A5030101658- Heat shock proteins research
- ATP Synthase and ATPases Research
- Glioma Diagnosis and Treatment
- Mitochondrial Function and Pathology
- Epigenetics and DNA Methylation
- RNA modifications and cancer
- Biochemical and Molecular Research
- HIV/AIDS drug development and treatment
- Cancer, Hypoxia, and Metabolism
- CRISPR and Genetic Engineering
- HIV Research and Treatment
- Telomeres, Telomerase, and Senescence
- Cancer Cells and Metastasis
- RNA Interference and Gene Delivery
- Cytomegalovirus and herpesvirus research
- Gut microbiota and health
- Cancer Research and Treatments
- Immune cells in cancer
- Radiation Therapy and Dosimetry
- RNA regulation and disease
- Cell Image Analysis Techniques
- DNA Repair Mechanisms
- Polyomavirus and related diseases
- Metabolomics and Mass Spectrometry Studies
- Cancer Immunotherapy and Biomarkers
Children's Medical Center
2021-2024
The University of Texas Southwestern Medical Center
2014-2024
Southwestern Medical Center
2024
University of Pennsylvania
2017
Abstract Cancer metabolism is rewired to support cell survival in response intrinsic and environmental stressors. Identification of strategies target these adaptions an area active research. We previously described a cytosolic aspartate aminotransaminase (GOT1)-driven pathway pancreatic cancer used maintain redox balance. Here, we sought identify metabolic dependencies following GOT1 inhibition exploit this feature provide additional insight into regulation metabolism. Using pharmacological...
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Highlights•Depletion of Clostridia species is associated with graft-versus-host disease in pediatric stem cell transplantation patients•Exposure to antianaerobic antibiotics (eg, clindamycin) disease•Shotgun sequencing identified 4 depleted patients•Clindamycin depletes and exacerbates mice•Clostridia supplementation mitigates miceAbstractAdult (SCT) patients graft-versus-host-disease (GVHD) exhibit significant disruptions gut microbial communities. These changes are higher overall mortality...
Abstract Background Historically, creating patient-derived models of lower-grade glioma (LGG) has been challenging, contributing to few experimental platforms that support laboratory-based investigations this disease. Although organoid modeling approaches have recently employed create in vitro high-grade (HGG), it is unknown whether approach can be successfully applied LGG. Methods In study, we developed an optimized protocol for the establishment organoids from LGG primary tissue samples by...
Abstract Mutational signatures in cancer genomes have implicated the APOBEC3 cytosine deaminases oncogenesis, possibly offering a therapeutic vulnerability. Elevated APOBEC3B expression has been detected solid tumors, but of APOBEC3A (A3A) not described to date. Here, we report that A3A is highly expressed subsets pediatric and adult acute myelogenous leukemia (AML). We modeled THP1 AML cell line by introducing an inducible gene. caused ATR-dependent phosphorylation Chk1 cell-cycle arrest,...
Abstract Purpose: To investigate the antitumor activity of a mitochondrial-localized HSP90 inhibitor, Gamitrinib, in multiple glioma models, and to elucidate mechanisms Gamitrinib gliomas. Experimental Design: A broad panel primary temozolomide (TMZ)-resistant human cell lines were screened by viability assays, flow cytometry, crystal violet assays therapeutic efficacy Gamitrinib. Seahorse used measure mitochondrial respiration cells. Integrated analyses RNA sequencing (RNAseq) reverse phase...
Alpha-ketoglutarate (α-KG) is required for chromatin demethylation but mechanisms controlling α-KG abundance in the nucleus are poorly defined. Therefore, we designed a biosensor system to monitor this metabolite pool human cells using an α-KG-responsive cyanobacterial transcription factor, NtcA. We then coupled with genetic screen identify genes that regulate nucleus, defining inter-organelle pathway which sequential mitochondrial activities of GPT2 transaminase and SLC25A11 transporter...
To investigate the therapeutic role of a novel telomere-directed inhibitor, 6-thio-2'-deoxyguanosine (THIO) in gliomas both vitro and vivo.A panel human mouse glioma cell lines was used to test efficacy THIO using viability assays, flow cytometric analyses, immunofluorescence. Integrated analyses RNA sequencing reverse-phase protein array data revealed potential antitumor mechanisms THIO. Four patient-derived xenografts (PDX), two organoids (PDO), were further THIO.THIO effective majority...
Metabolism within the tumor microenvironment (TME) represents an increasing area of interest to understand glioma initiation and progression. Stable isotope tracing is a technique critical study metabolism. Cell culture models this disease are not routinely cultured under physiologically relevant nutrient conditions do retain cellular heterogeneity present in parental TME. Moreover, vivo, stable intracranial xenografts, gold standard for metabolic investigation, time consuming technically...
We previously demonstrated that reduced intrinsic electron transport chain (ETC) activity predicts and promotes sensitivity to the BCL-2 antagonist, venetoclax (Ven) in multiple myeloma (MM). Heme, an iron-containing prosthetic group, metabolite is fundamental maintaining ETC activity. Interrogation of CD2 subgroup MM from CoMMpass trial (NCT01454297), which can be used as a proxy for Ven-sensitive (VS MM), shows expression conserved heme biosynthesis pathway gene signature. Consistent with...
Commensal gut microbiota have been implicated in initiating and perpetuating intestinal graft versus host disease (iGVHD), but its role remains controversial. Recent murine studies shown that iGVHD results destruction of mucosal immune defenses resulting expansion pro-inflammatory bacteria (Enterobacteriaceae, ENTERO), by prophylactically treating mice with oral antibiotics suppress growth ENTERO, was significantly improved1. Furthermore, small-chain fatty acid producing (SCFA) Clostridia to...
The creation of patient-derived cancer organoids represents a key advance in preclinical modeling and has recently been applied to variety human solid tumor types. However, conventional methods used assess vivo tissue treatment response are poorly suited for the evaluation because they time-intensive involve destruction. To address this issue, we established suite 3-dimensional glioma organoids, treated them with chemoradiotherapy, stained non-toxic cell dyes, imaged using rapid laser...
INTRODUCTION: Glioma Surgically eXplanted Organoids (SXOs) are ex vivo three-dimensional models demonstrated to recapitulate the parental tumor microenvironment (TME). Human plasma-like medium (HPLM), a culture that mirrors physiologic nutrient conditions, has been found in other cancer subtypes induce transcriptional differences T-lymphocyte activation. We hypothesized SXO HPLM would maintain immune cell populations and physiologically relevant immune-modulatory pathways. METHODS: SXOs were...
SUMMARY Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors effective against they appear less active aggressive underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1 glioma cells hypersensitive to drugs targeting de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate (DHODH). We developed genetically...
Abstract Creating in vitro models of lower grade glioma represents a major challenge neuro-oncology research. There are few such that tractable and widely used, which has hindered understanding the biology these tumors. Recently, substantial progress been made generating patient-derived organoid high glioma, but modeling disease remains difficult. Based on our experience creating neurosphere cultures astrocytomas from genetically engineered mice, we hypothesized modifying generation...
Abstract The creation of patient-derived cancer organoids represents a key advance in preclinical modeling and has recently been applied to variety human solid tumor types. However, conventional methods used assess cellular viability tissue specimens are poorly suited for the evaluation because they time-intensive involve destruction. To address this issue, we established suite 3-dimensional glioma organoids, treated them with chemoradiotherapy, stained non-toxic cell dyes, imaged using...
Supplementary Data from Antitumor Activity of a Mitochondrial-Targeted HSP90 Inhibitor in Gliomas
Supplementary Figure from Antitumor Activity of a Mitochondrial-Targeted HSP90 Inhibitor in Gliomas
Supplementary Figure from Antitumor Activity of a Mitochondrial-Targeted HSP90 Inhibitor in Gliomas
Supplementary Figure from Antitumor Activity of a Mitochondrial-Targeted HSP90 Inhibitor in Gliomas