can be explained by a shared pharmacophore that can be optimized.

The BRAF kinase, within the mitogen activated protein kinase (MAPK) signaling pathway, harbors activating mutations in about half of melanomas and to a significant extent in many other cancers. A single valine to glutamic acid substitution at residue 600 (BRAFV600E) accounts for about 90% of these activating mutations. While BRAFV600E-selective small molecule inhibitors, such as debrafenib and vemurafenib, have shown therapeutic benefit, almost all patients develop resistance. Resistance often arises through reactivation of the MAPK pathway, typically through mutation of upstream RAS, downstream MEK, or splicing variants. RAF kinases signal as homo- and heterodimers, and another complication associated with small molecule BRAFV600E inhibition is drug-induced allosteric activation of a wild-type RAF subunit (BRAF or CRAF) of the kinase dimer, a process called "transactivation" or "paradoxical activation." Here, we used BRAFV600E and vemurafenib as a model system to develop chemically linked kinase inhibitors to lock RAF dimers in an inactive conformation that cannot undergo transactivation. This structure-based design effort resulted in the development of Vem-BisAmide-2, a compound containing two vemurafenib molecules connected by a bis amide linker. We show that Vem-BisAmide-2 has comparable inhibitory potency as vemurafenib to BRAFV600E both in vitro and in cells but promotes an inactive dimeric BRAFV600E conformation unable to undergo transactivation. The crystal structure of a BRAFV600E/Vem-BisAmide-2 complex and associated biochemical studies reveal the molecular basis for how Vem-BisAmide-2 mediates selectivity for an inactive over an active dimeric BRAFV600E conformation. These studies have implications for targeting BRAFV600E/RAF heterodimers and other kinase dimers for therapy.