Biology subjects

Kumaraswamy, A.

Publications and source records attributed to Kumaraswamy, A..

4 recordsLinked to original sources

bioRxiv2026

Genomic Determinants of Lethality and Therapeutic Vulnerability in Castration-Resistant Prostate Cancer

Despite extensive characterization, the molecular determinants that shape disease progression and therapeutic outcomes in metastatic castration-resistant prostate cancer (mCRPC) remain incompletely defined. This large, multi-institutional analysis reveals that the genomic determinants of outcomes in primary prostate cancer are distinct from those in castration-resistant disease. We identify androgen-regulated MYC fusions as potent primary genetic drivers catalyzing early progression. Additionally, across independent mCRPC cohorts, we validate TP53, RB1, and CDKN1B alterations as the strongest genetic drivers of poor survival. Mechanistically, CDKN1B loss induces an AR-positive epithelial-mesenchymal transition rather than neuroendocrine differentiation, while TP53 loss triggers whole-genome duplication and subsequent adaptive copy-number gains. Within TP53-altered tumors, AR amplifications confer improved survival while AR mutations are protective regardless of TP53 status. Integrating these genomic events with transcriptomic phenotypes, we derive CAPrisk, a multi-omic prognostic classifier. CAPrisk stratifies patients with mCRPC into three risk groups with >33-month survival differences and predicts outcomes across androgen receptor pathway inhibitors, taxanes, PARP-inhibitors, and radium-223. Together, these findings expand the clinical utility of genomic profiling in advanced prostate cancer and establish a framework for risk stratification in lethal disease. IN BRIEF (eTOC BLURB)Rebernick et al. analyze a multi-institutional cohort of 1,331 prostate cancer samples and identify the genomic determinants of progression to lethal, castration-resistant disease. They define rare AR-regulated MYC fusions and haploinsufficient CDKN1B loss as drivers of poor outcome while highlighting AR alterations as predictors of improved prognosis. They develop CAPrisk, a multi-omic classifier that stratifies patient outcomes across androgen receptor pathway inhibitors, taxanes, PARP-inhibitors, and radium-223. HIGHLIGHTS- AR-regulated MYC fusions are rare ([~]2%) truncal events driving aggressive disease. - Distinct AR alterations drive favorable outcomes in TP53-altered and non-altered contexts. - Haploinsufficient CDKN1B loss predicts poor survival in AR-positive tumors. - A multi-omic model predicts outcomes across four standard-of-care therapies. MI-OncoSeq TeamChandan Kumar, Erica Rabban, Kayla Muschong, Lakshmi P. Kunju, Javed Siddiqui, Yu Ning, Rui Wang, Fengyun Su, Yelena Kleyman-Smith, Josh N. Vo, Jin Chen, Rahul Mannan Stand Up To Cancer TeamWassim Abida, Joanna Cyrta, Glenn Heller, Davide Prandi, Joshua Armenia, Ilsa Coleman, Matteo Benelli, Eliezer M. Van Allen, Andrea Sboner, Tarcisio Fedrizzi, Juan Miguel Mosquera, Brian D. Robinson, Navonil De Sarkar, Lakshmi P. Kunju, Scott Tomlins, Daniel Nava Rodrigues, Massimo Loda, Anuradha Gopalan, Victor E. Reuter, Colin C. Pritchard, Joaquin Mateo, Diletta Bianchini, Susana Miranda, Suzanne Carreira, Pasquale Rescigno, Julie Filipenko, Jacob Vinson, Robert B. Montgomery, Himisha Beltran, Elisabeth I. Heath, Howard I. Scher, Philip W. Kantoff, Mary-Ellen Taplin, Nikolaus Schultz, Johann S. deBono, Francesca Demichelis, Peter S. Nelson, Mark A. Rubin, Charles Sawyers

Cancer Biology↗

bioRxiv2018

Adaptations during maturation in an identified honeybee interneuron responsive to waggle dance vibration signals

Honeybees are social insects, and individual bees take on different social roles as they mature, performing a multitude of tasks that involve multi-modal sensory integration. Several activities vital for foraging, like flight and waggle dance communication, involve sensing air vibrations using antennae. We investigated changes in the identified vibration-sensitive interneuron DL-Int-1 in the honeybee Apis mellifera during maturation by comparing properties of neurons from newly emerged and forager honeybees. Comparison of morphological reconstructions of the neurons revealed minor changes in gross dendritic features and consistent, region dependent and spatially localized changes in dendritic density. Comparison of electrophysiological properties showed an increase in the firing rate differences between stimulus and non-stimulus periods in foragers compared to newly emerged adult bees. The observed differences in neurons of foragers as compared to newly emerged adult honeybees indicate refined connectivity, improved signal propagation, and enhancement of response features important for the network processing of air vibration signals relevant for the waggle-dance communication of honeybees.

neuroscience↗

bioRxiv2018

A segmentation scheme for complex neuronal arbors and application to vibration sensitive neurons in the honeybee brain

The morphology of a neuron is strongly related to its physiological properties, and thus to information processing functions. Optical microscope images are widely used for extracting the structure of neurons. Although several approaches have been proposed to trace and extract complex neuronal structures from microscopy images, available methods remain prone to errors. In this study, we present a practical scheme for processing confocal microscope images and reconstructing neuronal structures. We evaluated this scheme using image data samples and associated gold standard reconstructions from the BigNeuron Project. In these samples, dendritic arbors belonging to multiple projection branches of the same neuron overlapped in space, making it difficult to automatically and accurately trace their structural connectivity. Our proposed scheme, which combines several software tools for image masking and filtering with an existing tool for dendritic segmentation and tracing, outperformed state-of-the-art automatic methods in reconstructing such neuron structures. For evaluating our scheme, we applied it to a honeybee local interneuron, DL-Int-1, which has complex arbors and is considered to be a critical neuron for encoding the information indicated in the waggle dance of the honeybee.

bioinformatics↗

bioRxiv2017

Network simulations of interneuron circuits in the honeybee primary auditory center

Processing of airborne vibration signals in the auditory system is essential for honeybee communication through the waggle dance language. Properties of neurons in the honeybee primary auditory center suggest a circuitry of excitatory and inhibitory neurons encoding these communication signals. To test this assumption, we simulated this network and analyzed the predicted responses for different types of inputs. In particular, we investigated the effect of specific inhibitory connections in the network. The results indicate that the experimentally observed responses of certain interneuron types are compatible with an inhibitory network of vibration processing in the primary auditory center of the honeybee.

bioinformatics↗