Biology subjects

Subramaniam, P.

Publications and source records attributed to Subramaniam, P..

3 recordsLinked to original sources

bioRxiv2023

Elucidating Compound Mechanism of Action and Polypharmacology with a Large-scale Perturbational Profile Compendium

Drug Mechanism of Action (MoA) is often represented as a small repertoire of tissue-independent, high-affinity binding targets. Yet drug activity and polypharmacology are also manifested through a broad range of off-target and tissue-specific effector proteins. To address this dichotomy, we generated a compendium of drug perturbation profiles for >700 oncology drugs in cell lines representing high-fidelity models of 23 aggressive tumor subtypes, as well as an integrative framework for the proteome-wide assessment of drug-mediated, tissue-specific differential protein activity. Extending MoA and polypharmacology assessment via proteome-wide, multi-tissue analyses revealed novel polypharmacology, including for MAPK, PI3K, and folate pathways inhibitors--as supported by Western blots, thermal shift assays, and structural analysis--as well as functional inhibitors of challenging oncoprotein targets, including MYC, CTNNB1, CENPF and UHRF1. The dataset and associated computational framework might be extensible to additional compound libraries, supporting global, quantitative approaches to defining the mechanisms of action of many drugs.

systems biology↗

bioRxiv2019

Feasibility of Remotely Supervised Transcranial Direct Current Stimulation and Cognitive Remediation: A Systematic Review

With technological advancements and an aging population, there is growing interest in delivering interventions at home. Transcranial Direct Current Stimulation (tDCS) and Cognitive Remediation (CR) have been widely studied, but mainly in laboratories or hospitals. Thus, the objectives of this review are to examine feasibility and the interventions components to support the domiciliary administration of tDCS and CR. We performed a systematic search of electronic databases, websites and reference lists of included articles from the first date available until October 31, 2018. Articles included had to meet the following criteria: original work published in English using human subjects, majority of tDCS or CR intervention administered remotely. A total of 39 studies were identified (16 tDCS, 23 CR/cognitive training, 5 using both tDCS & cognitive training). Four studies were single case studies and two were multiple case studies. The remaining 33 studies had a range of 9 - 135 participants. Five tDCS and nine CR/cognitive training studies were double blind randomized controlled trials. Most studies focused on schizophrenia (8/39) and multiple sclerosis (8/39). Literature examined suggests the feasibility of delivering tDCS or CR remotely with the support of information and communication technologies.

neuroscience↗

bioRxiv2019

A Modular Master Regulator Landscape Determines the Impact of Genetic Alterations on the Transcriptional Identity of Cancer Cells

Despite considerable pan-cancer efforts, the link between genomics and transcriptomics in cancer remains relatively weak and mostly based on statistical rather than mechanistic principles. By performing integrative analysis of transcriptomic and mutational profiles on a sample-by-sample basis, via regulatory/signaling networks, we identified a repertoire of 407 Master-Regulator proteins responsible for canalizing the genetics of 20 TCGA cohorts into 112 transcriptionally-distinct tumor subtypes. Further analysis highlighted a highly-recurrent regulatory architecture (oncotecture) with Master-Regulators organized into 24 modular MR-Blocks, regulating highly-specific tumor-hallmark functions and predictive of patient outcome. Critically, >50% of the somatic alterations identified in individual samples were in proteins affecting Master-Regulator activity, thus yielding novel insight into mechanisms linking tumor genetics and transcriptional identity and establishing novel non-oncogene dependencies. Experimental validation of functional mutations upstream of the most conserved MR-Block confirmed their ability to affect MR-protein activity, suggesting that the proposed methodology may effectively complement and extend current pan-cancer knowledge.

bioinformatics↗