Multicentric validation of the PathoDetect™ MTB RIF & INH assay for simultaneous detection of Mycobacterium tuberculosis, & drug resistance to rifampicin & isoniazid in presumptive pulmonary tuberculosis & drug-resistant TB patients.

Background & objectives Tuberculosis (TB) remains a major global health concern, with India accounting for 26 per cent of the global burden. Despite advances, access to rapid molecular diagnostics is limited, and the assays currently used in National TB Elimination Programme (NTEP) do not detect isoniazid (INH) resistance upfront. PathoDetect™ MTB RIF & INH is an indigenous closed-system assay that simultaneously detects Mycobacterium tuberculosis (MTB) and resistance to rifampicin (RIF) and INH.

Integrative proteogenomics and forward genetics reveals a novel mitotic vulnerability in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with few effective targeted therapies. Taxanes and other microtubule-targeting agents (MTAs) are frontline chemotherapies for TNBC; however, the molecular pathways that cause TNBC taxane sensitivity are largely unknown, preventing selection of taxane-responsive patients and development of more selective therapeutic strategies. In this study, we identified tumor-selective vulnerabilities in TNBC harboring inactivation of the tumor suppressor PTPN12 by integrating proteogenomic characterization and synthetic lethality screening.

Discovery of chromatin-based determinants of azacytidine and decitabine anti-cancer activity.

The DNA-incorporating nucleoside analogs azacytidine (AZA) and decitabine (DEC) have clinical efficacy in blood cancers, yet the precise mechanism by which these agents kill cancer cells has remained unresolved - specifically, whether their anti-tumor activity arises from conventional DNA damage or DNA hypomethylation via DNA methyltransferase 1 (DNMT1) inhibition. This incomplete mechanistic understanding has limited their broader therapeutic application, particularly in solid tumors, where early clinical trials showed limited efficacy. Here, through the assessment of drug sensitivity in over 600 human cancer models and comparison to a non-DNA-damaging DNMT1 inhibitor (GSK-3685032), we establish DNA hypomethylation, rather than DNA damage, as the primary killing mechanism of AZA and DEC across diverse cancer types.

Integrative analysis of lung adenocarcinoma across diverse ethnicities and exposures.

Lung adenocarcinomas (LUAD) are a pressing global health problem with enduring lethality and rapidly shifting epidemiology. Proteogenomic studies integrating proteomics and post-translational modifications with genomics can identify clinical strata and oncogenic mechanisms, but have been underpowered to examine effects of ethnicity, smoking and environmental exposures, or sex on this heterogeneous disease. This comprehensive proteogenomic analysis of LUAD tumors and matched normal adjacent tissues from 406 patients across diverse geographic and demographic backgrounds explores the impact of understudied driver mutations, prognostic role of chromosomal instability, patterns of immune signaling, differential and sex-specific effects of endogenous mutagens and environmental carcinogens, and pathobiology of early-stage tumors with "late-like" characteristics.

High-Throughput Proteomic and Phosphoproteomic Analysis of Formalin-Fixed Paraffin-Embedded Tissues.

Formalin-fixed, paraffin-embedded (FFPE) patient tissues are a valuable resource for proteomic studies with the potential to associate derived molecular insights with clinical annotations and outcomes. Here, we present an optimized, partially automated, plate-based workflow for FFPE proteomics combining pathology-guided macrodissection, xylene-free deparaffinization using Adaptive Focused Acoustics sonication for lysis and decrosslinking, optimized suspension trapping digestion and cleanup of peptides, and LC-MS/MS using Exploris 480, Orbitrap Astral, and timsTOF HT instrumentation. The workflow enables analysis of up to 96 dissected FFPE tissue samples or 10 μm scrolls, identifying 8000 to 10,000 unique proteins per sample with median CVs <20%.