A5071620573- Bladder and Urothelial Cancer Treatments
- Prostate Cancer Treatment and Research
- Tissue Engineering and Regenerative Medicine
- Urinary and Genital Oncology Studies
- Epigenetics and DNA Methylation
- Cancer Genomics and Diagnostics
- Cancer Immunotherapy and Biomarkers
- Cancer, Lipids, and Metabolism
- Estrogen and related hormone effects
- Cancer-related molecular mechanisms research
- Esophageal Cancer Research and Treatment
- Prostate Cancer Diagnosis and Treatment
- RNA Research and Splicing
- Renal cell carcinoma treatment
- Protein Degradation and Inhibitors
- Advanced Breast Cancer Therapies
- RNA modifications and cancer
- HIV Research and Treatment
- Immune cells in cancer
- Ferroptosis and cancer prognosis
- HIV/AIDS drug development and treatment
- Single-cell and spatial transcriptomics
- Hypothalamic control of reproductive hormones
- Cancer-related gene regulation
- Hormonal and reproductive studies
Washington University in St. Louis
2015-2023
National Centre for Cell Science
2018-2022
Savitribai Phule Pune University
2018-2022
Barnes-Jewish Hospital
2020-2021
Jewish Hospital
2020-2021
Guru Gobind Singh Indraprastha University
2019
University of Michigan–Ann Arbor
2012-2014
Prostate Cancer Foundation
2014
The University of Texas MD Anderson Cancer Center
2014
Cornell University
2014
Metastatic prostate cancer is treated with drugs that antagonize androgen action, but most patients progress to a more aggressive form of the disease called castration-resistant cancer, driven by elevated expression receptor. Here we characterize diarylthiohydantoins RD162 and MDV3100, two compounds optimized from screen for nonsteroidal antiandrogens retain activity in setting increased receptor expression. Both bind greater relative affinity than clinically used antiandrogen bicalutamide,...
Abstract Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), most advanced form of this disease. While established and novel AR pathway–targeting agents display clinical efficacy metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In study, we report discovery development ARN-509, competitive inhibitor that fully antagonistic to overexpression, common important feature CRPC....
Abstract We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair genes promotes prostate cancer radioresistance, providing potential mechanism by which deprivation therapy synergizes with ionizing radiation. Using model castration-resistant cancer, we show second-generation antiandrogen results in downregulation genes. Next, primary cancers display significant spectrum AR output, correlates expression set RNA-seq and ChIP-seq, define these are both...
The second-generation antiandrogen enzalutamide was recently approved for patients with castration-resistant prostate cancer. Despite its success, the duration of response is often limited. For previous antiandrogens, one mechanism resistance mutation androgen receptor (AR). To prospectively identify AR mutations that might confer to enzalutamide, we performed a reporter-based mutagenesis screen and identified novel mutation, F876L, which converted into an agonist. Ectopic expression F876L...
In prostate cancer, resistance to the antiandrogen enzalutamide (Enz) can occur through bypass of androgen receptor (AR) blockade by glucocorticoid (GR). contrast fixed genomic alterations, here we show that GR-mediated is adaptive and reversible due regulation GR expression a tissue-specific enhancer. silenced in cancer combination AR binding EZH2-mediated repression at locus, but restored advanced cancers upon reversion both repressive signals. Remarkably, BET bromodomain inhibition...
Abstract Somatic mutations within non-coding regions and even exons may have unidentified regulatory consequences that are often overlooked in analysis workflows. Here we present RegTools ( www.regtools.org ), a computationally efficient, free, open-source software package designed to integrate somatic variants from genomic data with splice junctions bulk or single cell transcriptomic identify cause aberrant splicing. We apply over 9000 tumor samples both DNA RNA sequence data. discovers...
Background The standard of care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy, which typically preceded by neoadjuvant chemotherapy. However, the inability to assess minimal residual disease (MRD) noninvasively limits our ability offer bladder-sparing treatment. Here, we sought develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis. Methods and findings We applied Cancer Personalized Profiling Deep Sequencing (uCAPP-Seq), targeted next-generation...
Abstract Disruption of KDM6A, a histone lysine demethylase, is one the most common somatic alternations in bladder cancer. Insights into how KDM6A mutations affect epigenetic landscape to promote carcinogenesis could help reveal potential new treatment approaches. Here, we demonstrated that loss triggers an switch disrupts urothelial differentiation and induces neoplastic state characterized by increased cell proliferation. In cancer cells with intact FOXA1 interacted activate genes...
RXRA regulates transcription as part of a heterodimer with 14 other nuclear receptors, including the peroxisome proliferator-activated receptors (PPARs). Analysis from TCGA raised possibility that hyperactive PPAR signaling, either due to gamma gene amplification or hot-spot mutation (S427F/Y) drives 20-25% human bladder cancers. Here, we characterize mutant RXRA, demonstrating it induces enhancer/promoter activity in context RXRA/PPAR heterodimers cancer cells. Structure-function studies...
Abstract Somatic mutations within non-coding regions and even exons may have unidentified regulatory consequences that are often overlooked in analysis workflows. Here we present RegTools ( www.regtools.org ), a computationally efficient, free, open-source software package designed to integrate somatic variants from genomic data with splice junctions bulk or single cell transcriptomic identify cause aberrant splicing. was applied over 9,000 tumor samples both DNA RNA sequence data. We...
Abstract Purpose: Palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, blocks proliferation in RB and cyclin D–dependent manner preclinical prostate cancer models. We hypothesized that cotargeting androgen receptor cell cycle with palbociclib would improve outcomes patients metastatic hormone-sensitive (mHSPC). Patients Methods: A total of 60 RB-intact mHSPC were randomized (1:2) to Arm 1: deprivation (AD) or 2: AD + palbociclib. Primary endpoint was PSA response rate (RR) after 28...
Immune checkpoint blockade (ICB) provides clinical benefit to a minority of patients with urothelial carcinoma (UC). The role CD4+ T cells in ICB-induced antitumor activity is not well defined; however, are speculated play supportive the development CD8+ that kill tumor after recognition antigens presented by MHC class I. To investigate mechanisms against UC, we developed mouse organoid-based transplantable models have histologic and genetic similarity human bladder cancer. We found ICB can...
ABSTRACT Nef proteins from human immunodeficiency virus type 1 (HIV-1) and simian (SIV) have been found to associate with an active cellular serine/threonine kinase designated Nef-associated (Nak). The exact identity of Nak remains controversial, two recent studies indicating that may be either Pak1 or Pak2. In this study, we investigated the hypothesis such discrepancies arise use different alleles cell types by individual investigators. We first confirm Pak2 but not is cleaved caspase 3 in...
The GnRH receptor (GnRH-R) belongs to the rhodopsin/-adrenergic family of G protein-coupled receptors.The intracellular domains these receptors, particularly regions closest plasma membrane in loops 2 (2i) and 3 (3i) as well some located membrane-proximal end COOH-terminus, are frequently important sites for protein coupling specificity determination.Although studies mouse human GnRH-R have identified loop 2i a critical determinant q/11 -mediated signal transduction pathway, given...
Long noncoding RNAs constitute a major fraction of the eukaryotic transcriptome, and together with proteins, they intricately fine-tune various growth regulatory signals to control cellular homeostasis. Here, we describe functional characterisation novel pair long intergenic (lincRNAs) comprised complementary, fully overlapping sense antisense transcripts Genomic Instability Inducing RNA (Ginir) Ginir (Giniras), respectively, from mouse cells. This transcript is expressed in spatiotemporal...
Abstract G-protein signaling components have been attributed many biological roles in plants, but the extent of involvement coupled receptor 1 ( GCR1 ) with Gα GPA1 remained unknown. To address this, we performed transcriptomic analyses on Arabidopsis gpa1-5gcr1-5 double mutant and identified 656 differentially expressed genes (DEGs). MapMan Gene Ontology revealed global transcriptional changes associated external stimulus, cell wall organization/biogenesis secondary metabolite process among...
ABSTRACT We have characterized the functional integrity of seven primary Nef isolates: five from a long-term nonprogressing human immunodeficiency virus (HIV)-infected individual and one each two patients with AIDS. One Nefs was defective for CD4 downregulation, others were PAK-2 activation, activation major histocompatibility complex (MHC) class I downregulation. Five tested found to be enhancement particle infectivity. The structural basis defects has been analyzed by constructing...