A comparative analytical study on outcome of secondary peritonitis using Mannheim's peritonitis index in geographically diverse Indian patients.

Objectives: Secondary peritonitis is caused by infection of the peritoneal cavity due to perforation of the alimentary tract. Mannheim's peritonitis index (MPI) is a prognostic scoring system that predicts outcomes in peritonitis. Increasing MPI scores correlate with poor outcomes and mortality. The objective of this study is to evaluate the effectiveness of MPI-based prognosis and its impact on Indian patients with secondary peritonitis. Material and Methods: For understanding the effectiveness of the MPI scoring system, a cross-sectional data analysis of published studies on secondary peritonitis from 10 geographical locations in India was performed. The 10-site study results were compared with unpublished in-house study data for individual MPI parameters to analyze any variations of MPI score-based predictions across a diverse Indian population. Patients were divided into risk groups on the basis of MPI scores: <21 mild, MPI= 21-29 moderate, MPI> 29 severe risk. Results: We observed a significant correlation between mortality with age and gender as reported worldwide. Site of perforations were prevalent in the upper alimentary tract with the majority being gastro-duodenal for the Indian population as opposed to distal parts in the western population. Higher lethality in India is often associated with evolution time, organ failure, and sepsis due to delayed presentation and poor management. Conclusion: MPI scoring is effective in predicting risk across geographically diverse Indian populations. The sensitivity and specificity of MPI scores are more reliable and a score >29 specifically recommends aggressive resuscitation & monitoring of patients, initiation of broad-spectrum antibiotics, and intensive care support to reduce mortality and morbidity.

PGC1 alpha coactivates ERG fusion to drive antioxidant target genes under metabolic stress.

The presence of ERG gene fusion; from developing prostatic intraepithelial neoplasia (PIN) lesions to hormone resistant high grade prostate cancer (PCa) dictates disease progression, altered androgen metabolism, proliferation and metastasis1-3. ERG driven transcriptional landscape may provide pro-tumorigenic cues in overcoming various strains like hypoxia, nutrient deprivation, inflammation and oxidative stress. However, insights on the androgen independent regulation and function of ERG during stress are limited. Here, we identify PGC1α as a coactivator of ERG fusion under various metabolic stress. Deacetylase SIRT1 is necessary for PGC1α-ERG interaction and function. We reveal that ERG drives the expression of antioxidant genes; SOD1 and TXN, benefitting PCa growth. We observe increased expression of these antioxidant genes in patients with high ERG expression correlates with poor survival. Inhibition of PGC1α-ERG axis driven transcriptional program results in apoptosis and reduction in PCa xenografts. Here we report a function of ERG under metabolic stress which warrants further studies as a therapeutic target for ERG fusion positive PCa.

An integrated epigenome and transcriptome analysis identifies PAX2 as a master regulator of drug resistance in high grade pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is notoriously difficult to treat due to its aggressive, ever resilient nature. A major drawback lies in its tumor grade; a phenomenon observed across various carcinomas, where highly differentiated and undifferentiated tumor grades, termed as low and high grade respectively, are found in the same tumor. One eminent problem due to such heterogeneity is drug resistance in PDAC. This has been implicated to ABC transporter family of proteins that are upregulated in PDAC patients. However, the regulation of these transporters with respect to tumor grade in PDAC is not well understood. To combat these issues, a study was designed to identify novel genes that might regulate drug resistance phenotype and be used as targets. By integrating epigenome with transcriptome data, several genes were identified based around high grade PDAC. Further analysis indicated oncogenic PAX2 transcription factor as a novel regulator of drug resistance in high grade PDAC cell lines. It was observed that silencing of PAX2 resulted in increased susceptibility of high grade PDAC cells to various chemotherapeutic drugs. Mechanistically, the study showed that PAX2 protein can bind and alter transcriptionally; expression of many ABC transporter genes in high grade PDAC cell lines. Overall, the study indicated that PAX2 significantly upregulated ABC family of genes resulting in drug resistance and poor survival in PDAC.