Comprehensive analysis of alternative splicing across multiple transcriptomic cohorts reveals prognostic signatures in prostate cancer.

BACKGROUND: Alternative splicing (AS) plays a crucial role in transcriptomic diversity and is a hallmark of cancer that profoundly influences the development and progression of prostate cancer (PCa), a prevalent and potentially life-limiting cancer among men. Accumulating evidence has highlighted the association between AS dysregulation and the onset and progression of PCa. However, a comprehensive and integrative analysis of AS profiles at the event level, utilising data from multiple high-throughput cohorts and evaluating the prognosis of PCa progression, remains lacking and calls for thorough exploration. RESULTS: We identified a differentially expressed retained intron event in ZWINT across three distinct cohorts, encompassing an original array-based dataset profiled by us previously and two RNA sequencing (RNA-seq) datasets. Subsequent in-depth analyses of these RNA-seq datasets revealed  141 altered events, of which 21 demonstrated a significant association with patients' biochemical recurrence-free survival (BCRFS). We formulated an AS event-based prognostic signature, capturing six pivotal events in genes CYP4F12, NFATC4, PIGO, CYP3A5, ALS2CL, and FXYD3. This signature effectively differentiated  high-risk patients diagnosed with PCa, who experienced shorter BCRFS, from their low-risk counterparts. Notably, the signature's predictive power surpassed traditional clinicopathological markers in forecasting 5-year BCRFS, demonstrating robust performance in both internal and external validation sets. Lastly, we constructed a novel nomogram that integrates patients' Gleason scores with pathological tumour stages, demonstrating improved prognostication of BCRFS. CONCLUSIONS: Prediction of clinical progression remains elusive in PCa. This research uncovers novel splicing events associated with BCRFS, augmenting existing prognostic tools, thus potentially refining clinical decision-making.

Gene expression analysis reveals a 5-gene signature for progression-free survival in prostate cancer.

Prostate cancer (PCa) is the second most common male cancer worldwide, but effective biomarkers for the presence or progression risk of disease are currently elusive. In a series of nine matched histologically confirmed PCa and benign samples, we carried out an integrated transcriptome-wide gene expression analysis, including differential gene expression analysis and weighted gene co-expression network analysis (WGCNA), which identified a set of potential gene markers highly associated with tumour status (malignant vs. benign). We then used these genes to establish a minimal progression-free survival (PFS)-associated gene signature (GS) (PCBP1, PABPN1, PTPRF, DANCR, and MYC) using least absolute shrinkage and selection operator (LASSO) and stepwise multivariate Cox regression analyses from The Cancer Genome Atlas prostate adenocarcinoma (TCGA-PRAD) dataset. Our signature was able to predict PFS over 1, 3, and 5 years in TCGA-PRAD dataset, with area under the curve (AUC) of 0.64-0.78, and our signature remained as a prognostic factor independent of age, Gleason score, and pathological T and N stages. A nomogram combining the signature and Gleason score demonstrated improved predictive capability for PFS (AUC: 0.71-0.85) and was superior to the Cambridge Prognostic Group (CPG) model alone and some conventionally used clinicopathological factors in predicting PFS. In conclusion, we have identified and validated a novel five-gene signature and established a nomogram that effectively predicted PFS in patients with PCa. Findings may improve current prognosis tools for PFS and contribute to clinical decision-making in PCa treatment.

Mode of action of Cr(VI) in immunocytes of earthworms: Implications for animal health.

Chromium (Cr) is one of the major and most detrimental pollutant, widely present in the environment as a result of several anthropogenic activities. In mammalian cells, Cr(VI) is known to enhance reactive oxygen species (ROS) production and to cause toxic and genotoxic effects. Less commonly investigated are the effects and mode of action of this contaminant in invertebrates, particularly in soil organisms. In this work, earthworms of the species Eisenia andrei were exposed for 1 and 3 days to various sublethal concentrations of Cr(VI) (2, 15, 30µgmL-1) using the paper contact toxicity test. In amoeboid leukocytes we investigated intracellular ROS and lipoperoxide production, oxidative DNA damage, and the effects on different cell functions. The analysis of the results shows that Cr(VI) triggered severe adverse reactions; the first events were an increase of intracellular ROS levels, generating in the cells oxidative stress conditions leading to membrane lipid peroxidation and oxidative DNA damage. Lysosomes showed relevant changes such as a strong membrane destabilization, which was accompanied by an increased catabolism of cytoplasmic proteins and accumulation of lipofuscin. With an increase in the dose and/or time of exposure, the physiological status of intracellular organelles (such as lysosomes, nucleus and mitochondria) showed further impairment and amoebocyte immune functions were adversely affected, as shown by the decrease of the phagocytic activity. By mapping the responses of the different parameters evaluated, diagnostic of (oxidative) stress events, against lysosomal membrane stability, a "health status" indicator (able to describe the stress syndrome from its early phase to pathology), we have shown that this biomarker is suitable as a prognostic test for health of earthworms. This is viewed as a crucial step toward the derivation of explanatory frameworks for prediction of pollutant impact on animal health.