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Genomic sequencing of thousands of tumors has revealed many genes associated with specific types of cancer. Similarly, large scale CRISPR functional genomics efforts have mapped genes required for cancer cell proliferation or survival in hundreds of cell lines. Despite this, for specific disease subtypes, such as metastatic prostate cancer, there are likely a number of undiscovered tumor specific driver genes that may represent potential drug targets. To identify such genetic dependencies, we performed genome-scale CRISPRi screens in metastatic prostate cancer models. We then created a pipeline in which we integrated pan-cancer functional genomics data with our metastatic prostate cancer functional and clinical genomics data to identify genes that can drive aggressive prostate cancer phenotypes. Our integrative analysis of these data reveals known prostate cancer specific driver genes, such as AR and HOXB13, as well as a number of top hits that are poorly characterized. In this study we highlight the strength of an integrated clinical and functional genomics pipeline and focus on two top hit genes, KIF4A and WDR62. We demonstrate that both KIF4A and WDR62 drive aggressive prostate cancer phenotypes in vitro and in vivo in multiple models, irrespective of AR-status, and are also associated with poor patient outcome.

Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes that were detectable only with integrated whole-genome approaches. Notably, we observed that 22% of tumors exhibited a novel epigenomic subtype associated with hypermethylation and somatic mutations in TET2, DNMT3B, IDH1 and BRAF. We also identified intergenic regions where methylation is associated with RNA expression of the oncogenic driver genes AR, MYC and ERG. Finally, we showed that differential methylation during progression preferentially occurs at somatic mutational hotspots and putative regulatory regions. This study is a large integrated study of whole-genome, whole-methylome and whole-transcriptome sequencing in metastatic cancer that provides a comprehensive overview of the important regulatory role of methylation in metastatic castration-resistant prostate cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Here we train cis-regulatory models of prostate tissue gene expression and impute expression transcriptome-wide for 233,955 European ancestry men (14,616 prostate cancer (PrCa) cases, 219,339 controls) from two large cohorts. Among 12,014 genes evaluated in the UK Biobank, we identify 38 associated with PrCa, many replicating in the Kaiser Permanente RPGEH. We report the association of elevated TMPRSS2 expression with increased PrCa risk (independent of a previously-reported risk variant) and with increased tumoral expression of the TMPRSS2:ERG fusion-oncogene in The Cancer Genome Atlas, suggesting a novel germline-somatic interaction mechanism. Three novel genes, HOXA4, KLK1, and TIMM23, additionally replicate in the RPGEH cohort. Furthermore, 4 genes, MSMB, NCOA4, PCAT1, and PPP1R14A, are associated with PrCa in a trans-ethnic meta-analysis (N = 9117). Many genes exhibit evidence for allele-specific transcriptional activation by PrCa master-regulators (including androgen receptor) in Position Weight Matrix, Chip-Seq, and Hi-C experimental data, suggesting common regulatory mechanisms for the associated genes.

A new species of nemacheilid loach, Schistura sonarengaensis sp. nov., is described from three cave‐dwelling populations (Barak–Surma–Meghna drainage) in the South Garo Hills district of Meghalaya, India. The new species possesses prominent eyes but is easily distinguished from all the congeners of the genus Schistura from Barak–Surma–Meghna and adjacent rivers drainages of northeast Indian (except S. syngkai) in having 13–26 vertically elongated to circular mid‐lateral black blotches (brownish in life) overlayered on a grayish‐black mid‐lateral stripe on a dull white or pale‐beige (golden brown in life) body. However, it can be easily distinguished from S. syngkai in having a complete (vs. incomplete) lateral line with more 72–89 (vs. 19–42) lateral‐line pored scales, greater pre‐dorsal length (48.5–53.1 vs. 41.9–44.1 %SL), a wider body at dorsal‐fin origin (11.3–16.7 vs. 9.4–10.3 %SL), greater dorsal (18.1–21.1 vs. 15.1–17.0 %SL) and lateral (20.9–24.1 vs. 17.4–18.9 %SL) head length, a wider head (14.5–18.5 vs. 11.6–13.3 %SL), and moderately forked (vs. emarginated) caudal fin. Further, molecular analysis confirms the distinctiveness of S. sonarengaensis sp. nov. from its congeners found in northeast India by significant divergences with uncorrected genetic distance ranging from 3.7% to 17.3% in the mitochondrial cytochrome c oxidase subunit I (COI) gene dataset. The phylogenetic position of the new species with its sister species was evaluated using maximum likelihood and Bayesian analysis. The species delimitation approaches assemble species by automatic partitioning (ASAP) and Poisson tree processes (PTP) utilized for testing species assignments consistently identified our test group as a distinct species from its sister species. Although the new species lacks typical morphological adaptations usually associated with a subterranean life, such as complete absence (or vestigial presence) of eyes and pigmentation, it exhibits a reduction of pigmentation when compared to the epigean congeners. [ABSTRACT FROM AUTHOR]

While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.

Approximately 20% of metastatic prostate cancers harbor mutations in genes required for DNA repair by homologous recombination repair (HRR) such as BRCA2 HRR defects confer synthetic lethality to PARP inhibitors (PARPi) such as olaparib and talazoparib. In ovarian or breast cancers, olaparib resistance has been associated with HRR restoration, including by BRCA2 mutation reversion. Whether similar mechanisms operate in prostate cancer, and could be detected in liquid biopsies, is unclear. Here, we identify BRCA2 reversion mutations associated with olaparib and talazoparib resistance in patients with prostate cancer. Analysis of circulating cell-free DNA (cfDNA) reveals reversion mutation heterogeneity not discernable from a single solid-tumor biopsy and potentially allows monitoring for the emergence of PARPi resistance.Significance: The mechanisms of clinical resistance to PARPi in DNA repair-deficient prostate cancer have not been described. Here, we show BRCA2 reversion mutations in patients with prostate cancer with metastatic disease who developed resistance to talazoparib and olaparib. Furthermore, we show that PARPi resistance is highly multiclonal and that cfDNA allows monitoring for PARPi resistance. Cancer Discov; 7(9); 999-1005. ©2017 AACR.See related commentary by Domchek, p. 937See related article by Kondrashova et al., p. 984See related article by Goodall et al., p. 1006This article is highlighted in the In This Issue feature, p. 920.

The analysis of means (ANOM) is a method that can compare the mean of each treatment with the overall mean. As one-way ANOVA, the conventional ANOM is not robust under unequal variances. We applied two inference procedures, single-stage and modified single-stage sampling, to solve heteroscedastic analysis of means (HANOM) under unbalanced design. Using proposed weighted average across groups, the influence of the unknown mean and variance are both eliminated. To validate the stability of HANOM under several scenarios of unequal variances and sample sizes, simulation studies of empirical type I error rate are conducted to test the quality of procedures. A real application is provided for illustrating these two procedures clearly. In addition, we build an user-friendly interface to show the results of the HANOM by using Shiny package in R software. [ABSTRACT FROM AUTHOR]

Introduction: Latent trigger points (TrPs) are a type of musculoskeletal disorder. That can detrimentally affect athletic performance. Purpose: This study to classify athletes into latent-trigger point (L-TrPs) and non-trigger point (non-TrPs) group base on pain pressure threshold (PPT), force production and range of motion (ROM). Materials and methods: Total 45 L-TrPs and 45 non-TrPs athletes were selected. The diagnostic criteria proposed by Simons were employed to identify L-TrPs. Pressure algometry was used for PPT, HUMAC NORM ISOKINETIC machine for force production and Kinovea software for ROM analysis. Independent t test and discriminant analysis were conducted. Standardized discriminant coefficient, canonical correlation and Wilks' Lambda was calculated and p-value was judges at 5% level of significance. Results: Standardized discriminant coefficient showing that Average PPT hold first position followed by Average Extension ROM followed by Average Flexion ROM while Average force production stands on last position for discriminating ability to classification of the L-TrPs and non-TrPs among the athletes. It also observed that by using PPT, force production, and ROM, the model accurately classifies athletes with both L-TrPs and non-TrPs, with an accuracy ranging from 85% to 93%. This highlights the potential significance of these factors in distinguishing between athletes with and without TrPs. Conclusion: From this statistical analysis it concluded that PPT is the most significant contributor to classify the latent and non-TrPs groups. Therefore, regular pain assessment is required to maintain the performance of an individual. Whereas force production and ROM should not be ignored as the model 85%-95% accurately classifies these groups. [ABSTRACT FROM AUTHOR]

The cysteine‐free acyclic peptides present in marine cone snail venom have been much less investigated than their disulfide bonded counterparts. Precursor protein sequences derived from transcriptomic data, together with mass spectrometric fragmentation patterns for peptides present in venom duct tissue extracts, permit the identification of mature peptides. Twelve distinct gene superfamiles have been identified with precursor lengths between 64 and 158 residues. In the case of Conus monile, three distinct mature peptides have been identified, arising from two distinct protein precursors. Mature acyclic peptides are often post‐translationally modified, with C‐terminus amidation, a feature characteristic of neuropeptides. In the present study, 20 acyclic peptides from Conus monile and Conus betulinus were identified. The common modifications of C‐terminus amidation, gamma carboxylation of glutamic acid (E to ϒ), N‐terminus conversion of Gln (Q) to a pyroglutamyl residue (Z), and hydroxylation of Pro (P) to Hyp (O) are observed in one or more peptides identified in this study. Proteolytic trimming of sequences by cleavage at the C‐terminus of Asn (N) residues is established. The presence of an asparagine endopeptidase is strengthened by the identification of legumain‐like sequences in the transcriptome assemblies from diverse Conus species. Such sequences may be expected to have a cleavage specificity at Asn‐Xxx peptide bonds. [ABSTRACT FROM AUTHOR]

Naturally infected Channa punctata exhibiting bacterial septicemic syndrome including ulcerations along with mortality records were collected from a fish farm in Assam during winter season (early November 2020 to early January 2021). The moribund fishes were subjected for bacterial isolation followed by identification of the bacteria. Two dominant emerging bacterial pathogens were identified as Aeromonas veronii (isolate ZooGURD-01) and Aeromonas hydrophila (isolate ZooGURD-05) by standard biochemical characterization and 16S rRNA and rpo B gene amplification. Re-infection experiments of both the bacterial isolates in healthy disease-free C. punctata showed similar symptoms to that of natural infection thus confirming their virulence. The LD50 calculated during challenge test for both the isolates ZooGURD-01 and ZooGURD-05 found to be pathogenic at 2.6 × 104 and 1.6 × 104 CFU/fish respectively. Further PCR amplification of specific virulent genes (aerolysin, hemolysin and enterotoxin) confirmed pathogenicity for both isolates. Histopathological examinations of liver and kidney in re-infection experiments showed prominent changes supporting bacterial septicaemia. Antibiotic sensitivity pattern showed that the isolates ZooGURD-01 and ZooGURD-05 were sensitive to 22 and 19 out of 25 antimicrobials respectively. The present study was the first report on the mortality of farmed C. punctata associated with natural infection caused by A. veronii and A. hydrophila with no record of pathogenicity of A. veronii in C. punctata. [ABSTRACT FROM AUTHOR]