Identification of PPARgamma ligands with One-dimensional Drug Profile Matching.

INTRODUCTION: Computational molecular database screening helps to decrease the time and resources needed for drug development. Reintroduction of generic drugs by second medical use patents also contributes to cheaper and faster drug development processes. We screened, in silico, the Food and Drug Administration-approved generic drug database by means of the One-dimensional Drug Profile Matching (oDPM) method in order to find potential peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. The PPARgamma action of the selected generics was also investigated by in vitro and in vivo experiments. MATERIALS AND METHODS: The in silico oDPM method was used to determine the binding potency of 1,255 generics to 149 proteins collected. In vitro PPARgamma activation was determined by measuring fatty acid-binding protein 4/adipocyte protein gene expression in a Mono Mac 6 cell line. The in vivo insulin sensitizing effect of the selected compound (nitazoxanide; 50-200 mg/kg/day over 8 days; n = 8) was established in type 2 diabetic rats by hyperinsulinemic euglycemic glucose clamping. RESULTS: After examining the closest neighbors of each of the reference set's members and counting their most abundant neighbors, ten generic drugs were selected with oDPM. Among them, four enhanced fatty acid-binding protein/adipocyte protein gene expression in the Mono Mac 6 cell line, but only bromfenac and nitazoxanide showed dose-dependent actions. Induction by nitazoxanide was higher than by bromfenac. Nitazoxanide lowered fasting blood glucose levels and improved insulin sensitivity in type 2 diabetic rats. CONCLUSION: We demonstrated that the oDPM method can predict previously unknown therapeutic effects of generic drugs. Nitazoxanide can be the prototype chemical structure of the new generation of insulin sensitizers

Chiral properties of SU(3) sextet fermions

SU(3) gauge theory with overlap fermions in the 2-index symmetric (sextet) and fundamental representations is considered. A priori it is not known what the pattern of chiral symmetry breaking is in a higher dimensional representation although the general expectation is that if two representations are both complex, the breaking pattern will be the same. This expectation is verified for the sextet at N_f = 0 in several exact zero mode sectors. It is shown that if the volume is large enough the same random matrix ensemble describes both the sextet and fundamental Dirac eigenvalues. The number of zero modes for the sextet increases approximately 5-fold relative to the fundamental in accordance with the index theorem for small lattice spacing but zero modes which do not correspond to integer topological charge do exist at larger lattice spacings. The zero mode number dependence of the random matrix model predictions correctly match the simulations in each sector and each representation.Comment: 38 pages (12 pages text and gazillion tables/figures), minor modification, references adde

Evolution of Mafic Alkaline Melts Crystallized in the Uppermost Lithospheric Mantle: a Melt Inclusion Study of Olivine-Clinopyroxenite Xenoliths Northern Hungary

ISSN:0022-3530ISSN:1460-241

Izominvazív hólyagrák képvezérelt sugárkezelése intravesicalisan befecskendezett lipiodolos jelöléssel: A hólyagmegtartó kezelés új lehetősége.

INTRODUCTION AND AIM: To implement lipiodol as a fiducial marker of the tumor bed for image-guided radiotherapy with simultaneous integrated boost technique as part of radiochemotherapy for muscle invasive bladder tumors. METHOD: Since April 2016, radiochemotherapy was performed in 3 male patients with muscle invasive, transitional cell bladder carcinoma. Prior to radiochemotherapy, tumor bed resection was performed for each patient, at the same time 10 ml of lipiodol solution was injected submucosally into the resection site, thus marking the tumor bed for escalated dose irradiation. During radiochemotherapy 51 Gy (1.7 Gy/die) to the pelvis, 57 Gy (1.9 Gy/die) to the whole bladder, and 63 Gy (2.1 Gy/die) to the lipiodol-labeled tumor bed was delivered with simultaneous integrated boost technique. The accuracy of the irradiation was controlled by daily kilovoltage CT. Early radiogenic urogenital and gastrointestinal side effects were recorded according to Radiation Therapy Oncology Group side-effects grading recommendation. RESULTS: Substantial perioperative side effect or toxicity were not observed during and after the injection of lipiodol. The prescribed dose was successfully delivered in all patients. Radiotherapy duration was 6 weeks. The lipiodol-labeled tumor bed was clearly visible on daily kilovoltage cone beam CT. In one patient grade II cystitis and proctitis was observed, another patient experienced only grade I cystitis. These complaints improved with symptomatic medication. In the third patient no significant side effect occurred. CONCLUSIONS: The injection of lipiodol into the bladder wall is a safe technique, without any perioperative toxicity or complication. The tumor bed demarcated by lipiodol was visible both on treatment planning and kilovoltage CTs. The total treatment time was shortened by 4 days. The treatment was well tolerated, early side effects were moderate, or slight. Orv Hetil. 2017; 158(51): 2041-2047

Right ventricular contraction patterns in healthy children using three-dimensional echocardiography

Background: The right ventricle (RV) has complex geometry and function, with motion along three separate axes—longitudinal, radial, and anteroposterior. Quantitative assessment of RV function by two-dimension echocardiography (2DE) has been limited as a consequence of this complexity, whereas newer three dimensional (3D) analysis offers the potential for more comprehensive assessment of the contributors to RV function. The aims of this study were to quantify the longitudinal, radial and anteroposterior components of global RV function using 3D echocardiography in a cohort of healthy children and to examine maturational changes in these parameters. Methods: Three-dimensional contours of the RV were generated from a cohort of healthy pediatric patients with structurally normal hearts at two centers. Traditional 2D and 3D echo characteristics were recorded. Using offline analysis of 3D datasets, RV motion was decomposed into three components, and ejection fractions (EF) were calculated (longitudinal-LEF; radial-REF; and anteroposterior-AEF). The individual decomposed EF values were indexed against the global RVEF. Strain values were calculated as well. Results: Data from 166 subjects were included in the analysis; median age was 13.5 years (range 0 to 17.4 years). Overall, AEF was greater than REF and LEF (29.2 ± 6.2% vs. 25.1 ± 7.2% and 25.7 ± 6.0%, respectively; p < 0.001). This remained true when indexed to overall EF (49.8 ± 8.7% vs. 43.3 ± 11.6% and 44.4 ± 10%, respectively; p < 0.001). Age-related differences were present for global RVEF, REF, and all components of RV strain. Conclusions: In healthy children, anteroposterior shortening is the dominant component of RV contraction. Evaluation of 3D parameters of the RV in children is feasible and enhances the overall understanding of RV function, which may allow improvements in recognition of dysfunction and assessment of treatment effects in the future

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.