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Hepatocyte growth factor (HGF) is a pleiotrophic factor involved in cellular proliferation, migration and morphogenesis. HGF is required for normal tissue and organ development during embryogenesis, but in the adult HGF has been demonstrated to drive normal tissue repair and inhibit fibrotic remodeling. HGF has two naturally occurring human isoforms as a result of alternative splicing, NK1 and NK2. While NK1 has been defined as an agonist for HGF receptor, Met, NK2 is defined as a partial Met antagonist. Furthermore, under conditions of fibrotic remodeling, NK2 is still expressed while full length HGF is suppressed. Furthermore, the mechanism by which NK2 partially signals through Met is not completely understood. Here, we investigated the mitogenic, motogenic, and anti-apoptotic activities of NK2 compared with full length HGF in primary human bronchial epithelial cells (BEpC) and bovine pulmonary artery endothelial cells (PAEC). In human BEpC, NK2 partial activated Met, inducing Met phosphorylation at Y1234/1235 in the tyrosine-kinase domain but not at Y1349 site in the multifunctional docking domain. Partial phosphorylation of Met by NK2 resulted in activation of MAPK and STAT3, but not AKT. This correlated with motogenesis and survival in a MAPK-dependent manner, but not cell proliferation. Overexpression of a constitutively active AKT complemented NK2 signaling, allowing NK2 to induce cell proliferation. These data indicate that NK2 and HGF drive motogenic and anti-apoptotic signaling but only HGF drives cell proliferation by activating AKT-pathway signaling. These results have implications for the biological consequences of differential regulation of the two isoforms under pro-fibrotic conditions. [ABSTRACT FROM AUTHOR]

Background The duration of oral antibiotic acne therapy for adolescents compared with guidelines was recently investigated; however it was uncertain if duration of antibiotics for adult acne therapy differed. Objective This study aimed to evaluate duration of oral antibiotics for adult acne compared with guidelines and determine possible cost-savings. Methods This was a retrospective cohort study of MarketScan Commercial Claims and Encounters database that incorporated claims data to determine duration and costs of antibiotic treatment among adults ages 21 years and older. Results Of 17,448 courses, 84.5% (14,737) aligned with duration guidelines, although 12,040 (69.0%) courses did not include concomitant topical retinoid therapy. Mean savings of $592.26 per person could result if prolonged courses met guidelines. Mean (median) costs of generic and branded formulations for the most frequent course duration (90-179 days) were $103.77 ($54.27) and $1421.61 ($1462.25), respectively. Limitations Actual patient prescription adherence is uncertain and database lacks information regarding acne severity, patient physical characteristics, and clinical outcomes. Conclusions The majority of oral antibiotic course durations follow guidelines, although topical retinoids are underused. Costs of antibiotic therapy were lower for shorter courses and those using generic medications; the cost-effectiveness of these modifications has not been investigated. [ABSTRACT FROM AUTHOR]

Hepatocyte growth factor (HGF) signaling promotes tumor invasiveness in renal cell carcinoma (RCC) and other cancers. In clear cell RCC, VHL loss generates pseudohypoxia that exacerbates HGF-driven invasion through β-catenin deregulation. Hypoxia also enhances HGF-driven invasiveness by papillary RCC cells, but in the absence of VHL, loss signaling integration involves three parallel routes: 1) hypoxia-induced reactive oxygen species production and decreased DUSP2 expression, leading to enhanced mitogen-activated protein kinase (MAPK) cascade activation; 2) reactive oxygen species-induced diacylglycerol production by phospholipase Cγ, leading to protein kinase C activation and increased protein phosphatase-2A activity, thereby suppressing HGF-induced Akt activation; and 3) a profound shift from HGF-enhanced, proliferation- oriented metabolism to autophagy-dependent invasion and suppression of proliferation. This tripartite signaling integration was not unique to RCC or HGF; in RCC cells, invasive synergy induced by the combination of hypoxia and epidermal growth factor occurred through the same mechanism, and in estrogen receptor-positive breast cancer cells, this mechanism was suppressed in the absence of estrogen. These results define the molecular basis of growth factor and hypoxia invasive synergy in VHL-competent papillary RCC cells, illustrate the plasticity of invasive and proliferative tumor cell states, and provide signaling profiles by which they may be predicted. [ABSTRACT FROM AUTHOR]

Background: Duration of oral antibiotic therapy in acne has not been widely studied. Recent guidelines suggest it should be limited to 3 to 6 months. Objective: We sought to compare the duration of oral antibiotic use with recent guidelines and determine the potential cost-savings related to shortened durations. Methods: This is a retrospective cohort study from the MarketScan Commercial Claims and Encounters database. Claims data were used to determine duration and costs of antibiotic therapy. Results: The mean course duration was 129 days. The majority (93%) of courses were less than 9 months. Among the 31,634 courses, 18,280 (57.8%) did not include concomitant topical retinoid therapy. The mean (95% confidence interval) duration with and without topical retinoid use was 133 (131.5-134.7) days and 127 (125.4-127.9) days, respectively. The mean excess direct cost of antibiotic treatment for longer than 6 months was $580.99/person. Limitations: Claims cannot be attributed to a specific diagnosis or provider. The database does not provide information on acne severity. Conclusions: Duration of antibiotic use is decreasing when compared with previous data. However, 5547 (17.53%) courses exceeded 6 months, highlighting an opportunity for reduced antibiotic use. If courses greater than 6 months were shortened to 6 months, savings would be $580.99/person. [Copyright &y& Elsevier]

The effect of anthraquinone disulfonate (AQDS) on the decolorization of the azo dye Reactive Red 198 (RR198) and the anthraquinone dye Reactive Blue 4 (RB4), as well as the effect of RB4 on the decolorization of RR198, both AQDS and RB4 serving as redox mediators, was assessed. An anaerobic, continuous-flow, fluidized-bed bioreactor with an immobilized halo tolerant mixed culture was used in this study. All tests were performed at a reactor temperature of 35°C, a hydraulic retention time of 6.1 h, pH 7.2±0.1, with glucose used as the carbon and electron source. AQDS at relatively low influent concentrations (10-150 µM) enhanced the extent of RR198 reduction, but had a negligible effect on the biodecolorization of RB4. At an equal concentration of 50 µM, RB4 and AQDS had a similar enhancing effect on the biodecolorization of the azo dye RR198. Therefore, anthraquinone dyes can serve as redox mediators in mixed spent textile dye baths potentially leading to enhanced reductive biodecolorization rate and extent of other types of dyes (i.e., azo dyes). [ABSTRACT FROM AUTHOR]

Reductive decolorization of two anthraquinone reactive dyes (Reactive Blue 4, RB4; Reactive Blue 19, RB19) under methanogenic conditions was performed using a mixed, methanogenic culture. Decolorization of the two anthraquinone dyes was investigated to evaluate the rate and extent of color removal as well as to assess possible toxic effects of the dyes and their decolorization product(s) on the methanogenic culture as a function of initial dye concentration ranging from 50 to 300 mg L−1. A dextrin/peptone mixture was used as the carbon and electron source. A high rate and extent of color removal was achieved ranging from 4.3 to 29.9 mg L−1 h−1 and 73–91% for RB4, and 13.0–74.4 mg L−1 h−1 and 90–95% for RB19. Initial RB4 concentrations up to 100 mg L−1 did not result in any significant inhibition. Both the 200 and 300 mg L−1 RB4-amended cultures, and all RB19-amended cultures resulted in severe inhibition of both acidogenesis and methanogenesis. Sequential dye addition at 300 mg L−1 for both RB4 and RB19 resulted in accumulation of volatile fatty acids (VFAs) and a very low methane production at the end of the first dye addition after 44 days of incubation. However, at the end of the second dye addition, after a relatively long incubation (384 days), recovery of methanogens in the RB4-amended culture was observed in contrast to the complete inhibition of methanogenesis in the RB19-amended culture. Therefore, RB19 resulted in a higher degree of inhibition of both acidogenesis and methanogenesis than RB4. Addition of dextrin/peptone to dye-inhibited cultures resulted in acidogenesis and a gradual recovery of methanogenesis (mainly aceticlastic methanogenesis) in the RB4-inhibited culture, and a slow recovery of acidogenesis but no recovery of methanogenesis in the RB19-inhibited culture. In contrast, addition of 80% H2−20% CO2 gas to dye-inhibited cultures resulted in recovery of hydrogenotrophic methanogenesis in both the RB4- and RB19-inhibited cultures. In spite of the relatively severe inhibition of the two anthraquinone dyes on the mixed, methanogenic culture, a high extent of color removal was achieved. [Copyright &y& Elsevier]

Abstract: The protease angiotensin converting enzyme (ACE) is a key regulator of blood pressure homeostasis, and is responsible for proteolytic activation of angiotensin I to angiotensin II (Ang II), a potent vasoconstrictor, and proteolytic inactivation of bradykinin, a vasodilator. Recent studies have also implicated ACE and Ang II dysregulation in the progression of fibrotic tissue diseases. Although many studies have utilized bovine tissues and cells for investigating the regulation of ACE gene expression, the bovine ACE promoter has not been previously characterized. Here we present the analysis of the bovine ACE promoter. We investigated cis elements regulated by phorbol 12-myristate 13-acetate (PMA). Sequence analysis shows that the bovine ACE promoter contains several putative binding sites for the transcription factors ATF-2, Ets-1, Egr-1 and SP1/SP3. Chromatin immunoprecipitation (ChIP) indicated that the activation of the bovine ACE promoter by PMA involves histone H4 acetylation, and that PMA induced Egr-1 and ATF-2 binding to the ACE promoter, whereas Ets-1 binding was suppressed by PMA. The regulatory roles of these transcription factors in the bovine ACE gene regulation were confirmed by co-expression of either wild type or dominant negative transcription factors with the luciferase reporter constructs. The bovine and human ACE promoters share similarities in binding sites for transcription factors and PMA regulation within the core regions but contain significant differences in the distal promoter regions. [Copyright &y& Elsevier]

Summary: The natural product englerin A (EA) binds to and activates protein kinase C-θ (PKCθ). EA-dependent activation of PKCθ induces an insulin-resistant phenotype, limiting the access of tumor cells to glucose. At the same time, EA causes PKCθ-mediated phosphorylation and activation of the transcription factor heat shock factor 1, an inducer of glucose dependence. By promoting glucose addiction, while simultaneously starving cells of glucose, EA proves to be synthetically lethal to highly glycolytic tumors. [ABSTRACT FROM AUTHOR]

Abstract: A laboratory anaerobic membrane bioreactors (AnMBRs) (10L volume) was operated at 30°C and fed with artificial sewage containing 30% protein at COD loading rate 5.1kg/m3-d to investigate membrane fouling with two membranes. Biomass attached to the membrane surface and formed a foulant layer on the membrane. The foulant layers from polyvinylidene fluoride ultrafiltration membranes coated with PEBAX (cPVDF) and an uncoated polyetherimide (PEI) ultrafiltration membranes were analyzed and compared to suspended biomass in the reactor, using terminal restriction fragments (T-RFs) of the 16S rRNA gene and a clone library. One species of OP11 bacteria was present at high relative abundance in the foulant layers of both membranes. By contrast, Bacteroidetes and Firmicutes (LGC) species were present at low relative abundance in the foulant layers but high relative abundance in the suspended biomass. Similar differences were observed for other species. The results suggest that some minority species like OP11 play a direct role in fouling by attaching to the membrane surface while others, including some that likely play a major role in the metabolism of influent organics, play a less important or indirect role. In the AnMBR, the EPS was predominately proteinaceous. EPS and microbial cells of the foulant layer contributed to membrane fouling. The results also indicate that fouling of PEI was faster than cPVDF and this reaffirm the importance of the membrane material in fouling. [ABSTRACT FROM AUTHOR]