A5009776692- Melanoma and MAPK Pathways
- Cancer-related Molecular Pathways
- Chronic Myeloid Leukemia Treatments
- melanin and skin pigmentation
- Neurobiology and Insect Physiology Research
- Chronic Lymphocytic Leukemia Research
- Microtubule and mitosis dynamics
- Advanced Fluorescence Microscopy Techniques
- Estrogen and related hormone effects
- Immune cells in cancer
- Cancer Genomics and Diagnostics
- Cutaneous Melanoma Detection and Management
- Exercise and Physiological Responses
- Pancreatic and Hepatic Oncology Research
- Cancer, Lipids, and Metabolism
- Adipose Tissue and Metabolism
- Genomics and Chromatin Dynamics
- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Long-Term Effects of COVID-19
- CRISPR and Genetic Engineering
- Lipoproteins and Cardiovascular Health
- Advanced Breast Cancer Therapies
- Pharmacological Effects and Toxicity Studies
- Heart Rate Variability and Autonomic Control
Vellore Institute of Technology University
2025
The University of Texas MD Anderson Cancer Center
2023-2024
Rosalind Franklin University of Medicine and Science
2022-2024
Birmingham Women’s and Children’s NHS Foundation Trust
2024
Oregon Health & Science University
2022
Imperial College London
2009-2020
Saint Louis University
2018-2019
Hammersmith Hospital
2006-2018
Royal Bolton Hospital
2017
Genentech
2015
Exposure to ultraviolet light is a major causative factor in melanoma, although the relationship between risk and exposure complex. We hypothesized that clinical heterogeneity explained by genetically distinct types of melanoma with different susceptibility light.We compared genome-wide alterations number copies DNA mutational status BRAF N-RAS 126 melanomas from four groups which degree differs: 30 skin chronic sun-induced damage 40 without such damage; 36 palms, soles, subungual (acral)...
The RAS/mitogen-activated protein kinase pathway sends external growth-promoting signals to the nucleus. BRAF, a critical serine/threonine in this pathway, is frequently activated by somatic mutation melanoma. Using cohort of 115 patients with primary invasive melanomas, we show that BRAF mutations are statistically significantly more common melanomas occurring on skin subject intermittent sun exposure than elsewhere (23 43 patients; P<.001, two-sided Fisher's exact test). By contrast,...
Abstract Normal progression through the cell cycle requires sequential action of cyclin-dependent kinases CDK1, CDK2, CDK4, and CDK6. Direct or indirect deregulation CDK activity is a feature almost all cancers has led to development inhibitors as anticancer agents. The CDK-activating kinase (CAK) plays critical role in regulating by mediating activating phosphorylation As such, CDK7, which also regulates transcription part TFIIH basal factor, an attractive target for drugs. Computer...
Recent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting targeting the transcriptional machinery provides new approaches treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating C-terminal domain (CTD) of RNA polymerase II (PolII) enable initiation. CDK7 additionally regulates activities a number factors, including estrogen receptor (ER)-α. Here we describe new, orally bioavailable inhibitor,...
Estrogen receptor α (ERα) is the key transcriptional driver in a large proportion of breast cancers. We report that APOBEC3B (A3B) required for regulation gene expression by ER and acts causing C-to-U deamination at binding regions. show these changes lead to generation DNA strand breaks through activation base excision repair (BER) non-homologous end-joining (NHEJ) pathways. provide evidence transient cytidine A3B aids chromatin modification remodelling regulatory regions target genes...
In green fluorescent protein (GFP), chromophore biosynthesis is initiated by a spontaneous main-chain condensation reaction. Nucleophilic addition of the Gly67 amide nitrogen to Ser65 carbonyl carbon catalyzed fold and leads heterocyclic intermediate. To investigate this mechanism, we substituted highly conserved residues Arg96 Glu222 in enhanced GFP (EGFP). R96M variant, rate formation greatly reduced (time constant = 7.5 × 103 h, pH 7) exhibits dependence. E222Q also attenuated at...
The mature form of green fluorescent protein (GFP) is generated by a spontaneous self-modification process that essentially irreversible. A key step in chromophore biosynthesis involves slow air oxidation an intermediate species, which the backbone atoms residues 65−67 have condensed to five-membered heterocycle. We investigated kinetics hydrogen peroxide evolution during vitro GFP maturation and found H2O2 coproduct prior acquisition fluorescence at stoichiometry 1:1 (peroxide/chromophore)....
Cyclin-dependent protein kinases (CDKs) are central to the appropriate regulation of cell proliferation, apoptosis, and gene expression. Abnormalities in CDK activity common features cancer, making family members attractive targets for development anticancer drugs. Here, we report identification a pyrazolo[1,5-a]pyrimidine derived compound, 4k (BS-194), as selective potent inhibitor, which inhibits CDK2, CDK1, CDK5, CDK7, CDK9 (IC50 = 3, 30, 250, 90 nmol/L, respectively). Cell-based studies...
Abstract Purpose: CDK-activating kinase (CAK) is required for the regulation of cell cycle and a trimeric complex consisting cyclin-dependent 7 (CDK7), Cyclin H, accessory protein, MAT1. CDK7 also plays critical role in regulating transcription, primarily by phosphorylating RNA polymerase II, as well transcription factors such estrogen receptor-α (ER). Deregulation transcriptional control are general features tumor cells, highlighting potential use inhibitors novel cancer therapeutics....
Combined hyperlipidemia is a common disorder, characterized by highly atherogenic lipoprotein profile and substantially increased risk of coronary heart disease. The purpose this study was to establish whether variations apolipoprotein A5 (APOA5), newly discovered gene lipid metabolism located 30 kbp downstream the APOA1/C3/A4 cluster, contributes transmission familial combined (FCHL).We performed linkage association tests on 128 families. Two independent alleles, APOA5c.56G APOC3c.386G,...
To meet the growing demand for synthetic genes more robust, scalable and inexpensive gene assembly technologies must be developed. Here, we present a protocol high-quality directly from low-cost marginal-quality microarray-synthesized oligonucleotides. Significantly, eliminated time- money-consuming oligonucleotide purification steps through use of hybridization-based selection embedded in process. The was tested on mixtures up to 2000 oligonucleotides eluted microarrays obtained three...
Liver receptor homologue 1 (LRH-1) is an orphan nuclear that has been implicated in the progression of breast, pancreatic and colorectal cancer (CRC). To determine mechanisms underlying growth promotion by LRH-1 CRC, we undertook global expression profiling following siRNA-mediated knockdown HCT116 cells, which require for HT29 does not regulate growth. Interestingly, cell cycle inhibitor p21 (CDKN1A) was regulated cells. regulation observed where p53 mutated. dependence confirmed with...
Abstract Exercise changes the tumor microenvironment by remodeling blood vessels and increasing infiltration cytotoxic immune cells. The mechanisms driving these remain unclear. Herein, we demonstrate that exercise normalizes vasculature upregulates endothelial expression of VCAM1 in YUMMER 1.7 B16F10 murine models melanoma but differentially regulates growth, hypoxia, response. We found suppressed growth increased CD8+ T-cell not tumors. Single-cell RNA sequencing flow cytometry revealed...
Previous studies have suggested that the helical repeat formed by residues 143–164 of apolipoprotein A-I (apoA-I) contributes to lecithin:cholesterol acyltransferase (LCAT) activation. To identify specific polar involved in this process, we examined residue conservation and topology apoA-I from all known species. We observed hydrophobic/hydrophilic interface helix contains a cluster three strictly conserved arginine (R149, R153, R160), these create only significant positive electrostatic...
Deregulation of the cell cycle by mechanisms that lead to elevated activities cyclin-dependent kinases (CDK) is a feature many human diseases, cancer in particular. We identified small-molecule inhibitors selectively inhibit CDK7, kinase phosphorylates cell-cycle CDKs promote their activities. To investigate selectivity these we used combination structural, biophysical, and modelling approaches. determined crystal structures CDK7-selective compounds ICEC0942 ICEC0943 bound CDK2, build models...
Abstract Background The aim was to carry out phase 4 international field-testing of the European Organisation for Research and Treatment Cancer (EORTC) breast reconstruction (BRECON) module. primary objective finalization its scale structure. Secondary objectives were evaluation reliability, validity, responsiveness, acceptability interpretability in patients with cancer undergoing mastectomy reconstruction. Methods EORTC module development guidelines followed. Patients recruited from 28...
Repeat radiation therapy (RT) using photons/X-rays for locally recurrent breast cancer results in increased short and long-term toxicity. Proton beam RT (PBRT) can minimize dose to surrounding organs, thereby potentially reducing Here, we report the toxicity clinical outcomes women who underwent re-irradiation chest wall PBRT.This was a retrospective study analyzing 16 consecutive patients between 2013 2018 with PBRT. For disease, maximal safe resection, including salvage mastectomy, wide...
Background- Combined hyperlipidemia is a common disorder characterized by highly atherogenic lipoprotein profile and increased risk of coronary heart disease. The etiology the lipid abnormalities (increased serum cholesterol triglyceride or either alone) unknown.We assembled 2 large cohorts families with familial combined (FCHL) performed disease quantitative trait linkage analyses to evaluate inheritance abnormalities. Chromosomal regions 6q16.1-q16.3, 8p23.3-p22, 11p14.1-q12.1 produced...
Abstract Estrogen receptor α (ERα) is a key transcriptional regulator in the majority of breast cancers. ERα-positive patients are frequently treated with tamoxifen, but resistance common. In this study, we refined previously identified 111-gene outcome prediction-classifier, revealing FEN1 as strongest determining factor patient prognostication. levels were predictive tamoxifen-treated patients, and played causal role ERα-driven cell growth. impacted activity ERα by facilitating coactivator...
The Hispanic/Latino population is not uniform. Prevalence and clinical outcomes of cardiac arrhythmias in ethnic background subgroups are variable, but the reasons for differences unclear. Vectorcardiographic Global Electrical Heterogeneity (GEH) has been shown to be associated with adverse cardiovascular outcomes. purpose this study was compare GEH subpopulations. We hypothesized that ethnicity category moderates an association prevalent disease (CVD) GEH. Cross-sectional analysis HCHS/SOL...