👤 Vijayalakshmi Mahadevan

Alzheimer disease neuropathologic change (ADNC) is the most common pathology underlying cognitive impairment and dementia in the aging population, but there is significant variation in outcome between affected individuals. Moreover, other common neurodegenerative processes are often concurrent and may significantly worsen cognition, but the degree to which these processes interact and affect the We performed a cross-sectional cohort study of 586 participants from the National Alzheimer’s Coordinating Center (NACC) database, who were ≥ 65 years of age and displayed high-level ADNC at autopsy, and who had available longitudinal cognitive data and Clinical Dementia Rating (CDR) performed within the final 24 months of life. This cohort was subdivided into “resilient” individuals/those with minimal progression of cognitive decline (MinP; Individuals with rapid progression were more likely to have at least one These data suggest that resilience and progression in ADNC are impacted by AD-relevant genetics and the severity of late-stage ADNC (even within the narrow range of values compatible with high-level ADNC), additional pathologic features, and potentially the clinical management of underlying systemic disorders. The online version contains supplementary material available at 10.1186/s13195-025-01904-6. Show less

Epithelial to Mesenchymal transition (EMT) drives cancer metastasis and is governed by genetic and epigenetic alterations at multiple levels of regulation. It is well established that loss/mutation of p53 confers oncogenic function to cancer cells and promotes metastasis. Though transcription factors like ZEB1, SLUG, SNAIL and TWIST have been implied in EMT signalling, p53 mediated alterations in the epigenetic machinery accompanying EMT are not clearly understood. This work attempts to explore epigenetic signalling during EMT in colorectal cancer (CRC) cells with varying status of p53. Towards this, we have induced EMT using TGFβ on CRC cell lines with wild type, null and mutant p53 and have assayed epigenetic alterations after EMT induction. Transcriptomic profiling of the four CRC cell lines revealed that the loss of p53 confers more mesenchymal phenotype with EMT induction than its mutant counterparts. This was also accompanied by upregulation of epigenetic writer and eraser machinery suggesting an epigenetic signalling cascade triggered by TGFβ signalling in CRC. Significant agonist and antagonistic relationships observed between EMT factor SNAI1 and SNAI2 with epigenetic enzymes KDM6A/6B and the chromatin organiser SATB1 in p53 null CRC cells suggest a crosstalk between epigenetic and EMT factors. The observed epigenetic regulation of EMT factor SNAI1 correlates with poor clinical outcomes in 270 colorectal cancer patients taken from TCGA-COAD. This unique p53 dependent interplay between epigenetic enzymes and EMT factors in CRC cells may be exploited for development of synergistic therapies for CRC patients presenting to the clinic with loss of p53. Show less

Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations. Show less

This study reports the prevalence of five clinically significant variants associated with increased risk of cardiovascular disorders, and variable responses of individuals to commonly prescribed cardiovascular drugs in a South Indian population from the state of Kerala. Genomic DNA isolated from 100 out-patient samples from Kerala were sequenced to examine the frequency of clinically relevant polymorphisms in the genes MYBPC3 (cardiomyopathy), SLCO1B1 (statin-induced myopathy), CYP2C9, VKORC1 (response to warfarin) and CYP2C19 (response to clopidogrel). Our analyses revealed the frequency of a 25 bp deletion variant of MYBPC3 associated with risk of cardiomyopathy was 7%, and the SLCO1B1 "C" allele associated with risk for statin-induced myopathy was 15% in this sample group. Among the other variants associated with dose-induced toxicity of warfarin, VKORC1 (c.1639G>A), was detected at 22%, while CYP2C9*3 and CYP2C9*2 alleles were present at a frequency of 15% and 3% respectively. Significantly, the tested sample population showed high prevalence (66%) of CYP2C19*2 variant, which determines response to clopidogrel therapy. We have identified that certain variants associated with cardiovascular disease and related drug response in the five genes, especially those in VKORC1, CYP2C19 and MYBPC3, are highly prevalent in the Kerala population, with almost 2 times higher prevalence of CYP2C19*2 variant compared with other regions in the country. Since the variants chosen in this study have relevance in disease phenotype and/or drug response, and are detected at a higher frequency, this study is likely to encourage clinicians to perform genetic testing before prescribing therapy. Show less