Neonatal vitamin A administration increases intramuscular fat by promoting angiogenesis and preadipocyte formation.

To explore the effects and underlying mechanism of vitamin A on beef marbling fat development, angus steers were injected vitamin A at birth and 1 month of age and in vitro experiments were performed to investigate the effects of retinoic acid (RA) on angiogenesis and adipogenesis of intramuscular stromal vascular (SVF) cells. Results showed that vitamin A administration increased the intramuscular PDGFRα+ adipose progenitors, improved adipogenic potential of intramuscular SVF cells and dramatically upregulated VEGFA. At slaughter, vitamin A increased intramuscular triacylglycerols by 45% without affecting overall fatness. In a 3D culture system, RA promoted capillary sprout development and promoted the subsequent adipogenesis of intramuscular SVF cells by activating VEGFA/VEGFR2 signaling. However, during terminal adipogenesis, RA downregulated PPARγ, C/EBPα and inhibited lipid accumulation. In conclusion, vitamin A/RA upregulate VEGFA and stimulate intramuscular vascular capillary development, which increases intramuscular adipose progenitors and contributes to adipocyte formation. When administrated at neonatal stage, vitamin A promotes beef marbling development without affecting overall fatness.

Population pharmacokinetic/pharmacodynamic modelling of nifekalant in healthy Chinese volunteers.

Nifekalant is a class III antiarrhythmic drug, and its major adverse effect is prolongation of the QT interval. This study analysed data generated from a pharmacokinetic (PK) study to develop a population PK/pharmacodynamics (PD) model for describing the relationship between plasma concentrations and prolongation of the QT interval over time following intravenous administration of nifekalant. This open-labelled, phase I clinical study comprised two dose level groups of eight healthy Chinese volunteers. Concentrations of nifekalant in plasma samples collected at set time-points were determined using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. A PK/PD model was constructed using a non-linear mixed-effects approach (Phoenix NLME 8.1). Furthermore, demographic covariates of the model were investigated and a concentration factor (ConcƟ) was introduced as the only covariate which improved the performance of the model. The final population PK model exhibited one-order elimination with two-compartment distribution and adequately described nifekalant plasma concentrations over time. The QT interval prolongation was best described by an indirect effect model with an inhibition build-up effect, representing the relationship between plasma concentrations and effect. The final population PK/PD model may facilitate more accurate predictions of the drug profile in clinical settings in the future.

Integrated Molecular Characterization of Testicular Germ Cell Tumors.

We studied 137 primary testicular germ cell tumors (TGCTs) using high-dimensional assays of genomic, epigenomic, transcriptomic, and proteomic features. These tumors exhibited high aneuploidy and a paucity of somatic mutations. Somatic mutation of only three genes achieved significance-KIT, KRAS, and NRAS-exclusively in samples with seminoma components. Integrated analyses identified distinct molecular patterns that characterized the major recognized histologic subtypes of TGCT: seminoma, embryonal carcinoma, yolk sac tumor, and teratoma. Striking differences in global DNA methylation and microRNA expression between histology subtypes highlight a likely role of epigenomic processes in determining histologic fates in TGCTs. We also identified a subset of pure seminomas defined by KIT mutations, increased immune infiltration, globally demethylated DNA, and decreased KRAS copy number. We report potential biomarkers for risk stratification, such as miRNA specifically expressed in teratoma, and others with molecular diagnostic potential, such as CpH (CpA/CpC/CpT) methylation identifying embryonal carcinomas.

Integrated Molecular Characterization of Uterine Carcinosarcoma.

We performed genomic, epigenomic, transcriptomic, and proteomic characterizations of uterine carcinosarcomas (UCSs). Cohort samples had extensive copy-number alterations and highly recurrent somatic mutations. Frequent mutations were found in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous uterine carcinomas. Transcriptome sequencing identified a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases that was attributable to epigenetic alterations at microRNA promoters. The range of EMT scores in UCS was the largest among all tumor types studied via The Cancer Genome Atlas. UCSs shared proteomic features with gynecologic carcinomas and sarcomas with intermediate EMT features. Multiple somatic mutations and copy-number alterations in genes that are therapeutic targets were identified.

Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin.

Recent genomic analyses of pathologically defined tumor types identify "within-a-tissue" disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All data sets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies.