Enhancement of autophagy is a potential modality for tumors refractory to radiotherapy

Radiotherapy is a well-established treatment for cancer. However, the existence of radioresistant cells is one of the major obstacles in radiotherapy. In order to understand the mechanism of cellular radioresistance and develop more effective radiotherapy, we have established clinically relevant radioresistant (CRR) cell lines, which continue to proliferate under daily exposure to 2 Gray (Gy) of X-rays for >30 days. X-ray irradiation significantly induced autophagic cells in parental cells, which was exiguous in CRR cells, suggesting that autophagic cell death is involved in cellular radiosensitivity. An autophagy inducer, rapamycin sensitized CRR cells to the level of parental cells and suppressed cell growth. An autophagy inhibitor, 3-methyladenine induced radioresistance of parental cells. Furthermore, inhibition of autophagy by knockdown of Beclin-1 made parental cells radioresistant to acute radiation. These suggest that the suppression of autophagic cell death but not apoptosis is mainly involved in cellular radioresistance. Therefore, the enhancement of autophagy may have a considerable impact on the treatment of radioresistant tumor

Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.</p

DIPLOMARBEIT An Evaluation of Enterprise Application Integration Solutions and the Role of Web Services

The worldwide globalization and the rapidly changing consumer demands challenge the e-Business market. Flexible business processes are the basis to remain competitive. Thus, the way of thinking about information comes from business and not from technology. This causes a growing dependency on information systems entailing larger and more complex IT infrastructures. However, such IT infrastructures consist of many isolated solutions whereby new applications are often newly developed although the required functionalities are already provided by legacy systems. In order to find a key, integration becomes more and more important. Unfortunately, systems are usually integrated via proprietary point-to-point connections to implement one specific process without any adaptability which causes a multiplicity of interconnections. Therefore, integration becomes a major aspect within development issues nowadays which evokes a new buzzword- enterprise application integration, shortly EAI. The main idea behind an EAI system is that external resources are integrated onl

On the rate of black hole binary mergers in galactic nuclei due to dynamical hardening

We assess the contribution of dynamical hardening by direct three-body scattering interactions to the rate of stellar-mass black hole binary (BHB) mergers in galactic nuclei. We derive an analytic model for the single-binary encounter rate in a nucleus with spherical and disc components hosting a super-massive black hole (SMBH). We determine the total number of encounters NGW needed to harden a BHB to the point that inspiral due to gravitational wave emission occurs before the next three-body scattering event. This is done independently for both the spherical and disc components. Using a Monte Carlo approach, we refine our calculations for NGW to include gravitational wave emission between scattering events. For astrophysically plausible models, we find that typically NGW ≲ 10. We find two separate regimes for the efficient dynamical hardening of BHBs: (1) spherical star clusters with high central densities, low-velocity dispersions, and no significant Keplerian component and (2) migration traps in discs around SMBHs lacking any significant spherical stellar component in the vicinity of the migration trap, which is expected due to effective orbital inclination reduction of any spherical population by the disc. We also find a weak correlation between the ratio of the second-order velocity moment to velocity dispersion in galactic nuclei and the rate of BHB mergers, where this ratio is a proxy for the ratio between the rotation- and dispersion-supported components. Because discs enforce planar interactions that are efficient in hardening BHBs, particularly in migration traps, they have high merger rates that can contribute significantly to the rate of BHB mergers detected by the advanced Laser Interferometer Gravitational-Wave Observatory

Serum leptin levels correlate negatively with the capacity of vitamin D to modulate the in vitro cytokines production by CD4+ T cells in asthmatic patients

Both obesity and low vitamin D levels have been associated with allergic asthma (AA) severity. In the present study, severity of AA was associated with obesity but to the in vitro IgE production. In those patients, higher levels of IL-5, IL-6 and IL-17 were quantified in CD4+ T-cell cultures as compared with patients with mild and moderate AA. In addition, the lowest IL-10 levels were detected in the cell cultures from patients with a worse prognosis. Interestingly, the occurrence of AA elevates the plasma levels of leptin, and this adipokine was positively correlated with the release of IL-5, IL-6 and IL-17, but inversely correlated with IL-10 production, by CD4+ T-cells from patients. In AA-derived CD4+ T-cell cultures, 1,25(OH)2D3 was less efficient at inhibiting IL-5, IL-6 and IL-17 production, and up regulating IL-10 release, as those from healthy subjects. Interestingly, the in vitro immunomodulatory effects of vitamin D were inversely correlated with serum leptin levels. In summary, our findings suggested that obesity, probably due to the overproduction of leptin, negatively impacts AA as it favors imbalance between Th2/Th17 and regulatory phenotypes. The deleterious effects of leptin may also be due to its ability to counter-regulate the immunosuppressive effects of vitamin D

Associação entre o estado de saúde autorreferido de adultos e a área de localização do domicílio: uma análise de regressão logística ordinal usando a PNAD 2008 Association between self-reported state of health among adults and the location of the home: ordinal logistic regression analysis using PNAD 2008

O ambiente urbano influencia a saúde e os comportamentos humanos, sendo necessário um melhor entendimento dos determinantes da saúde das populações que vivem nas cidades. A partir dos dados da Pesquisa Nacional por Amostra de Domicílios (PNAD) 2008, usando modelos logísticos ordinais incorporando o plano amostral, o presente artigo avalia a associação entre a área de localização do domicílio (urbana e rural) e o estado de saúde autorreferido da população adulta brasileira, controlando para um conjunto de fatores individuais e do ambiente intradomiciliar e extradomiciliar. Os resultados indicam que ao controlar por fatores individuais e ambientais, a associação entre a área de localização do domicílio e o estado de saúde autorreferido dos adultos se modifica (passando de OR=1,51 para OR=0,96) e perde a sua significância estatística (p-valor=0,208). Entretanto, foram observadas interações estatisticamente significantes entre a área de localização do domicílio e as seguintes variáveis: sexo, cor/raça, morbidade autorreferida, posse de bens básicos e percentual de domicílios adequados quanto a qualidade de moradia.<br>The urban environment influences human health and behavior, and a clearer understanding of the health determinants of populations living in cities is needed. Using data from the National Household Sampling Survey (PNAD) 2008, with ordinal logistic models incorporating the sampling plan, this study assessed the association between the location of the home (urban or rural) and the self-reported state of health of the adult Brazilian population, taking into account a set of individual and environmental factors inside and outside the home. The results indicated that after allowing for individual and environmental factors, the association between the location of the home and the self-reported state of health is changing (going from OR = 1.51 to OR = 0.96) and losing its statistical significance (p-value = 0.208). However, statistically significant interactions were observed between the location of the home and the following variables: sex, color/race, self-reported morbidity, possession of basic goods and percentage of households with adequate living conditions