Biology subjects

Velu, P.

Publications and source records attributed to Velu, P..

3 recordsLinked to original sources

bioRxiv2021

Systemic Tissue and Cellular Disruption from SARS-CoV-2 Infection revealed in COVID-19 Autopsies and Spatial Omics Tissue Maps

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus has infected over 115 million people and caused over 2.5 million deaths worldwide. Yet, the molecular mechanisms underlying the clinical manifestations of COVID-19, as well as what distinguishes them from common seasonal influenza virus and other lung injury states such as Acute Respiratory Distress Syndrome (ARDS), remains poorly understood. To address these challenges, we combined transcriptional profiling of 646 clinical nasopharyngeal swabs and 39 patient autopsy tissues, matched with spatial protein and expression profiling (GeoMx) across 357 tissue sections. These results define both body-wide and tissue-specific (heart, liver, lung, kidney, and lymph nodes) damage wrought by the SARS-CoV-2 infection, evident as a function of varying viral load (high vs. low) during the course of infection and specific, transcriptional dysregulation in splicing isoforms, T cell receptor expression, and cellular expression states. In particular, cardiac and lung tissues revealed the largest degree of splicing isoform switching and cell expression state loss. Overall, these findings reveal a systemic disruption of cellular and transcriptional pathways from COVID-19 across all tissues, which can inform subsequent studies to combat the mortality of COVID-19, as well to better understand the molecular dynamics of lethal SARS-CoV-2 infection and other viruses.

microbiology↗

bioRxiv2020

Host, Viral, and Environmental Transcriptome Profiles of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused thousands of deaths worldwide, including >18,000 in New York City (NYC) alone. The sudden emergence of this pandemic has highlighted a pressing clinical need for rapid, scalable diagnostics that can detect infection, interrogate strain evolution, and identify novel patient biomarkers. To address these challenges, we designed a fast (30-minute) colorimetric test (LAMP) for SARS-CoV-2 infection from naso/oropharyngeal swabs, plus a large-scale shotgun metatranscriptomics platform (total-RNA-seq) for host, bacterial, and viral profiling. We applied both technologies across 857 SARS-CoV-2 clinical specimens and 86 NYC subway samples, providing a broad molecular portrait of the COVID-19 NYC outbreak. Our results define new features of SARS-CoV-2 evolution, nominate a novel, NYC-enriched viral subclade, reveal specific host responses in interferon, ACE, hematological, and olfaction pathways, and examine risks associated with use of ACE inhibitors and angiotensin receptor blockers. Together, these findings have immediate applications to SARS-CoV-2 diagnostics, public health, and new therapeutic targets.

molecular biology↗

bioRxiv2018

Classes of ITD predict outcomes in patients with AML treated with FLT3 inhibitors

Recurrent internal tandem duplication (ITD) mutations are observed in various cancers including acute myeloid leukemia (AML). ITD mutations of Fms-like tyrosine kinase 3 (FLT3) receptor increase kinase activity, and are associated with poor prognostic outcomes. Currently, several small-molecule FLT3 inhibitors (FLT3i) are in clinical trials for targeted therapy of high-risk FLT3-ITD-positive AML. However, the variability of survival following FLT3i treatment suggests that the mere presence of FLT3-ITD mutations in a patient might not guarantee effective clinical response to targeted inhibition of FLT3 kinase. Motivated by the heterogeneity of FLT3-ITD mutations, we sought to investigate the effects of FLT3-ITD structural features on response to treatment in AML patients. To this end, we developed HeatITup (HEAT diffusion for Internal Tandem dUPlication), an algorithm to efficiently and accurately identify ITDs and classify them based on their nucleotide composition into newly defined categories of \"typical\" or \"atypical\". Typical ITDs insert sequences are entirely endogenous to the FLT3 locus whereas atypical ITDs contain nucleotides exogenous to the wildtype FLT3. We applied HeatITup to our cohort of de novo and relapsed AML patients. Individuals with AML carrying typical ITDs benefited significantly more from FLT3i than patients with atypical ITDs, regardless of whether FLT3i was used after initial induction or at relapse. Furthermore, analysis of the TCGA AML cohort demonstrated improved survival for patients with typical ITDs treated with induction chemotherapy. These results underscore the importance of structural discernment of complex somatic mutations such as ITDs in progressing towards personalized treatment for AML patients.

cancer biology↗