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Bhargava, S.

Publications and source records attributed to Bhargava, S..

2 recordsLinked to original sources

New Radiological Classification of Glioma and validation with the survival analysis

Radiology based classification of glioma independent of histological or genetic markers predicting survival of patients is an unmet need. Until now radiology is chasing these markers rather than focussing directly on the clinical outcome. Our study is first of its kind to come up with the independent new radiological classification of gliomas encompassing both low-and high-grade gliomas under single classification system. TCGA-LGG and REMBRANDT public domain dataset of glioma were analyzed as training and testing dataset respectively. Based on MRI images, gliomas were classified into six types in detailed classification & three types in simplified classification system. Survival analysis using Kaplan Meier and Cox regression was done. Secondary objective was to evaluate the sensitivity and specificity of novel signs with existing histological and genetic markers. The study predicted survival in both training and testing dataset independent of genetic or histological information. Novel signs, "Ball on Christmas tree" sign(highly specific), Type-4 lineage sign(highly sensitive) identifies IDH-wild and high-grade gliomas (grade-III and IV) while Type-2 lineage sign showed good specificity in identifying 1p19q non co-deleted IDH-mutated, ATRX del/mutated, Grade-II gliomas. There is a substantial interobserver agreement for the classification and novel signs. New radiological classification of glioma predicts the survival of patients independent of genetic or histological information. This can act as a scaffolding to formulate and streamline the treatment guidelines for glioma patients. This classification has potential of improving the quality of care of glioma patients by predicting the survival without the need of invasive biopsy.

cancer biology

Pharmacological inhibition of longevity regulator PAPP-A restrains mesenchymal stromal cell activity

Reducing insulin-like growth factor (IGF) signaling is one of the best conserved and characterized mechanisms to extend longevity. Pregnancy associated plasma protein A (PAPP-A) is a secreted metalloprotease that increases IGF availability by cleaving IGF binding proteins. PAPP-A inhibition reduces local IGF signaling, limits the progression of multiple age-related diseases, and extends lifespan, but the mechanisms behind these pleiotropic effects remains unknown. Here, we developed and utilized a PAPP-A neutralizing antibody to discover that adulthood inhibition of this protease reduced collagen and extracellular matrix (ECM) gene expression in multiple tissues in mice. Using bone marrow to explore this effect, we identified mesenchymal stromal cells (MSCs) as the source of PAPP-A and primary responders to PAPP-A inhibition. Short-term treatment with anti-PAPP-A reduced IGF signaling in MSCs, altered MSC expression of collagen/ECM, and decreased MSC number. This affected MSC-dependent functions, decreasing myelopoiesis and osteogenesis. Our data demonstrate that PAPP-A inhibition reduces the activity and number of IGF-dependent mesenchymal progenitor cells and their differentiated progeny, and that this reduction leads to functional changes at the tissue level. MSC-like cells are present in virtually all tissues, and aberrant collagen and ECM production from mesenchymal cells drives aspects of aging and age-related diseases, thus this may be a mechanism by which PAPP-A deficiency enhances lifespan and healthspan. SummaryInhibition of PAPP-A, a regulator of IGF signaling, decreases multi-tissue collagen and extracellular matrix gene expression and modulates mesenchymal stromal cell activity in murine bone marrow.

physiology