Beyond the androgen receptor II: New approaches to understanding and treating metastatic prostate cancer; Report from the 2017 Coffey‐Holden Prostate Cancer Academy Meeting

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138883/1/pros23424.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138883/2/pros23424_am.pd

Recurrent structural variation, clustered sites of selection, and disease risk for the complement factor H (CFH) gene family

Data deposition: The data reported in this paper have been deposited as a National Center for Biotechnology Information BioProject (accession no. PRJNA401648). Author contributions: S.C. and E.E.E. designed research; S.C., C.B., L.H., K.P., K.M.M., M.S., A.E.W., V.D., T.A.G.-L., and R.K.W. performed research; S.C., J.H., C.B., L.H., K.P., K.M.M., M.S., A.E.W., V.D., F.G., A.J.R., R.H.G., T.A.G.-L., R.K.W., B.H.F.W., P.N.B., R.A., and E.E.E. contributed new reagents/analytic tools; S.C., B.J.N., J.H., and E.E.E. analyzed data; and S.C., B.J.N., and E.E.E. wrote the paper.Peer reviewedPublisher PD

Cortical-Bone Fragility - Insights from sFRP4 Deficiency in Pyle's Disease

BACKGROUND Cortical-bone fragility is a common feature in osteoporosis that is linked to non - vertebral fractures. Regulation of cortical-bone homeostasis has proved elusive. The study of genetic disorders of the skeleton can yield insights that fuel experimental therapeutic approaches to the treatment of rare disorders and common skeletal ailments. METHODS We evaluated four patients with Pyle’s disease, a genetic disorder that is characterized by cortical-bone thinning, limb deformity, and fractures; two patients were examined by means of exome sequencing, and two were examined by means of Sanger se - quencing. After a candidate gene was identified, we generated a knockout mouse model that manifested the phenotype and studied the mechanisms responsible for altered bone architecture. RESULTS In all affected patients, we found biallelic truncating mutations in SFR P4 , the gene encoding secreted frizzled-related protein 4, a soluble Wnt inhibitor. Mice deficient in Sfrp4 , like persons with Pyle’s disease, have increased amounts of trabecular bone and unusually thin cortical bone, as a result of differential regulation of Wnt and bone morphogenetic protein (BMP) signaling in these two bone compartments. Treat - ment of Sfrp4- deficient mice with a soluble Bmp2 receptor (RAP-661) or with anti - bodies to sclerostin corrected the cortical-bone defect. CONCLUSIONS Our study showed that Pyle’s disease was caused by a deficiency of sFRP4, that cortical- bone and trabecular-bone homeostasis were governed by different mechanisms, and that sFRP4-mediated cross-regulation between Wnt and BMP signaling was critical for achieving proper cortical-bone thickness and stability. (Funded by the Swiss Na - tional Foundation and the National Institutes of Health.

Nomogram-based Prediction of Overall Survival in Patients with Metastatic Urothelial Carcinoma Receiving First-line Platinum-based Chemotherapy: Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC)

The available prognostic models for overall survival (OS) in patients with metastatic urothelial carcinoma (UC) have been derived from clinical trial populations of cisplatin-treated patients

Multilinear analysis of Time-Resolved Laser-Induced Fluorescence Spectra of U(VI) containing natural water samples

Natural waters’ uranium level monitoring is of great importance for health and environmental protection. One possible detection method is the Time-Resolved Laser-Induced Fluorescence Spectroscopy (TRLFS), which offers the possibility to distinguish different uranium species. The analytical identification of aqueous uranium species in natural water samples is of distinct importance since individual species differ significantly in sorption properties and mobility in the environment. Samples originate from former uranium mine sites and have been provided by Wismut GmbH, Germany. They have been characterized by total elemental concentrations and TRLFS spectra. Uranium in the samples is supposed to be in form of uranyl(VI) complexes mostly with carbonate (CO32− ) and bicarbonate (HCO3− ) and to lesser extend with sulphate (SO42− ), arsenate (AsO43− ), hydroxo (OH− ), nitrate (NO3− ) and other ligands. Presence of alkaline earth metal dications (M = Ca2+ , Mg2+ , Sr2+ ) will cause most of uranyl to prefer ternary complex species, e.g. Mn(UO2)(CO3)32n-4 (n ∊ {1; 2}). From species quenching the luminescence, Cl− and Fe2+ should be mentioned. Measurement has been done under cryogenic conditions to increase the luminescence signal. Data analysis has been based on Singular Value Decomposition and monoexponential fit of corresponding loadings (for separate TRLFS spectra, the “Factor analysis of Time Series” (FATS) method) and Parallel Factor Analysis (PARAFAC, all data analysed simultaneously). From individual component spectra, excitation energies T00, uranyl symmetric mode vibrational frequencies ωgs and excitation driven U-Oyl bond elongation ΔR have been determined and compared with quasirelativistic (TD)DFT/B3LYP theoretical predictions to cross -check experimental data interpretation

External quality assessment of SARS-CoV-2-sequencing: An ESGMD-SSM pilot trial across 15 European laboratories

Objective: This first pilot on external quality assessment (EQA) of SARS-CoV-2 whole genome sequencing, initiated by the ESCMID Study Group for Genomic and Molecular Diagnostics (ESGMD) and Swiss Society for Microbiology (SSM), aims to build a framework between laboratories in order to improve pathogen surveillance sequencing.Methods: Ten samples with varying viral loads were sent out to 15 clinical laboratories who had free choice of sequencing methods and bioinformatic analyses. The key aspects on which the individual centres were compared on were identification of 1) SNPs and indels, 2) Pango lineages, and 3) clusters between samples.Results: The participating laboratories used a wide array of methods and analysis pipelines. Most were able to generate whole genomes for all samples. Genomes were sequenced to varying depth (up to 100-fold difference across centres). There was a very good consensus regarding the majority of reporting criteria, but there were a few discrepancies in lineage and cluster assignment. Additionally, there were inconsistencies in variant calling. The main reasons for discrepancies were missing data, bioinformatic choices, and interpretation of data.Conclusions: The pilot EQA was an overall success. It was able to show the high quality of participating labs and provide valuable feedback in cases where problems occurred, thereby improving the sequencing setup of laboratories. A larger follow-up EQA should, however, improve on defining the variables and format of the report. Additionally, contamination and/or minority variants should be a further aspect of assessment.</p

Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors

Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing

When the horse runs off

text"When the horse runs off" is a one-act chamber opera, which features an original libretto by playwright Sarah Saltwick, and is based on a Buddhist fable. The piece is scored for four singers and six instrumentalists. Similar to the manner in which the original fable is used as a point of departure, the opera incorporates folk music of Nepal and China into a larger, more varied palette of sounds. These are places from which this fable could have originated, so this is a natural way to create a world within the piece that feels organic.Musi