Trace Amine-Associated Receptor 1 (TAAR1) Is a Positive Prognosticator for Epithelial Ovarian Cancer

Trace amine-associated receptor 1 (TAAR1) is a G_αs- protein coupled receptor that plays an important role in the regulation of the immune system and neurotransmission in the CNS. In ovarian cancer cell lines, stimulation of TAAR1 via 3-iodothyronamine (T₁AM) reduces cell viability and induces cell death and DNA damage. Aim of this study was to evaluate the prognostic value of TAAR1 on overall survival of ovarian carcinoma patients and the correlation of TAAR1 expression with clinical parameters. Ovarian cancer tissue of n = 156 patients who were diagnosed with epithelial ovarian cancer (serous, n = 110 (high-grade, n = 80; low-grade, n = 24; unknown, n = 6); clear cell, n = 12; endometrioid, n = 21; mucinous, n = 13), and who underwent surgery at the Department of Obstetrics and Gynecology, University Hospital of the Ludwig-Maximilians University Munich, Germany between 1990 and 2002, were analyzed. The tissue was stained immunohistochemically with anti-TAAR1 and evaluated with the semiquantitative immunoreactive score (IRS). TAAR1 expression was correlated with grading, FIGO and TNM-classification, and analyzed via the Spearman’s rank correlation coefficient. Further statistical analysis was obtained using nonparametric Kruskal-Wallis rank-sum test and Mann-Whitney-U-test. This study shows that high TAAR1 expression is a positive prognosticator for overall survival in ovarian cancer patients and is significantly enhanced in low-grade serous carcinomas compared to high-grade serous carcinomas. The influence of TAAR1 as a positive prognosticator on overall survival indicates a potential prognostic relevance of signal transduction of thyroid hormone derivatives in epithelial ovarian cancer. Further studies are required to evaluate TAAR1 and its role in the development of ovarian cancer.     

4th generation synchrotron source boosts crystalline imaging at the nanoscale

New 4th-generation synchrotron sources,with their increased brilliance,promise to greatly improve the performances of coherent X-ray microscopy.This perspective...     

Urinary Tract Tumor Organoids Reveal Eminent Differences in Drug Sensitivities When Compared to 2-Dimensional Culture Systems

Generation of organoids from urinary tract tumor samples was pioneered a few years ago. We generated organoids from two upper tract urothelial carcinomas and from one bladder cancer sample, and confirmed the expression of cytokeratins as urothelial antigens, vimentin as a mesenchymal marker, and fibroblast growth factor receptor 3 by immunohistochemistry. We investigated the dose response curves of two novel components, venetoclax versus {"type":"entrez-nucleotide","attrs":{"text":"S63845","term_id":"400540","term_text":"S63845"}}S63845, in comparison to the clinical standard cisplatin in organoids in comparison to the corresponding two-dimensional cultures. Normal urothelial cells and tumor lines RT4 and HT1197 served as controls. We report that upper tract urothelial carcinoma cells and bladder cancer cells in two-dimensional cultures yielded clearly different sensitivities towards venetoclax, {"type":"entrez-nucleotide","attrs":{"text":"S63845","term_id":"400540","term_text":"S63845"}}S63845, and cisplatin. Two-dimensional cultures were more sensitive at low drug concentrations, while organoids yielded higher drug efficacies at higher doses. In some two-dimensional cell viability experiments, colorimetric assays yielded different IC₅₀ toxicity levels when compared to chemiluminescence assays. Organoids exhibited distinct sensitivities towards cisplatin and to a somewhat lesser extent towards venetoclax or {"type":"entrez-nucleotide","attrs":{"text":"S63845","term_id":"400540","term_text":"S63845"}}S63845, respectively, and significantly different sensitivities towards the three drugs investigated when compared to the corresponding two-dimensional cultures. We conclude that organoids maintained inter-individual sensitivities towards venetoclax, {"type":"entrez-nucleotide","attrs":{"text":"S63845","term_id":"400540","term_text":"S63845"}}S63845, and cisplatin. The preclinical models and test systems employed may bias the results of cytotoxicity studies.     

In Vivo Inhibition of TRPC6 by SH045 Attenuates Renal Fibrosis in a New Zealand Obese (NZO) Mouse Model of Metabolic Syndrome

Metabolic syndrome is a significant worldwide public health challenge and is inextricably linked to adverse renal and cardiovascular outcomes. The inhibition of the transient receptor potential cation channel subfamily C member 6 (TRPC6) has been found to ameliorate renal outcomes in the unilateral ureteral obstruction (UUO) of accelerated renal fibrosis. Therefore, the pharmacological inhibition of TPRC6 could be a promising therapeutic intervention in the progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome. In the present study, we hypothesized that the novel selective TRPC6 inhibitor SH045 (larixyl N-methylcarbamate) ameliorates UUO-accelerated renal fibrosis in a New Zealand obese (NZO) mouse model, which is a polygenic model of metabolic syndrome. The in vivo inhibition of TRPC6 by SH045 markedly decreased the mRNA expression of pro-fibrotic markers (Col1α1, Col3α1, Col4α1, Acta2, Ccn2, Fn1) and chemokines (Cxcl1, Ccl5, Ccr2) in UUO kidneys of NZO mice compared to kidneys of vehicle-treated animals. Renal expressions of intercellular adhesion molecule 1 (ICAM-1) and α-smooth muscle actin (α-SMA) were diminished in SH045- versus vehicle-treated UUO mice. Furthermore, renal inflammatory cell infiltration (F4/80+ and CD4+) and tubulointerstitial fibrosis (Sirius red and fibronectin staining) were ameliorated in SH045-treated NZO mice. We conclude that the pharmacological inhibition of TRPC6 might be a promising antifibrotic therapeutic method to treat progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome.     

Clinical Phenotype of PDE6B-Associated Retinitis Pigmentosa

In this retrospective, longitudinal, observational cohort study, we investigated the phenotypic and genotypic features of retinitis pigmentosa associated with variants in the PDE6B gene. Patients underwent clinical examination and genetic testing at a single tertiary referral center, including best-corrected visual acuity (BCVA), kinetic visual field (VF), full-field electroretinography, full-field stimulus threshold, spectral domain optical coherence tomography, and fundus autofluorescence imaging. The genetic testing comprised candidate gene sequencing, inherited retinal disease gene panel sequencing, whole-genome sequencing, and testing for familial variants by Sanger sequencing. Twenty-four patients with mutations in PDE6B from 21 families were included in the study (mean age at the first visit: 32.1 ± 13.5 years). The majority of variants were putative splicing defects (8/23) and missense (7/23) mutations. Seventy-nine percent (38/48) of eyes had no visual acuity impairment at the first visit. Visual acuity impairment was mild in 4% (2/48), moderate in 13% (6/48), and severe in 4% (2/48). BCVA was symmetrical in the right and left eyes. The kinetic VF measurements were highly symmetrical in the right and left eyes, as was the horizontal ellipsoid zone (EZ) width. Regarding the genetic findings, 43% of the PDE6B variants found in our patients were novel. Thus, this study contributed substantially to the PDE6B mutation spectrum. The visual acuity impairment was mild in 83% of eyes, providing a window of opportunity for investigational new drugs. The EZ width was reduced in all patients and was highly symmetric between the eyes, making it a promising outcome measure. We expect these findings to have implications on the design of future PDE6B-related retinitis pigmentosa (RP) clinical trials.     

Phase formation and microstructure during laser sintering and crystallization of a 4.2 MgO·5.0 ZnO·44.1 CaO·26.7 Al<Subscript>2</Subscript>O<Subscript>3</Subscript>·20.0 SiO<Subscript>2</Subscript> glass

In order to produce housings for high-temperature applications, alumina is a highly advantageous material because it has a high chemical durability and withstands high temperatures. If alumina is to be sealed, materials are necessary which have an adapted coefficient of thermal expansion (8.6 × 10^?6 K^?1). If temperature-sensitive components have to be encapsulated, a rapid laser sealing process is highly advantageous. This process requires a glass which can rapidly be crystallized. In this paper, a glass powder with the composition 4.2 MgO·5.0 ZnO·44.1·CaO·26.7 Al₂O₃·20.0 SiO₂ was sintered and subsequently crystallized using a CO₂-laser. As crystalline phases, predominantly a solid solution of akermanite and gehlenite (AGSS) was formed and as phases with minor concentrations Al₂O₃, spinel/gahnite solid solution and ZnO. The AGSS grains have sizes of approximately 5 µm, and Mg and Zn are enriched at the grain boundaries. After sealing at temperatures of 985 and 1135 °C, a similar microstructure and similar grain sizes were observed. The AGSS seems to nucleate at the glass/Al₂O₃ interface but also in the bulk. The AGSS and all other phases do not show a preferred orientation. The resulting coefficients of thermal expansion fit well to that of Al₂O₃.     

The effect of different platinum concentrations as nucleation agent in the BaO/SrO/ZnO/SiO<Subscript>2</Subscript> glass system

The recently reported solid solution of Ba_1?xSr _x Zn₂Si₂O₇ has a similar structure to the high-temperature phase of BaZn₂Si₂O₇ and possesses a coefficient of thermal expansion close to zero or even negative. Without nucleating agents, glasses in this system show solely surface crystallization. In order to stimulate volume crystallization, different quantities of platinum were added to the glass. The characteristic temperatures of the glasses were obtained by differential scanning calorimetry. In order to achieve volume crystallization, a two-step thermal treatment (nucleation and crystal growth) above the glass transition temperature was carried out. The phase identification was performed by X-ray diffraction, and the microstructure was studied by scanning electron microscopy including energy-dispersive X-ray spectroscopy and electron backscatter diffraction.     

An SMO algorithm for the potential support vector machine

We describe a fast sequential minimal optimization (SMO) procedure for solving the dual optimization problem of the recently proposed potential support vector machine (P-SVM). The new SMO consists of a sequence of iteration steps in which the Lagrangian is optimized with respect to either one (single SMO) or two (dual SMO) of the Lagrange multipliers while keeping the other variables fixed. An efficient selection procedure for Lagrange multipliers is given, and two heuristics for improving the SMO procedure are described: block optimization and annealing of the regularization parameter epsilon. A comparison of the variants shows that the dual SMO, including block optimization and annealing, performs efficiently in terms of computation time. In contrast to standard support vector machines (SVMs), the P-SVM is applicable to arbitrary dyadic data sets, but benchmarks are provided against libSVM's epsilon-SVR and C-SVC implementations for problems that are also solvable by standard SVM methods. For those problems, computation time of the P-SVM is comparable to or somewhat higher than the standard SVM. The number of support vectors found by the P-SVM is usually much smaller for the same generalization performance.