41 results on '"Giselle Y. Lopez"'
Search Results
2. Supplementary Table 2 from Disruption of Wild-Type IDH1 Suppresses D-2-Hydroxyglutarate Production in IDH1-Mutated Gliomas
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Hai Yan, Darell D. Bigner, Roger E. McLendon, Yiping He, Giselle Y. Lopez, Rui Yang, B. Ahmed Rasheed, David M. Gooden, Ivan Spasojevic, Christopher G. Duncan, Zachary J. Reitman, and Genglin Jin
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PDF file-23KB, D-2HG in cell line lysate samples, as assessed by LC-MS/M
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- 2023
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Catalog
3. Supplementary Table 1 from Disruption of Wild-Type IDH1 Suppresses D-2-Hydroxyglutarate Production in IDH1-Mutated Gliomas
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Hai Yan, Darell D. Bigner, Roger E. McLendon, Yiping He, Giselle Y. Lopez, Rui Yang, B. Ahmed Rasheed, David M. Gooden, Ivan Spasojevic, Christopher G. Duncan, Zachary J. Reitman, and Genglin Jin
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PDF file-22KB, D-2HG in primary human glioma tissue samples, as assessed by LC-MS/MS
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- 2023
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4. Supplementary Figure 3 from Disruption of Wild-Type IDH1 Suppresses D-2-Hydroxyglutarate Production in IDH1-Mutated Gliomas
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Hai Yan, Darell D. Bigner, Roger E. McLendon, Yiping He, Giselle Y. Lopez, Rui Yang, B. Ahmed Rasheed, David M. Gooden, Ivan Spasojevic, Christopher G. Duncan, Zachary J. Reitman, and Genglin Jin
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PDF file-101KB, Mutant IDH1 in the absence of wild type IDH1 is not sufficient to efficiently produce D-2HG in HCT116 cells
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- 2023
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5. Frequent Mutations of POT1 Distinguish Pulmonary Sarcomatoid Carcinoma From Other Lung Cancer Histologies
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Erica Shen, Kyle M. Walsh, Giselle Y. Lopez, Joanne Xiu, and Rex C. Bentley
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Cancer Research ,Lung Neoplasms ,Chronic lymphocytic leukemia ,Telomere-Binding Proteins ,Adenocarcinoma of Lung ,Gene mutation ,medicine.disease_cause ,Shelterin Complex ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Biomarkers, Tumor ,medicine ,Humans ,Mutation frequency ,Lung cancer ,Sarcomatoid carcinoma ,Mutation ,business.industry ,High-Throughput Nucleotide Sequencing ,Sarcoma ,Prognosis ,medicine.disease ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,Cancer research ,KRAS ,Carcinogenesis ,business - Abstract
Introduction Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non–small-cell lung cancer (NSCLC) harboring mutations in many canonical NSCLC-driver genes (eg, TP53, KRAS, MET). Protection of telomeres 1 (POT1) mutations are observed in angiosarcoma and chronic lymphocytic leukemia, but their frequency in other solid tumors, including NSCLC subtypes, has not been rigorously explored. Materials and Methods We analyzed next-generation sequencing data from 62,368 tumors, including 11,134 NSCLCs and 100 PSCs. We performed logistic regression to identify associations between POT1 mutation frequency and tumor histology across 184 tumor categories, adjusting for tumor mutational burden. We further explored co-occurring gene mutations in genes previously reported to underlie PSC tumorigenesis. Results Across 184 tumor categories, POT1 mutations were most frequent in PSC and were 14 times more common in PSC (28%) than in other tumor types (P = 1.23 × 10-31) and 6.7 times more common in PSC than other NSCLCs (P = 5.1 × 10-17). PSCs harboring KRAS mutations were significantly more likely to harbor POT1 mutations (P = 1.3 × 10-3), whereas those with TP53 mutations were less likely to harbor POT1 mutations (P = .037). One-fourth of POT1-mutated PSCs harbored a second POT1 mutation. Across all PSCs, 83% of POT1 mutations were in the OB1/OB2 (DNA-binding) domain (P = 1.5 × 10-5), an enrichment not observed in other tumor types. Conclusion We report an unanticipated association between POT1 mutation and PSC. Unlike other molecular alterations that are frequent across NSCLC subtypes, POT1 mutations are largely unique to PSC. This finding may help to develop disease-defining molecular subgroups within PSC and presents opportunities for molecularly stratified prognostication and therapy. more...
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- 2020
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6. Papillary Glioneuronal Tumor With a Novel GPR37L1-PRKCA Fusion
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Janice S Ahn, Shih-Hsiu Wang, John F. Ervin, Giselle Y. Lopez, and Thomas J. Cummings
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Cellular and Molecular Neuroscience ,Pathology ,medicine.medical_specialty ,Neurology ,medicine ,Papillary glioneuronal tumor ,Neurology (clinical) ,General Medicine ,Biology ,Pathology and Forensic Medicine - Published
- 2021
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7. POT1 mutation spectrum in tumour types commonly diagnosed among POT1-associated hereditary cancer syndrome families
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Melissa L. Bondy, Erica Shen, Matthew N. Bainbridge, Rex C. Bentley, Joanne Xiu, Kyle M. Walsh, Giselle Y. Lopez, Amy B. Heimberger, and Ali Jalali
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0301 basic medicine ,Genome instability ,Mutation ,Colorectal cancer ,business.industry ,Context (language use) ,medicine.disease ,medicine.disease_cause ,Shelterin ,Article ,Germline ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Genetics ,Cancer research ,medicine ,Angiosarcoma ,Mutation frequency ,business ,Genetics (clinical) - Abstract
BackgroundThe shelterin complex is composed of six proteins that protect and regulate telomere length, including protection of telomeres 1 (POT1). Germline POT1 mutations are associated with an autosomal dominant familial cancer syndrome presenting with diverse malignancies, including glioma, angiosarcoma, colorectal cancer and melanoma. Although somatic POT1 mutations promote telomere elongation and genome instability in chronic lymphocytic leukaemia, the contribution of POT1 mutations to development of other sporadic cancers is largely unexplored.MethodsWe performed logistic regression, adjusted for tumour mutational burden, to identify associations between POT1 mutation frequency and tumour type in 62 368 tumours undergoing next-generation sequencing.ResultsA total of 1834 tumours harboured a non-benign mutation of POT1 (2.94%), of which 128 harboured a mutation previously reported to confer familial cancer risk in the setting of germline POT1 deficiency. Angiosarcoma was 11 times more likely than other tumours to harbour a POT1 mutation (p=1.4×10−20), and 65% of POT1-mutated angiosarcoma had >1 mutations in POT1. Malignant gliomas were 1.7 times less likely to harbour a POT1 mutation (p=1.2×10−3) than other tumour types. Colorectal cancer was 1.2 times less likely to harbour a POT1 mutation (p=0.012), while melanoma showed no differences in POT1 mutation frequency versus other tumours (p=0.67).ConclusionsThese results confirm a role for shelterin dysfunction in angiosarcoma development but suggest that gliomas arising in the context of germline POT1 deficiency activate a telomere-lengthening mechanism that is uncommon in gliomagenesis. more...
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- 2020
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8. Publisher Correction: Ganglioglioma deep transcriptomics reveals primitive neuroectoderm neural precursor‑like population
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Joshua A. Regal, María E. Guerra García, Vaibhav Jain, Vidyalakshmi Chandramohan, David M. Ashley, Simon G. Gregory, Eric M. Thompson, Giselle Y. López, and Zachary J. Reitman
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Neurology. Diseases of the nervous system ,RC346-429 - Published
- 2024
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9. Spatial transcriptomics reveals segregation of tumor cell states in glioblastoma and marked immunosuppression within the perinecrotic niche
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Mengyi Liu, Zhicheng Ji, Vaibhav Jain, Vanessa L. Smith, Emily Hocke, Anoop P. Patel, Roger E. McLendon, David M. Ashley, Simon G. Gregory, and Giselle Y. López
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Glioblastoma ,Spatial transcriptomics ,Single-cell sequencing ,Tumor microenvironment ,Perinecrotic niche ,Perivascular niche ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Glioblastoma (GBM) remains an untreatable malignant tumor with poor patient outcomes, characterized by palisading necrosis and microvascular proliferation. While single-cell technology made it possible to characterize different lineage of glioma cells into neural progenitor-like (NPC-like), oligodendrocyte-progenitor-like (OPC-like), astrocyte-like (AC-like) and mesenchymal like (MES-like) states, it does not capture the spatial localization of these tumor cell states. Spatial transcriptomics empowers the study of the spatial organization of different cell types and tumor cell states and allows for the selection of regions of interest to investigate region-specific and cell-type-specific pathways. Here, we obtained paired 10x Chromium single-nuclei RNA-sequencing (snRNA-seq) and 10x Visium spatial transcriptomics data from three GBM patients to interrogate the GBM microenvironment. Integration of the snRNA-seq and spatial transcriptomics data reveals patterns of segregation of tumor cell states. For instance, OPC-like tumor and NPC-like tumor significantly segregate in two of the three samples. Our differentially expressed gene and pathway analyses uncovered significant pathways in functionally relevant niches. Specifically, perinecrotic regions were more immunosuppressive than the endogenous GBM microenvironment, and perivascular regions were more pro-inflammatory. Our gradient analysis suggests that OPC-like tumor cells tend to reside in areas closer to the tumor vasculature compared to tumor necrosis, which may reflect increased oxygen requirements for OPC-like cells. In summary, we characterized the localization of cell types and tumor cell states, the gene expression patterns, and pathways in different niches within the GBM microenvironment. Our results provide further evidence of the segregation of tumor cell states and highlight the immunosuppressive nature of the necrotic and perinecrotic niches in GBM. more...
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- 2024
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10. BIOM-17. DIFFERENCES IN THE IMMUNE MICROENVIRONMENT OF GLIOMAS HARBORING IDH2 VERSUS IDH1 MUTATIONS
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Edward Pan, Kyle M. Walsh, Giselle Y. Lopez, Michael Glantz, Quinn T. Ostrom, Sonikpreet Aulakh, Ashley Sumrall, Mustafa Khasraw, Joanne Xiu, and David M. Ashley
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Cancer Research ,Tumor microenvironment ,Mutation ,IDH1 ,medicine.medical_treatment ,Immunotherapy ,26th Annual Meeting & Education Day of the Society for Neuro-Oncology ,Biology ,medicine.disease ,medicine.disease_cause ,IDH2 ,Oncology ,Glioma ,DNA methylation ,medicine ,Cancer research ,Neurology (clinical) ,Oligodendroglioma ,neoplasms - Abstract
INTRODUCTION IDH mutations are a defining feature of lower-grade glioma and secondary glioblastoma. Approximately 95% of glioma-associated IDH mutations are in codon 132 of IDH1, but a small proportion are in IDH2. IDH mutations produce the oncometabolite 2-hydroxyglutarate, which induces global DNA hypermethylation and is associated with an immunosuppressive tumor microenvironment. IDH1 is localized in the cytosol while IDH2 is found in the mitochondrial matrix, and mutations in these genes may have differing effects on the tumor microenvironment. METHODS Formalin-fixed, paraffin-embedded tissue from 633 IDH-mutant gliomas (615 IDH1-mutant, 18 IDH2-mutant) underwent whole-exome and whole-transcriptome sequencing at Caris Life Sciences (236 grade 2/3 astrocytoma, 158 grade 2/3 oligodendroglioma, 202 IDH-mutant glioblastoma, 37 glioma, NOS). QuantiSEQ was used to infer tumor-infiltrating immune cell populations from RNAseq data, and gene-set enrichment analyses (GSEA) were performed using Wikipathway. RESULTS IDH1-mutant gliomas had higher levels of pro-inflammatory M1 macrophages (P=0.04), modestly higher levels of monocytes (P=0.08), and lower levels of neutrophils (P=0.04) – typically considered immunosuppressive – compared with IDH2-mutant gliomas. No differences were observed in levels of B cells, dendritic cells, NK cells, or T cell subsets (Treg, CD4+, CD8+). IDH2-mutant gliomas were enriched for hallmark oligodendroglioma mutations (TERT promoter, CIC, FUBP1), while IDH1-mutant gliomas were enriched for hallmark astrocytoma mutations (ATRX, TP53). However, associations with tumor-infiltrating immune cells persisted after excluding 1p/19q co-deleted oligodendroglioma from analyses. GSEA revealed upregulation of the microglial TYROBP signaling pathway, the microglial phagocytic pathway, and of Type II Interferon signaling in IDH1-mutant gliomas versus IDH2-mutant gliomas. CONCLUSIONS Although IDH2 mutations are generally thought to function similarly to IDH1 mutations, we observe differences in tumor-infiltrating immune cells across groups. IDH2-mutant gliomas appeared to have a more immunosuppressive tumor microenvironment than their IDH1-mutant counterparts. Early-phase immunotherapy trials should consider covariate-adaptive randomization approaches to equally allocate IDH2-mutant gliomas across treatment arms. more...
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- 2021
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11. Molecular Stratification of Adult and Pediatric High Grade Gliomas
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Huifang Dai, Giselle Y. Lopez, and Yuanfan Yang
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Oncology ,medicine.medical_specialty ,Mutation ,Massive parallel sequencing ,Molecular pathology ,business.industry ,PDGFRA ,medicine.disease ,medicine.disease_cause ,Germline mutation ,Turcot Syndrome Type 1 ,Internal medicine ,medicine ,ROS1 ,Neurofibromatosis ,business - Abstract
Glioblastoma is the most common primary malignant brain tumor in adults. While less common in children, high grade glial and glioneuronal tumors are diagnosed in over 1000 pediatric patients per year in the United States. Given the marked advances in massively parallel sequencing over the last two decades, combined with advances in epigenetic studies such as methylation profiling, we now have a better understanding of the molecular features underlying and driving high grade gliomas in both adults and children. These molecular features are now used as part of the classification of these tumors, and aid in predicting their overall behavior and response to different therapeutic modalities. Herein, we describe the genetic characteristics of the most common high grade glial and glioneuronal tumors in adults and children, starting with the class-defining mutations, and moving into additional mutations commonly seen in the different tumor classes. As a broad category, high grade gliomas in adults can be divided into three main categories- (1) midline gliomas with H3 K27M mutations, (2) IDH-mutant glioblastomas, and (3) IDH-wildtype glioblastomas. Within children, there are many more categories. The histone mutation driven tumors are broadly divided into (1) midline gliomas with H3 K27M mutations and (2) hemispheric gliomas with H3 G34 R/V mutations. Additional high grade gliomas in children can be driven by many other drivers, including but not limited to amplifications of MYC/MYCN, PDGFRA, or EGFR. Infantile high grade gliomas represent another distinct category, driven by NTRK fusion or alterations in genes of the receptor tyrosine kinase signaling pathway, including ALK, ROS1, and MET. Finally, we briefly touch on some germline mutations that lead to an increased incidence of high grade gliomas, including those of neurofibromatosis type 1, Li-Fraumeni syndrome, and constitutional mismatch repair deficiency/Turcot syndrome type 1. more...
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- 2021
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12. Eosinophilic globules in a classic ependymoma: evidence of a possible secretory role
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Anne F. Buckley, Maureen Petersen, Giselle Y. Lopez, Thomas J. Cummings, Janice S Ahn, Allan H. Friedman, and Edward M López
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0301 basic medicine ,Ependymoma ,Male ,Pathology ,medicine.medical_specialty ,Cell type ,Ependymal Cell ,Adolescent ,Posterior fossa ,EOSINOPHILIC GLOBULES ,Infratentorial Neoplasms ,Pathology and Forensic Medicine ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Structural Biology ,law ,medicine ,Humans ,Chemistry ,medicine.disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Ultrastructure ,Electron microscope ,Subcommissural organ - Abstract
A number of neoplasms of the central nervous system can demonstrate diffuse eosinophilic globules, known to be secretory products of the corresponding cell type, but they have not been a salient feature in descriptions of classic ependymoma. Here, we present a case of a posterior fossa ependymoma demonstrating glassy PAS-positive, diastase-resistant, eosinophilic globules with light microscopic and ultrastructural features resembling Reissner fiber, the secretory product of the subcommissural organ. While there has been a single published description of an ependymoma with intra- and extracellular granulofibrillary material suggested to be evidence of secretory differentiation, ours is the first case to demonstrate diffuse eosinophilic globules in an ependymoma. The extent of globules allowed full study by electron microscopy to provide new insight into the secretory material and the surrounding structures. Our findings suggest that neoplastic ependymal cells can recapitulate the secretory capacity of the subcommissural organ. more...
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- 2020
13. Catastrophic stroke burden in a patient with uncontrolled psoriasis and psoriatic arthritis: a case report
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Karl Meisel, Giselle Y. Lopez, Cathra Halabi, Anthony S. Kim, David A. Solomon, Jeffrey W. Hofmann, Rene A. Colorado, and Joline M. Fan
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Aging ,Case Report ,Psoriatic ,Comorbidity ,Cardiovascular ,Systemic inflammation ,lcsh:RC346-429 ,030207 dermatology & venereal diseases ,0302 clinical medicine ,Fatal Outcome ,Risk Factors ,2.1 Biological and endogenous factors ,Myocardial infarction ,Aetiology ,Stroke ,Metabolic Syndrome ,education.field_of_study ,General Medicine ,Middle Aged ,Psoriatic arthritis ,Female ,Cognitive Sciences ,medicine.symptom ,Vasculitis ,medicine.medical_specialty ,Population ,Autoimmune Disease ,03 medical and health sciences ,Clinical Research ,Psoriasis ,Internal medicine ,medicine ,Humans ,Obesity ,education ,lcsh:Neurology. Diseases of the nervous system ,030203 arthritis & rheumatology ,Neurology & Neurosurgery ,business.industry ,Inflammatory and immune system ,Arthritis ,Arthritis, Psoriatic ,Neurosciences ,medicine.disease ,Atherosclerosis ,Brain Disorders ,Neurology (clinical) ,Metabolic syndrome ,business - Abstract
Background Psoriasis is the most common chronic inflammatory condition involving the T helper cell system. Population studies have demonstrated that patients with psoriasis and/or psoriatic arthritis have an increased risk of developing vascular risk factors, including diabetes, hypertension, and obesity, and increased risk of adverse vascular events, including myocardial infarction and stroke. Population studies have generally investigated the individual contributions of psoriasis and psoriatic arthritis to development of vascular risk factors; fewer studies have investigated the additive contribution of comorbid inflammatory disorders. We present a case of a woman with psoriasis, psoriatic arthritis, and comorbid vascular risk factors. Case presentation A 49 year-old Caucasian woman with a history of severe psoriasis and psoriatic arthritis since adolescence presented with bilateral lower extremity weakness. She was found to have acute bilateral watershed infarcts and multifocal subacute infarcts. Her evaluation revealed vascular risk factors and elevated non-specific systemic inflammatory markers; serum and cerebral spinal fluid did not reveal underlying infection, hypercoagulable state, or vasculitis. Over the course of days, she exhibited precipitous clinical deterioration related to multiple large vessel occlusions, including the bilateral anterior cerebral arteries and the left middle cerebral artery. Autopsy revealed acute thrombi and diffuse, severe atherosclerosis. Conclusion Patients with early onset inflammatory disease activity or comorbid inflammatory disorders may have an even higher risk of developing metabolic syndrome and adverse vascular events compared to patients with late-onset disease activity or with a single inflammatory condition. The described case illustrates the complex relationship between inflammatory disorders and vascular risk factors. The degree of systemic inflammation, as measured by severity of disease activity, has been shown to have a dose-response relationship with comorbid vascular risk factors and vascular events. Dysregulation of the Th1 and Th17 system has been implicated in the development of atherosclerosis and may explain the severe atherosclerosis seen in such chronic inflammatory conditions. Further research will help refine screening and management guidelines to account for comorbid inflammatory disorders and related disease severity. more...
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- 2020
14. EXTH-77. POLIO VIROTHERAPY OF MURINE BRAIN TUMORS INDUCES MICROGLIA PROLIFERATION AND INFLAMMATION THAT IS POTENTIATED BY IMMUNE CHECKPOINT BLOCKADE
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Gao Zhang, Matthias Gromeier, Michael C. Brown, Kevin Stevenson, Reb Kornahrens, Yuanfan Yang, and Giselle Y. Lopez
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Cancer Research ,Tumor microenvironment ,Cell cycle checkpoint ,Microglia ,business.industry ,medicine.medical_treatment ,Inflammation ,Immunotherapy ,26th Annual Meeting & Education Day of the Society for Neuro-Oncology ,Immune checkpoint ,Blockade ,medicine.anatomical_structure ,Oncology ,medicine ,Cancer research ,Neurology (clinical) ,Virotherapy ,medicine.symptom ,business - Abstract
Immunotherapy with polio:rhinovirus recombinant (PVSRIPO) has shown evidence of efficacy in a phase I clinical trial for recurrent GBM, resulting in durable radiographic responses and 21% long-term survival at 36 months. Ongoing research aims to enhance the clinical response rate by resolving the mechanisms of action and therapy resistance in vivo, thereby devising more effective therapies. Mouse glioma (CT2A) cells were intracranially implanted (day 0) in transgenic mice carrying poliovirus receptor CD155, and treated with intratumor PVSRIPO (5×105 pfu; day 6) to dissect early and late events following therapy. A blinded pathological review of 45 post-treatment tumors was performed. On day 8, a histological response, featured by tumor dissociation and shrinkage, with inflammation and microglia enrichment in the treated hemisphere, was common in PVSRIPO group (6/7) compared to controls (0/4). However, the response rate fell over time (7/12 on day 12; 1/7 on day 15) and the therapy was overcome by aggressive tumor regrowth. RNAseq was performed and Gene Set Enrichment Analysis of the tumor microenvironment revealed an acute type-I interferon (IFN)-related inflammation, correlating with the histological findings of profound proinflammatory engagement of microglia (Iba1+) widespread in the treated hemisphere. Microglia proliferation (Ki67+) was observed in the treated hemisphere, likely resulting from PVSRIPO infection, in CT2A and B16 intracranial models. This suggests an association of adaptive antitumor immunity—elicited by immediate intratumor type-I IFN-dominant inflammation—with tumor regression. Thus, buttressing type-I IFN directed antitumor CD8+T cell immunity, e.g. with blockade of the PD1:PD-L1 immune checkpoint, might contribute to tumor remission. Indeed, combination therapy with αPD-L1 antibody in the CT2A model showed longer median survival and higher long-term remission rate compared to monotherapy alone; CD8 T cell depletion can completely abrogate this efficacy with this therapy combination, confirming the role of anti-tumor immunity in this approach. more...
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- 2021
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15. Management of glioblastoma: State of the art and future directions
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Michael D. Malinzak, David M. Ashley, Mustafa Khasraw, Henry S. Friedman, Giselle Y. Lopez, and Aaron C. Tan
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Oncology ,medicine.medical_specialty ,Palliative care ,Bevacizumab ,medicine.medical_treatment ,Magnetic Field Therapy ,Brain tumor ,Antineoplastic Agents ,Disease ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Temozolomide ,Tumor Microenvironment ,Medicine ,Humans ,030212 general & internal medicine ,Precision Medicine ,business.industry ,Brain Neoplasms ,Incidence ,Brain ,Hematology ,Chemoradiotherapy, Adjuvant ,medicine.disease ,Prognosis ,Magnetic Resonance Imaging ,Isocitrate Dehydrogenase ,United States ,Clinical trial ,Radiation therapy ,Survival Rate ,Review Literature as Topic ,Treatment Outcome ,030220 oncology & carcinogenesis ,Mutation ,Immunotherapy ,Neoplasm Recurrence, Local ,business ,Glioblastoma ,medicine.drug - Abstract
Glioblastoma is the most common malignant primary brain tumor. Overall, the prognosis for patients with this disease is poor, with a median survival of
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- 2020
16. Proinflammatory cytokines and ARDS pulmonary edema fluid induce CD40 on human mesenchymal stromal cells-A potential mechanism for immune modulation
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Jae-Woo Lee, Matthew Schwede, Erin M. Wilfong, Eréne C. Niemi, Mary C. Nakamura, Xiaohui Fang, Giselle Y. Lopez, Roxanne H. Croze, Michael A. Matthay, and Zhao, You-Yang
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0301 basic medicine ,Lipopolysaccharides ,Male ,ARDS ,Critical Care and Emergency Medicine ,Transcription, Genetic ,Pulmonology ,Physiology ,Gene Expression ,0302 clinical medicine ,Medical Conditions ,Spectrum Analysis Techniques ,Stem Cell Research - Nonembryonic - Human ,Immune Physiology ,Cellular types ,Medicine and Health Sciences ,Edema ,Lung ,Acute Respiratory Distress Syndrome ,Immune Response ,Cells, Cultured ,Respiratory Distress Syndrome ,Innate Immune System ,Multidisciplinary ,Cultured ,Transdifferentiation ,Immune cells ,Pulmonary edema ,Flow Cytometry ,Up-Regulation ,Spectrophotometry ,Cytokines ,White blood cells ,Medicine ,Female ,Cytophotometry ,medicine.symptom ,Transcription ,Bronchoalveolar Lavage Fluid ,Research Article ,Cell biology ,Blood cells ,endocrine system ,Stromal cell ,General Science & Technology ,Cells ,Science ,Immunology ,T cells ,Inflammation ,Cytotoxic T cells ,Research and Analysis Methods ,Proinflammatory cytokine ,03 medical and health sciences ,Paracrine signalling ,Respiratory Disorders ,Rare Diseases ,Signs and Symptoms ,Genetic ,Respiratory Failure ,medicine ,Genetics ,Humans ,CD40 Antigens ,business.industry ,Mesenchymal stem cell ,Biology and Life Sciences ,Mesenchymal Stem Cells ,Molecular Development ,Stem Cell Research ,medicine.disease ,equipment and supplies ,030104 developmental biology ,Animal cells ,Cyclooxygenase 2 ,Immune System ,Cell Transdifferentiation ,Cancer research ,Clinical Medicine ,business ,Cell Adhesion Molecules ,030215 immunology ,Developmental Biology - Abstract
Human mesenchymal stem/stromal cells (hMSCs) are a promising therapy for acute respiratory distress syndrome (ARDS) and other inflammatory conditions. While considerable research has focused on paracrine effects and mitochondrial transfer that improve lung fluid balance, hMSCs are well known to have immunomodulatory properties as well. Some of these immunomodulatory properties have been related to previously reported paracrine effectors such as indoleamine-2,3-dioxygenase (IDO), but these effects cannot fully account for cell-contact dependent immunomodulation. Here, we report that CD40 is upregulated on hMSCs under the same conditions previously reported to induce IDO. Further, CD40 transcription is also upregulated on hMSCs by ARDS pulmonary edema fluid but not by hydrostatic pulmonary edema fluid. Transcription of CD40, as well as paracrine effectors TSG6 and PTGS2 remained significantly upregulated for at least 12 hours after withdrawal of cytokine stimulation. Finally, induction of this immune phenotype altered the transdifferentiation of hMSCs, one of their hallmark properties. CD40 may play an important role in the immunomodulatory effects of hMSCs in ARDS and inflammation. more...
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- 2020
17. OTME-16. Polio virotherapy of murine brain tumors causes microglia/macrophage proliferation and inflammation that is potentiated by immune checkpoint blockade
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Kevin Stevenson, William Kornahrens, Gao Zhang, Michael C. Brown, Matthias Gromeier, Giselle Y. Lopez, and Yuanfan Yang
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Tumor microenvironment ,Cell cycle checkpoint ,Microglia ,business.industry ,Final Category: Omics of Tumor Microenvironment ,Inflammation ,Immune checkpoint ,Blockade ,Supplement Abstracts ,medicine.anatomical_structure ,Immune system ,medicine ,Cancer research ,AcademicSubjects/MED00300 ,AcademicSubjects/MED00310 ,medicine.symptom ,Virotherapy ,business - Abstract
PVSRIPO is a novel viral immunotherapy that has shown evidence of efficacy in a phase I clinical trial for recurrent GBM, resulting in 21% survival rate at 36 months following treatment. To improve clinical response rate, it is critical to resolve the mechanisms of action and therapy resistance in vivo, thereby designing effective combination therapy strategies. We used immunocompetent mouse models of glioma (CT2A) and metastatic melanoma (B16) to dissect early and late events following virotherapy with PVSRIPO. A blinded systematic review of the pathology from 62 intracranial tumors, collected on different days following PVSRIPO (or control) treatment, was performed. An overall treatment effect, measured by tumor shrinkage, dis-cohesive growth pattern, microglia enrichment, was present in 88% of tumors on day 8, but the tissue response rate fell to 42% on days 10 & 12, and 14% on day 15. The control group showed no treatment effect throughout. RNAseq from the same set of samples showed acute induction of type-I interferon-related inflammation that faded with time in Gene Set Enrichment Analysis. This suggests that sustaining adaptive antitumor immunity elicited by immediate intratumor type-I IFN-dominant inflammation is critical to long term remission. Careful review of the post treatment pathology revealed an early enrichment of both T cells and microglia in the tumor microenvironment with a high Ki-67 proliferation index. We propose that the PVSRIPO therapy effect is dependent on macrophage/microglia mediated cellular immune response, likely in response to direct viral infection. This suggests potential therapeutic interventions, including blockade of the PD1:PD-L1 immune checkpoint, to potentiate antitumor CD8+T cells in response to PVSRIPO therapy. Indeed, combination therapy with αPD-L1 antibody in the CT2A model showed higher long term remission (37%, n=11), compared to either monotherapy; this effect is CD8+T cell- and macrophage-dependent, demonstrated by depletion studies in vivo. more...
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- 2021
18. BIOM-17. BRAF MUTATION IS AN EARLY EVENT IN THE EVOLUTION OF A SUBSET OF GLIOBLASTOMAS AND IS ASSOCIATED WITH INCREASED PD-L1 EXPRESSION
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Emil Lou, David M. Ashley, Zachary J. Reitman, W. Michael Korn, Michael Glantz, Surasak Phuphanich, Joanne Xiu, Kyle M. Walsh, Andrew Brenner, Giselle Y. Lopez, Ekokobe Fonkem, Sandeep Mittal, Macarena I. de la Fuente, Herbert B. Newton, Daniel Landi, Mustafa Khasraw, Ashley Love Sumrall, Erin Dunbar, Manjari Pandey, and Santosh Kesari more...
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Cancer Research ,Pilocytic astrocytoma ,Astrocytoma ,O-6-methylguanine-DNA methyltransferase ,Methylation ,Biology ,medicine.disease ,digestive system diseases ,Fusion gene ,Oncology ,Glioma ,Mutation (genetic algorithm) ,medicine ,Cancer research ,Neurology (clinical) ,neoplasms ,Allele frequency ,Biomarkers - Abstract
INTRODUCTION BRAF is a RAF-family kinase that regulates MAPK/ERK signaling. Activating BRAF mutations, including V600E, are common in circumscribed low-grade gliomas of childhood and young adulthood, but are uncommon in infiltrative astrocytomas, including glioblastoma. Their role in glioblastoma initiation and progression requires analysis of large datasets given the low frequency (1.0%) in TCGA IDH-wild-type glioblastomas. METHODS Molecular profiling was done on 4679 FFPE gliomas by next-generation sequencing at Caris Life Sciences, of which 3170 underwent RNA-sequencing for gene fusion and 4603 DNA-sequencing for mutations. MGMT promoter methylation was tested by pyrosequencing and PD-L1 IHC was performed using the SP142 clone. RESULTS Excluding variants of uncertain significance, BRAF mutations/fusions were most common in pleomorphic xanthoastrocytoma (PXA; N=12/24, 50%), glioneuronal tumors (N=6/13, 46%), pilocytic astrocytoma (PA; N=15/48, 31%), and ganglioglioma (n=5/18, 28%). BRAF fusions were uncommon (N=17), most frequent in PA (N=8/31, 26%) where they were associated with older age at daignosis (P=0.043), and typically involved KIAA1549 as fusion partner (70%). BRAF-mutated/fused glioblastoma patients (N=59/3126, 2%) were younger than BRAF-wild-type glioblastoma patients (54 versus 59 years, P=3.5x10-3); more likely to be MGMT-unmethylated (75% versus 56%, P=5.0x10-3); and 3x more likely to express PD-L1 (55% versus 17%, P=2.1x10-10). In tumors harboring a V600E mutation, the variant allele frequency (VAF) was similar in glioblastoma as in PXA, PA, ganglioglioma, and glioneuronal tumors (median VAF=35%). CONCLUSIONS BRAF-mutated glioblastoma were 3x more likely to express PD-L1 than BRAF-wild-type glioblastoma. We observed no differences in BRAF V600E clonality in BRAF-mutated glioblastoma compared to BRAF-mutated PXA, PA, ganglioglioma, and glioneuronal tumors, suggesting BRAF mutation is an initiating event in the clonal evolution of a subset of glioblastoma. There is rationale to evaluate combined BRAF inhibition with checkpoint inhibition in BRAF-mutated glioblastoma, potentially synergizing the complete response profile of the former with the durable response profile of the latter. more...
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- 2020
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19. Autoimmune pancerebellitis associated with pembrolizumab therapy
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Jeffrey R. Vitt, Elliot Dickerson, Nausheen F. Mahmood, Giselle Y. Lopez, Collin J. Kreple, and Megan B. Richie
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Male ,Cerebellar Ataxia ,Cell ,Clinical Sciences ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,medicine.disease_cause ,Methylprednisolone ,Antibodies ,Autoimmunity ,Autoimmune Diseases ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Immunity ,Monoclonal ,Medicine ,Humans ,Receptor ,Clinical/Scientific Notes ,Humanized ,Aged ,Neurology & Neurosurgery ,biology ,business.industry ,Melanoma ,Neurosciences ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Cognitive Sciences ,Neurology (clinical) ,Antibody ,business ,030217 neurology & neurosurgery - Abstract
Checkpoint proteins reduce immune-mediated responses to promote self-tolerance and prevent autoimmunity. Programmed cell death protein 1 (PD-1) is a checkpoint receptor protein expressed on leukocytes that inactivates T cell–mediated immunity when bound to ligand PD-L1. Certain tumors can escape immune-mediated destruction by expressing high concentrations of PD-L1, evading host surveillance.1 PD-1 pathway inhibitors effectively treat multiple malignancies including melanoma, non-small cell lung cancer, and squamous cell carcinoma.2 However, there is increasing recognition of immune-related adverse events (irAE) associated with checkpoint inhibitor therapy due to dysregulated immune system activation.1 We report immune-mediated cerebellitis following pembrolizumab. more...
- Published
- 2018
20. CDKN2A/B Loss is Associated with Anaplastic Transformation in a Case of NTRK2 Fusion-positive Pilocytic Astrocytoma
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Marilyn M. Li, Arie Perry, Giselle Y. Lopez, Mariarita Santi, and Brian Harding
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0301 basic medicine ,Histology ,Clinical Sciences ,Pilocytic Astrocytomas ,Astrocytoma ,Cdkn2a b ,Article ,Pathology and Forensic Medicine ,Malignant transformation ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,medicine ,Humans ,Neurofibromatosis ,Child ,Preschool ,neoplasms ,Grade I Astrocytomas ,Cyclin-Dependent Kinase Inhibitor p16 ,Cyclin-Dependent Kinase Inhibitor p15 ,Unusual case ,Membrane Glycoproteins ,Neurology & Neurosurgery ,Pilocytic astrocytoma ,Extramural ,business.industry ,Brain Neoplasms ,Neurosciences ,Brain ,medicine.disease ,nervous system diseases ,030104 developmental biology ,Neurology ,nervous system ,trkB ,Cancer research ,Female ,Cognitive Sciences ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Receptor - Abstract
Pilocytic astrocytomas are typically grade I astrocytomas, only rarely progressing to anaplastic counterparts [1]. In the case of anaplastic pilocytic astrocytomas, some are associated with neurofibromatosis type 1 (NF1) [2], others are associated with radiation treatment [2], and the remainder appear de novo. These de novo tumours can be particularly challenging to distinguish from glioblastomas, which are grade IV and carry a worse prognosis. Here we report an unusual case of malignant transformation of a pilocytic astrocytoma in the absence of NF1 alterations or radiation treatment. more...
- Published
- 2018
21. Metastatic cervical paravertebral solitary fibrous tumor detected by fluorodeoxyglucose positron emission tomography-computed tomography
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Maya Vella, Courtney Lawhn-Heath, Giselle Y. Lopez, Hoiwan Cheung, and Carina Mari Aparici
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lcsh:Medical physics. Medical radiology. Nuclear medicine ,Solitary fibrous tumor ,medicine.medical_specialty ,Metastatic lesions ,lcsh:R895-920 ,Computed tomography ,Metastases ,Fluorodeoxyglucose positron emission tomography ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Radiology, Nuclear Medicine and imaging ,Head and neck ,Cancer ,Hemangiopericytoma ,medicine.diagnostic_test ,business.industry ,Soft tissue ,medicine.disease ,030220 oncology & carcinogenesis ,Right posterior ,Biomedical Imaging ,Radiology ,Nuclear Medicine ,business ,030217 neurology & neurosurgery ,4.2 Evaluation of markers and technologies - Abstract
Solitary fibrous tumors/hemangiopericytomas (SFT/HPC) are soft tissue tumors that can arise from the abdomen, pleura, head and neck, or extremities. We report an unusual case of recurrent hemangiopericytoma in a 67-year-old female presenting with a painless and palpable mass within her right posterior neck. Eight years after initial resection of the mass, a follow-up MRI showed multiple enlarging calvarial lesions. A whole body FDG-PET/CT revealed not only hypermetabolic calvarial lesions but also numerous hypermetabolic axillary node and osseous metastases. Though the majority of these soft tissue tumors exhibit benign behavior and carry a favorable prognosis, patients with these slow growing tumors are at risk for local recurrence and distant metastases which demonstrate substantial FDG avidity. Additional studies are needed to clarify the role of whole body FDG-PET/CT in the surveillance of SFT/HPC to detect recurrent or metastatic lesions. Keywords: Solitary fibrous tumor, Hemangiopericytoma, Metastases more...
- Published
- 2018
22. Supratentorial Tanycytic Ependymoma in an Adult Male: Case Report and Review of Literature
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Katherine B. Peters, Roger E. McLendon, and Giselle Y. Lopez
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Adult ,Pathology ,medicine.medical_specialty ,Ependymal Cell ,Adult male ,business.industry ,Central nervous system ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,medicine.anatomical_structure ,Supratentorial tanycytic ependymoma ,Oncology ,Tanycytic ependymoma ,Medicine ,Published online: March, 2015 ,business ,Clear cell ,Pediatric population - Abstract
Ependymomas, tumors of the ependymal cells, are very rare and usually present in the pediatric population. Furthermore, there are even rarer variants of ependymomas that can include cellular, papillary, clear cell, and tanycytic subtypes. We present a case of a supratentorial tanycytic ependymoma in an adult male and review the literature in regard to this rare primary central nervous system neoplasm. more...
- Published
- 2015
23. Perilesional edema associated with an intracranial calcifying pseudoneoplasm of the neuraxis in a child: case report and review of imaging features
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Shailesh Asaikar, Nalin Gupta, Tarik Tihan, Michael Safaee, Giselle Y. Lopez, Soren Jonzzon, and Orit A. Glenn
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Male ,Pathology ,medicine.medical_specialty ,Contrast enhancement ,Radiography ,Brain tumor ,GFAP = glial fibrillary acidic protein ,Resection ,Lesion ,Paediatrics and Reproductive Medicine ,03 medical and health sciences ,0302 clinical medicine ,Edema ,medicine ,Humans ,Child ,Pathological ,CAPNON ,Brain Diseases ,Neurology & Neurosurgery ,business.industry ,Neurosciences ,Brain ,Calcinosis ,General Medicine ,calcifying pseudoneoplasm of the neuraxis ,medicine.disease ,Signal on ,CAPNON = calcifying pseudoneoplasm of the neuraxis ,Brain Disorders ,pediatric ,030220 oncology & carcinogenesis ,oncology ,Biomedical Imaging ,medicine.symptom ,business ,030217 neurology & neurosurgery ,brain tumor - Abstract
Calcifying pseudoneoplasms of the neuraxis (CAPNONs) are rare, nonneoplastic lesions of the CNS. Their radiographic features have been well described, with prominent calcifications seen on CT imaging and generally uniform hypointensity on T1- and T2-weighted MRI sequences, with variable patterns of contrast enhancement. They are not associated with significant perilesional edema. The authors present an unusual case of an 8-year-old boy who was found to have a 2.5-cm right frontal mass that demonstrated reduced signal on T2-weighted sequences, heterogeneous contrast enhancement, and extensive perilesional edema on MRI sequences. The differential diagnoses included a chronic infection or neoplasm. He underwent gross-total resection of a firm, calcified mass that had clear boundaries between it and the surrounding gliotic brain. Pathological analysis demonstrated a well-circumscribed lesion with islands of lamellar calcifications and intervening spindle cells, consistent with a CAPNON. At 8 months after surgery the patient remained seizure free, and MRI revealed no evidence of residual lesion and significant improvement in perilesional edema. This particular case highlights the potential for unusual presentation of CAPNON and the rare presence of perilesional edema. more...
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- 2018
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24. Diffuse midline gliomas with subclonal H3F3A K27M mutation and mosaic H3.3 K27M mutant protein expression
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Arie Perry, John Paul Bouffard, Yaron A. Moshel, Kurt A. Jaeckle, Bette K. Kleinschmidt-DeMasters, David A. Solomon, Giselle Y. Lopez, Joanna J. Phillips, Marc K. Rosenblum, and Nancy Ann Oberheim Bush more...
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Genetics ,Mutation ,K27m mutation ,Fatal outcome ,business.industry ,medicine.disease_cause ,Molecular biology ,Article ,Pathology and Forensic Medicine ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Mutant protein ,030220 oncology & carcinogenesis ,Gene expression ,medicine ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Published
- 2017
25. Occipital Headache in Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS)
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Bardia Nourbakhsh, Giselle Y. Lopez, Christian Cordano, and Andrew W. Bollen
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Inflammation ,030218 nuclear medicine & medical imaging ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,Occipital headache ,Medicine ,Humans ,Brain Diseases ,Chronic lymphocytic inflammation ,business.industry ,Headache ,Brain ,Neurology ,Chronic Disease ,Steroids ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Central Nervous System Agents - Published
- 2017
26. Diffuse non-midline glioma with H3F3A K27M mutation: a prognostic and treatment dilemma
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David A. Solomon, Nancy Ann Oberheim Bush, Mitchel S. Berger, Giselle Y. Lopez, and Arie Perry
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Pathology ,medicine.medical_specialty ,IDH1 R132H ,Psychoanalysis ,K27m mutation ,Clinical Sciences ,Midline Structure ,lcsh:RC346-429 ,Pathology and Forensic Medicine ,Histones ,Young Adult ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Diffuse Glioma ,0302 clinical medicine ,Glioma ,Humans ,Medicine ,Letter to the Editor ,lcsh:Neurology. Diseases of the nervous system ,Brain Neoplasms ,business.industry ,Neurosciences ,Brain ,Prognosis ,medicine.disease ,K27M Mutation ,3. Good health ,030220 oncology & carcinogenesis ,Mutation ,Female ,Biochemistry and Cell Biology ,Neurology (clinical) ,Eosinophilic Granular Body ,business ,030217 neurology & neurosurgery - Abstract
Author(s): Lopez, Giselle; Oberheim Bush, Nancy Ann; Berger, Mitchel S; Perry, Arie; Solomon, David A
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- 2017
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27. Ganglioglioma deep transcriptomics reveals primitive neuroectoderm neural precursor-like population
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Joshua A. Regal, María E. Guerra García, Vaibhav Jain, Vidyalakshmi Chandramohan, David M. Ashley, Simon G. Gregory, Eric M. Thompson, Giselle Y. López, and Zachary J. Reitman
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Single cell RNA-sequencing ,CITE-seq ,Spatial transcriptomics ,Ganglioglioma ,Glioneuronal tumors ,Brain tumors ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Gangliogliomas are brain tumors composed of neuron-like and macroglia-like components that occur in children and young adults. Gangliogliomas are often characterized by a rare population of immature astrocyte-appearing cells expressing CD34, a marker expressed in the neuroectoderm (neural precursor cells) during embryogenesis. New insights are needed to refine tumor classification and to identify therapeutic approaches. We evaluated five gangliogliomas with single nucleus RNA-seq, cellular indexing of transcriptomes and epitopes by sequencing, and/or spatially-resolved RNA-seq. We uncovered a population of CD34+ neoplastic cells with mixed neuroectodermal, immature astrocyte, and neuronal markers. Gene regulatory network interrogation in these neuroectoderm-like cells revealed control of transcriptional programming by TCF7L2/MEIS1-PAX6 and SOX2, similar to that found during neuroectodermal/neural development. Developmental trajectory analyses place neuroectoderm-like tumor cells as precursor cells that give rise to neuron-like and macroglia-like neoplastic cells. Spatially-resolved transcriptomics revealed a neuroectoderm-like tumor cell niche with relative lack of vascular and immune cells. We used these high resolution results to deconvolute clinically-annotated transcriptomic data, confirming that CD34+ cell-associated gene programs associate with gangliogliomas compared to other glial brain tumors. Together, these deep transcriptomic approaches characterized a ganglioglioma cellular hierarchy—confirming CD34+ neuroectoderm-like tumor precursor cells, controlling transcription programs, cell signaling, and associated immune cell states. These findings may guide tumor classification, diagnosis, prognostication, and therapeutic investigations. more...
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- 2023
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28. Clinico-pathological description of three paediatric medulloblastoma cases withMLL2/3gene mutations
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Hai Yan, Darell D. Bigner, Linda G. Leithe, Yiping He, Sridharan Gururangan, Giselle Y. Lopez, Herbert E. Fuchs, Gerald A. Grant, and Roger E. McLendon
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Medulloblastoma ,Vincristine ,Pathology ,medicine.medical_specialty ,Histology ,Myeloid ,medicine.medical_treatment ,Gene mutation ,Biology ,Fourth ventricle ,medicine.disease ,Pathology and Forensic Medicine ,Hydrocephalus ,Radiation therapy ,medicine.anatomical_structure ,Neurology ,Physiology (medical) ,medicine ,Neurology (clinical) ,Exome sequencing ,medicine.drug - Abstract
Medulloblastoma is the most common paediatric malignant tumour. To identify altered genetic events in a comprehensive manner, we recently performed exome sequencing of a series of medulloblastomas [1]. This study identified mutations in genes involved in chromatin modification in 20% of patients examined, including the myeloid/lymphoid or mixed lineage leukemia (MLL) family genes MLL2 and MLL3, which were not previously known to be associated with medulloblastoma [1]. The majority of those alterations were nonsense or frameshift mutations, indicating that MLL2 and MLL3 are new medulloblastoma tumour suppressor genes [1]. Subsequent exome sequencing studies further validated MLL2 pathway mutations as medulloblastoma driver events [2-4]. In this report, we present detailed histopathological characteristics of three cases with MLL2/3 gene mutations. The male patient discussed in case #1 initially presented as a 5-year-old with a profound frontal headache associated with nausea and vomiting, following receipt of an immunization booster. Five days later the headache returned, and he was noted to have a gait imbalance; a magnetic resonance imaging scan showed a fourth ventricular mass (Figure 1A). Histopathological analysis revealed a medulloblastoma. Therapy consisted of craniospinal irradiation with a posterior fossa boost and chemotherapy consisting of a bone marrow transplant protocol of vincristine, amifostine, cisplatin, and cyclophosphamide. He is now 5 years post therapy without evidence of disease. Figure A) CT demonstrates a hyperdense 3x4 centimeter midline posterior fossa mass that appears to fill the fourth ventricle, containing punctate calcifications and cystic components. B) Haematoxylin and eosin staining of histological sections from Case #1, ... Case #2 is of a male patient who presented as an 11-year-old who began to experience decreased appetite and headaches that awoke him, associated with nausea and vomiting. A computed tomography scan showed marked hydrocephalus with a 4 cm mass in the posterior fossa. Histopathological analysis identified a medulloblastoma. Post-operatively, he underwent cranio-spinal radiation therapy and chemotherapy with vincristine, cisplatin, and cyclophosphamide supplemented with hyperalimentation via gastric tube placement. Now at six years post-diagnosis, he is doing well at recent follow-up. Case #3 is a female patient who presented as a 7-year-old with a three-week history of headache associated with morning nausea and vomiting, dizziness and recent onset of double vision. Radiographic studies revealed an enhancing mass lesion in the fourth ventricle. Axial and sagittal gadolinium-enhanced images demonstrated diffuse leptomeningeal spread of disease. Histopathological analysis disclosed a medulloblastoma. Cytological examination of her post-operative cerebrospinal fluid revealed malignant cytology. The patient began craniospinal X-ray therapy. Three months following initial diagnosis, she died of disease. Postmortem examination of the brain and spinal cord revealed extensive spread along the subarachnoid space of the cerebellum, forebrain, brain stem, and spinal cord. The term medulloblastoma describes a series of heterogeneous brain tumours originating in the cerebellum. This heterogeneity is reflected at two levels: (1) tumours are histopathologically and molecularly distinct; (2) there is a lack of tight correlation between histopathological and molecular subtypes, as tumours within each histopathological subtype are also molecularly heterogeneous. Accordingly, additional genetic alterations, and analysis of the histopathological characteristics associated with them, may provide information for improving tumour subclassification. As a first step toward that purpose, we present three medulloblastoma cases with MLL2/3 mutations. Intriguingly, all three cases demonstrate features of a moderate to severe large-cell/anaplastic subtype (Figure 1B). However, despite these similarities, clinical outcomes varied. Patient #3 had both MLL2 and MLL3 mutations and, unlike the first two patients, had a poor clinical outcome. However, Patient #3 also had MYC amplification (frequently associated with a poor prognosis [5]). The role of MLL2/MLL3 complexes in medulloblastoma are unknown, yet genetic and biological evidence supports a tumour suppressor role [1-4, 6], and studies have identified MLL2/3 gene mutations in a variety of other cancers. MLL family genes are essential for histone modification and play roles in regulating other developmentally critical pathways [7, 8]. One of these pathways impacted by MLL2, retinoic acid signaling [9], may in turn impact orthodenticle homeobox 2 (OTX2) expression [10]. Because increased OTX2 expression was noted (Table 1, Figure 1C), it is tempting to postulate that MLL2/3 inactivation, and the subsequence changes in histone methylation, may present a mechanism for OTX2 overexpression, and thus dysregulation of OTX2-associated pathways. Additionally, it is possible that loss of MLL2/MLL3 function impairs cell differentiation and renders cells susceptible to transformation. All cases presented here demonstrated anaplastic features, geographic necrosis and characteristics of the same histopathological subclass. Molecular subclassification, completed for Cases #1 and #2, revealed Group 3 classification for both cases (classification based on Northcott et al. 2011[11]). Because of the presence of MYC amplification and the extremely poor prognosis, it is likely that the tumour in Case #3 is also a Group 3 tumor. It is expected that improved subclassification will provide guidance for therapy and risk assessment in the clinical setting. MLL2/3 mutations add one more genetic variable for subclassification of medulloblastomas. MLL2/3 pathway mutations were found to be distributed among various histological groups in previous studies [2, 4]. Additionally, studies have found MLL2/3 mutations to be distributed among various molecular subgroups [2-4]. To clarify the subclassification issue, more detailed histopathological analysis of a large number of patients with MLL2/3 mutations will be necessary. We favour the possibility that dysregulation of the MLL2/3 pathway affects the histopathological and clinical characteristics of medulloblastoma, and we suggest an analysis of more cases is warranted. more...
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- 2014
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29. Transformation by the R Enantiomer of 2-Hydroxyglutarate Linked to EglN Activation
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William G. Kaelin, Hai Yan, Päivi Joensuu, Gang Lu, Christopher G. Duncan, Shakti Ramkissoon, Ulrich Bergmann, Ryan E. Looper, Samuel Weiss, Stefan Gross, Sungwoo Lee, Jeremy Travins, Keith L. Ligon, Julie-Aurore Losman, Giselle Y. Lopez, Roel G.W. Verhaak, and Peppi Koivunen more...
- Subjects
0303 health sciences ,Multidisciplinary ,IDH1 ,biology ,Succinate dehydrogenase ,IDH2 ,Molecular biology ,Article ,03 medical and health sciences ,Enzyme activator ,0302 clinical medicine ,Isocitrate dehydrogenase ,Hypoxia-inducible factors ,030220 oncology & carcinogenesis ,Fumarase ,biology.protein ,Procollagen-proline dioxygenase ,030304 developmental biology - Abstract
The identification of succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH) mutations in human cancers has rekindled the idea that altered cellular metabolism can transform cells. Inactivating SDH and FH mutations cause the accumulation of succinate and fumarate, respectively, which can inhibit 2-oxoglutarate (2-OG)-dependent enzymes, including the EGLN prolyl 4-hydroxylases that mark the hypoxia inducible factor (HIF) transcription factor for polyubiquitylation and proteasomal degradation. Inappropriate HIF activation is suspected of contributing to the pathogenesis of SDH-defective and FH-defective tumours but can suppress tumour growth in some other contexts. IDH1 and IDH2, which catalyse the interconversion of isocitrate and 2-OG, are frequently mutated in human brain tumours and leukaemias. The resulting mutants have the neomorphic ability to convert 2-OG to the (R)-enantiomer of 2-hydroxyglutarate ((R)-2HG). Here we show that (R)-2HG, but not (S)-2HG, stimulates EGLN activity, leading to diminished HIF levels, which enhances the proliferation and soft agar growth of human astrocytes. These findings define an enantiomer-specific mechanism by which the (R)-2HG that accumulates in IDH mutant brain tumours promotes transformation and provide a justification for exploring EGLN inhibition as a potential treatment strategy. more...
- Published
- 2012
30. Gastrin-Releasing Peptide, Immune Responses, and Lung Disease
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Simone Degan, Mary E. Sunday, Katharine Kevill, and Giselle Y. Lopez
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Lung Diseases ,T-Lymphocytes ,Disease ,Lung injury ,Models, Biological ,General Biochemistry, Genetics and Molecular Biology ,Pathogenesis ,Immune System Phenomena ,Immune system ,History and Philosophy of Science ,Gastrin-releasing peptide ,medicine ,Animals ,Humans ,Bronchopulmonary Dysplasia ,Innate immune system ,Lung ,business.industry ,General Neuroscience ,Infant, Newborn ,medicine.disease ,Immunity, Innate ,medicine.anatomical_structure ,Gastrin-Releasing Peptide ,Bronchopulmonary dysplasia ,Immunology ,Bombesin ,business ,hormones, hormone substitutes, and hormone antagonists - Abstract
Gastrin-releasing peptide (GRP) is produced by pulmonary neuroendocrine cells (PNECs), with highest numbers of GRP-positive cells present in fetal lung. Normally GRP-positive PNECs are relatively infrequent after birth, but PNEC hyperplasia is frequently associated with chronic lung diseases. To address the hypothesis that GRP mediates chronic lung injury, we present the cumulative evidence implicating GRP in bronchopulmonary dysplasia (BPD), the chronic lung disease of premature infants who survive acute respiratory distress syndrome. The availability of well-characterized animal models of BPD was a critical tool for demonstrating that GRP plays a direct role in the early pathogenesis of this disease. Potential mechanisms by which GRP contributes to injury are analyzed, with the main focus on innate immunity. Autoreactive T cells may contribute to lung injury late in the course of disease. A working model is proposed with GRP triggering multiple cell types in both the innate and adaptive immune systems, promoting cascades culminating in chronic lung disease. These observations represent a paradigm shift in the understanding of the early pathogenesis of BPD, and suggest that GRP blockade could be a novel treatment to prevent this lung disease in premature infants. more...
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- 2008
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31. Biochemical properties of recombinant human and mouse N-acetylglutamate synthase
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Dashuang Shi, Mendel Tuchman, Giselle Y. Lopez, Maria Panglao, Hiroki Morizono, Nantaporn Haskins, and Ljubica Caldovic
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Arginine ,N-Acetylglutamate synthase ,Recombinant Fusion Proteins ,Endocrinology, Diabetes and Metabolism ,Protein domain ,Amino-Acid N-Acetyltransferase ,urologic and male genital diseases ,Biochemistry ,Cofactor ,Mice ,Endocrinology ,Genetics ,Animals ,Humans ,Molecular Biology ,chemistry.chemical_classification ,biology ,ATP synthase ,urogenital system ,Protein Structure, Tertiary ,Amino acid ,Enzyme Activation ,Enzyme ,chemistry ,Urea cycle ,biology.protein - Abstract
N-Acetylglutamate synthase (NAGS, EC 2.3.1.1) is a mitochondrial enzyme that catalyzes the formation of N-acetylglutamate (NAG) from glutamate and acetylcoenzyme A. NAG is an obligatory activator of carbamylphosphate I (CPSI), the first and a rate limiting enzyme of ureagenesis. The enzymatic activity of NAGS increases in the presence of arginine. Since the level of NAGS activity depends on the concentrations of two amino acids, glutamate and arginine, and it supplies the essential cofactor for CPSI, NAGS may play an important role in the regulation of ureagenesis. The amino acid sequences of human and mouse NAGS consist of three regions with different degrees of conservation: the mitochondrial targeting signal (MTS), the variable domain, and the conserved domain. Removal of the MTS results in mature NAGS (NAGS-M) while removal of the MTS and the variable domain results in conserved NAGS (NAGS-C). The biochemical properties of purified recombinant human and mouse NAGS-M and NAGS-C were determined in this study with the goal of better understanding the role of the variable domain in NAGS function. The activity of all four proteins doubled in the presence of arginine, while the affinities for substrates changed less than two fold. The turnover numbers of NAGS-C are double those of NAGS-M proteins. Processing of NAGS-M to form NAGS-C results in an enzyme with higher catalytic activity and could play a role in the regulation of NAG production, CPSI function, and urea synthesis. more...
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- 2006
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32. Current state of the evolving MMMN cancer progression models of cancer
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Marc D. Samsky, Sam Thiagalingam, Hai Yan, Cory Adamson, Rosanne Jones, and Giselle Y. Lopez
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medicine ,Cancer research ,Biology ,medicine.disease ,Glioblastoma - Published
- 2015
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33. IDH1 mutation identified in one human melanoma metastasis, but not correlated with metastases to the brain
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Hai Yan, Darell D. Bigner, Zachary J. Reitman, David A. Solomon, Giselle Y. Lopez, Todd Waldman, Roger E. McLendon, Steven A. Rosenberg, and Yardena Samuels
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Genetics ,Mutation ,IDH1 ,Melanoma ,Biophysics ,Cell Biology ,Biology ,medicine.disease ,medicine.disease_cause ,Biochemistry ,Primary tumor ,IDH2 ,Metastasis ,chemistry.chemical_compound ,Isocitrate dehydrogenase ,chemistry ,medicine ,Cancer research ,Molecular Biology ,Nicotinamide adenine dinucleotide phosphate - Abstract
Isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) are enzymes which convert isocitrate to alpha-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+to NADPH). IDH1/2 were recently identified as mutated in a large percentage of progressive gliomas. These mutations occur at IDH1(R132) or the homologous IDH2(R172). Melanomas share some genetic features with IDH1/2-mutated gliomas, such as frequent TP53 mutation. We sought to test whether melanoma is associated with IDH1/2 mutations. Seventy-eight human melanoma samples were analyzed for IDH1(R132) and IDH2(R172) mutation status. A somatic, heterozygous IDH1 c.C394T (p.R132C) mutation was identified in one human melanoma metastasis to the lung. Having identified this mutation in one metastasis, we sought to test the hypothesis that certain selective pressures in the brain environment may specifically favor the cell growth or survival of tumor cells with mutations in IDH1/2, regardless of primary tumor site. To address this, we analyzed IDH1(R132) and IDH2(R172) mutation status 53 metastatic brain tumors, including nine melanoma metastases. Results revealed no mutations in any samples. This lack of mutations would suggest that mutations in IDH1(R132) or IDH2(R172) may be necessary for the formation of tumors in a cell-lineage dependent manner, with a particularly strong selective pressure for mutations in progressive gliomas; this also suggests the lack of a particular selective pressure for growth in brain tissue in general. Studies on the cell-lineages of tumors with IDH1/2 mutations may help clarify the role of these mutations in the development of brain tumors. more...
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- 2010
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34. EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis
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Matthew L. Hedberg, Lin Wang, Sung Hak Kim, Jeffery J. Raizer, Shi Yuan Cheng, John A. Kessler, Haizhong Feng, Andrew T. Parsa, Philip E. Auron, Wei-Qiang Gao, Ichiro Nakano, Mutsuko Minata, Angel Alvarez, An Jey A. Su, Giselle Y. Lopez, Chung Kwon Kim, Ryo Nishikawa, Motoo Nagane, Christopher G. Duncan, Hui Kuan Lin, Frank B. Furnari, Bo Hu, Webster K. Cavenee, Roger E. McLendon, Hai Yan, Jennifer R. Grandis, and Darell D. Bigner more...
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Proto-Oncogene Proteins c-akt ,Carcinogenesis ,Cells ,Immunology ,medicine.disease_cause ,Medical and Health Sciences ,Rare Diseases ,Downregulation and upregulation ,Cell surface receptor ,medicine ,2.1 Biological and endogenous factors ,Humans ,Aetiology ,Phosphorylation ,Protein kinase B ,Cells, Cultured ,Cancer ,TNF Receptor-Associated Factor 6 ,Cultured ,biology ,Brain Neoplasms ,Membrane Proteins ,General Medicine ,Glioma ,Ubiquitin ligase ,ErbB Receptors ,Head and Neck Neoplasms ,biology.protein ,Cancer research ,Signal transduction ,Signal Transduction ,Research Article - Abstract
Aberrant activation of EGFR in human cancers promotes tumorigenesis through stimulation of AKT signaling. Here, we determined that the discoidina neuropilin-like membrane protein DCBLD2 is upregulated in clinical specimens of glioblastomas and head and neck cancers (HNCs) and is required for EGFR-stimulated tumorigenesis. In multiple cancer cell lines, EGFR activated phosphorylation of tyrosine 750 (Y750) of DCBLD2, which is located within a recently identified binding motif for TNF receptor-associated factor 6 (TRAF6). Consequently, phosphorylation of DCBLD2 Y750 recruited TRAF6, leading to increased TRAF6 E3 ubiquitin ligase activity and subsequent activation of AKT, thereby enhancing EGFR-driven tumorigenesis. Moreover, evaluation of patient samples of gliomas and HNCs revealed an association among EGFR activation, DCBLD2 phosphorylation, and poor prognoses. Together, our findings uncover a pathway in which DCBLD2 functions as a signal relay for oncogenic EGFR signaling to promote tumorigenesis and suggest DCBLD2 and TRAF6 as potential therapeutic targets for human cancers that are associated with EGFR activation. more...
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- 2013
35. Disruption of wild-type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas
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Genglin Jin, Hai Yan, Christopher G. Duncan, Zachary J. Reitman, Darell D. Bigner, Giselle Y. Lopez, David M. Gooden, Roger E. McLendon, Yiping He, Ivan Spasojevic, Rui Yang, and B.K. Ahmed Rasheed
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Cancer Research ,IDH1 ,Genotype ,Biology ,Astrocytoma ,Article ,Glutarates ,Glioma ,Cell Line, Tumor ,medicine ,Humans ,Allele ,neoplasms ,Brain Neoplasms ,Wild type ,medicine.disease ,Isocitrate Dehydrogenase ,nervous system diseases ,Isocitrate dehydrogenase ,Oncology ,Tumor progression ,Mutation ,Cancer research ,Glioblastoma ,Anaplastic astrocytoma - Abstract
Point mutations at Arg132 of the cytoplasmic NADP+-dependent isocitrate dehydrogenase 1 (IDH1) occur frequently in gliomas and result in a gain of function to produce the “oncometabolite” D-2-hydroxyglutarate (D-2HG). The mutated IDH1 allele is usually associated with a wild-type IDH1 allele (heterozygous) in cancer. Here, we identify 2 gliomas that underwent loss of the wild-type IDH1 allele but retained the mutant IDH1 allele following tumor progression from World Health Organization (WHO) grade III anaplastic astrocytomas to WHO grade IV glioblastomas. Intratumoral D-2HG was 14-fold lower in the glioblastomas lacking wild-type IDH1 than in glioblastomas with heterozygous IDH1 mutations. To characterize the contribution of wild-type IDH1 to cancer cell D-2HG production, we established an IDH1-mutated astrocytoma (IMA) cell line from a WHO grade III anaplastic astrocytoma. Disruption of the wild-type IDH1 allele in IMA cells by gene targeting resulted in an 87-fold decrease in cellular D-2HG levels, showing that both wild-type and mutant IDH1 alleles are required for D-2HG production in glioma cells. Expression of wild-type IDH1 was also critical for mutant IDH1-associated D-2HG production in the colorectal cancer cell line HCT116. These insights may aid in the development of therapeutic strategies to target IDH1-mutated cancers. Cancer Res; 73(2); 496–501. ©2012 AACR. more...
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- 2012
36. Mutant IDH1 is required for IDH1 mutated tumor cell growth
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Giselle Y. Lopez, Darell D. Bigner, Genglin Jin, Hai Yan, Yiping He, Christopher G. Duncan, Christopher J. Pirozzi, Ivan Spasojevic, Lee H. Chen, and Jie Feng
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IDH1 ,Somatic cell ,Fibrosarcoma ,Biology ,cell survival ,03 medical and health sciences ,0302 clinical medicine ,Duke Cancer Institute ,Cell Line, Tumor ,medicine ,Humans ,RNA, Small Interfering ,Clonogenic assay ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,Cell growth ,medicine.disease ,Isocitrate Dehydrogenase ,3. Good health ,Isocitrate dehydrogenase ,Oncology ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,HT1080 ,RNA Interference ,Brief Reports - Abstract
// Genglin Jin 1 , Christopher J. Pirozzi 1 , Lee H. Chen 1 , Giselle Y. Lopez 1 , Christopher G. Duncan 1 , Jie Feng 1 , Ivan Spasojevic 2 , Darell D. Bigner 1 , Yiping He 1 , and Hai Yan 1 1 The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, and The Department of Pathology, 2 The Clinical Pharmacology Laboratory, Duke Cancer Institute and Department of Medicine/Oncology , Duke University Medical Center, Durham, North Carolina, USA Correspondence: Hai Yan, email: // Keywords : IDH1, cell survival Received : July 27, 2012, Accepted : August 04, 2012, Published : August 09, 2012 Abstract Frequent somatic hotspot mutations in isocitrate dehydrogenase 1 (IDH1) have been identified in gliomas, acute myeloid leukemias, chondrosarcomas, and other cancers, providing a likely avenue for targeted cancer therapy. However, whether mutant IDH1 protein is required for maintaining IDH1 mutated tumor cell growth remains unknown. Here, using a genetically engineered inducible system, we report that selective suppression of endogenous mutant IDH1 expression in HT1080, a fibrosarcoma cell line with a native IDH1 R132C heterozygous mutation, significantly inhibits cell proliferation and decreases clonogenic potential. Our findings offer insights into changes that may contribute to the inhibition of cell proliferation and offer a strong preclinical rationale for utilizing mutant IDH1 as a valid therapeutic target. more...
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- 2012
37. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas
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Fausto J. Rodriguez, Hai-Jing Yan, Nickolas Papadopoulos, Darell D. Bigner, Gregory J. Riggins, Yuchen Jiao, Giselle Y. Lopez, Nishant Agrawal, B.K. Ahmed Rasheed, Roger E. McLendon, Patrick J. Killela, Christopher M. Heaphy, Roeland F. de Wilde, Luis A. Diaz, Chetan Bettegowda, Henry S. Friedman, Bert Vogelstein, Peter C. Burger, Sueli Mieko Oba-Shinjo, Allan H. Friedman, Matthias Holdhoff, Yiping He, Alan K. Meeker, Suely Kazue Nagahashi Marie, Kenneth W. Kinzler, Zachary J. Reitman, Christopher J. Pirozzi, Eric S. Lipp, and Sergio Rosemberg more...
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Adult ,Male ,X-linked Nuclear Protein ,Oligoastrocytoma ,IDH1 ,ALT ,Biology ,medicine.disease_cause ,IDH2 ,03 medical and health sciences ,0302 clinical medicine ,Mixed Gliomas ,Glioma ,medicine ,Humans ,Gene Silencing ,neoplasms ,ATRX ,Mutation ,Brain Neoplasms ,DNA Helicases ,Nuclear Proteins ,RNA-Binding Proteins ,Telomere ,medicine.disease ,Prognosis ,Phenotype ,Immunohistochemistry ,Research Papers ,Isocitrate Dehydrogenase ,3. Good health ,nervous system diseases ,DNA-Binding Proteins ,Repressor Proteins ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Neoplasm Grading ,030217 neurology & neurosurgery - Abstract
Mutations in the critical chromatin modifier ATRX and mutations in CIC and FUBP1, which are potent regulators of cell growth, have been discovered in specific subtypes of gliomas, the most common type of primary malignant brain tumors. However, the frequency of these mutations in many subtypes of gliomas, and their association with clinical features of the patients, is poorly understood. Here we analyzed these loci in 363 brain tumors. ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%), and ATRX mutations are associated with IDH1 mutations and with an alternative lengthening of telomeres phenotype. CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas ( more than 10%). This analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). Patients with I-CF gliomas had a significantly longer median overall survival (96 months) than patients with I-A gliomas (51 months) and patients with gliomas that did not harbor either signature (13 months). The genetic signatures distinguished clinically distinct groups of oligoastrocytoma patients, which usually present a diagnostic challenge, and were associated with differences in clinical outcome even among individual tumor types. In addition to providing new clues about the genetic alterations underlying gliomas, the results have immediate clinical implications, providing a tripartite genetic signature that can serve as a useful adjunct to conventional glioma classification that may aid in prognosis, treatment selection, and therapeutic trial design. more...
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- 2012
38. Isocitrate dehydrogenase mutations in gliomas: mechanisms, biomarkers and therapeutic target
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Giselle Y. Lopez, Changcun Guo, Hai Yan, and Christopher J. Pirozzi
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Isocitrates ,IDH1 ,Protein Conformation ,Biology ,Isozyme ,IDH2 ,Article ,Glioma ,medicine ,Humans ,Point Mutation ,chemistry.chemical_classification ,Brain Neoplasms ,Point mutation ,medicine.disease ,Prognosis ,Isocitrate Dehydrogenase ,Isoenzymes ,Isocitrate dehydrogenase ,Enzyme ,Neurology ,Biochemistry ,chemistry ,Ketoglutaric Acids ,Neurology (clinical) ,Biomarkers - Abstract
Isocitrate dehydrogenases, IDH1 and IDH2, decarboxylate isocitrate to α-ketoglutarate (α-KG) and reduce NADP to NADPH. Point mutations of IDH1 and IDH2 have been discovered in gliomas. IDH mutations cause loss of native enzymatic activities and confer novel activity of converting α-KG to 2-hydroxyglutarate (2-HG). The mechanisms of IDH mutations in gliomagenesis, and their value as diagnostic, prognostic marker and therapeutic target have been extensively studied. This review is to summarize the findings of these studies.Crystal structural studies revealed conformation changes in mutant IDHs, which may explain the gain of function by mutant IDHs. The product of mutant IDHs, 2-HG, is an inhibitor of α-KG-dependent dioxygenases, which may cause genome-wide epigenetic changes in human gliomas. IDH mutations are a favorable prognostic factor for human glioma and can be used as biomarker for differential diagnosis and subclassification rather than predictor of response to treatment. Preliminary data suggested that inhibiting production of the substrate of mutant IDH enzymes caused slow-down of glioma cell growth.As valuable diagnostic and prognostic markers of human gliomas, there is still a lack of knowledge on biological functions of mutant IDHs, making targeting IDHs in glioma both difficult and unsecured. more...
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- 2011
39. IDH1(R132) mutation identified in one human melanoma metastasis, but not correlated with metastases to the brain
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Giselle Y, Lopez, Zachary J, Reitman, David, Solomon, Todd, Waldman, Darell D, Bigner, Roger E, McLendon, Steven A, Rosenberg, Yardena, Samuels, and Hai, Yan
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Lung Neoplasms ,Skin Neoplasms ,Brain Neoplasms ,Mutation ,Humans ,Female ,Middle Aged ,Neoplasm Metastasis ,Selection, Genetic ,Melanoma ,Isocitrate Dehydrogenase ,Article - Abstract
Isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) are enzymes which convert isocitrate to alpha-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+to NADPH). IDH1/2 were recently identified as mutated in a large percentage of progressive gliomas. These mutations occur at IDH1(R132) or the homologous IDH2(R172). Melanomas share some genetic features with IDH1/2-mutated gliomas, such as frequent TP53 mutation. We sought to test whether melanoma is associated with IDH1/2 mutations. Seventy-eight human melanoma samples were analyzed for IDH1(R132) and IDH2(R172) mutation status. A somatic, heterozygous IDH1 c.C394T (p.R132C) mutation was identified in one human melanoma metastasis to the lung. Having identified this mutation in one metastasis, we sought to test the hypothesis that certain selective pressures in the brain environment may specifically favor the cell growth or survival of tumor cells with mutations in IDH1/2, regardless of primary tumor site. To address this, we analyzed IDH1(R132) and IDH2(R172) mutation status 53 metastatic brain tumors, including nine melanoma metastases. Results revealed no mutations in any samples. This lack of mutations would suggest that mutations in IDH1(R132) or IDH2(R172) may be necessary for the formation of tumors in a cell-lineage dependent manner, with a particularly strong selective pressure for mutations in progressive gliomas; this also suggests the lack of a particular selective pressure for growth in brain tissue in general. Studies on the cell-lineages of tumors with IDH1/2 mutations may help clarify the role of these mutations in the development of brain tumors. more...
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- 2010
40. Catastrophic stroke burden in a patient with uncontrolled psoriasis and psoriatic arthritis: a case report
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Joline M. Fan, David A. Solomon, Giselle Y. López, Jeffrey W. Hofmann, Rene A. Colorado, Anthony S. Kim, Karl Meisel, and Cathra Halabi
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Atherosclerosis ,Stroke ,Psoriasis ,Psoriatic arthritis ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Psoriasis is the most common chronic inflammatory condition involving the T helper cell system. Population studies have demonstrated that patients with psoriasis and/or psoriatic arthritis have an increased risk of developing vascular risk factors, including diabetes, hypertension, and obesity, and increased risk of adverse vascular events, including myocardial infarction and stroke. Population studies have generally investigated the individual contributions of psoriasis and psoriatic arthritis to development of vascular risk factors; fewer studies have investigated the additive contribution of comorbid inflammatory disorders. We present a case of a woman with psoriasis, psoriatic arthritis, and comorbid vascular risk factors. Case presentation A 49 year-old Caucasian woman with a history of severe psoriasis and psoriatic arthritis since adolescence presented with bilateral lower extremity weakness. She was found to have acute bilateral watershed infarcts and multifocal subacute infarcts. Her evaluation revealed vascular risk factors and elevated non-specific systemic inflammatory markers; serum and cerebral spinal fluid did not reveal underlying infection, hypercoagulable state, or vasculitis. Over the course of days, she exhibited precipitous clinical deterioration related to multiple large vessel occlusions, including the bilateral anterior cerebral arteries and the left middle cerebral artery. Autopsy revealed acute thrombi and diffuse, severe atherosclerosis. Conclusion Patients with early onset inflammatory disease activity or comorbid inflammatory disorders may have an even higher risk of developing metabolic syndrome and adverse vascular events compared to patients with late-onset disease activity or with a single inflammatory condition. The described case illustrates the complex relationship between inflammatory disorders and vascular risk factors. The degree of systemic inflammation, as measured by severity of disease activity, has been shown to have a dose-response relationship with comorbid vascular risk factors and vascular events. Dysregulation of the Th1 and Th17 system has been implicated in the development of atherosclerosis and may explain the severe atherosclerosis seen in such chronic inflammatory conditions. Further research will help refine screening and management guidelines to account for comorbid inflammatory disorders and related disease severity. more...
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- 2020
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41. Transcriptional Regulation of N-Acetylglutamate Synthase
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Mendel Tuchman, Sonal Sodha, Maria Panglao, Sandra Kirsch Heibel, Leonardo Mariño-Ramírez, Giselle Y. Lopez, and Ljubica Caldovic
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Transcription, Genetic ,Gene Expression ,lcsh:Medicine ,Biochemistry ,Mice ,Transcription (biology) ,Molecular Cell Biology ,Transcriptional regulation ,Hepatocyte Nuclear Factor 1-alpha ,Cyclic AMP Response Element-Binding Protein ,Promoter Regions, Genetic ,lcsh:Science ,0303 health sciences ,Multidisciplinary ,biology ,Ccaat-enhancer-binding proteins ,Enzyme Classes ,030302 biochemistry & molecular biology ,Enzymes ,Enhancer Elements, Genetic ,Urea cycle ,Research Article ,Sp1 Transcription Factor ,Molecular Sequence Data ,Amino-Acid N-Acetyltransferase ,Carbamoyl-Phosphate Synthase (Ammonia) ,CREB ,Gene Expression Regulation, Enzymologic ,Molecular Genetics ,03 medical and health sciences ,Species Specificity ,Sequence Homology, Nucleic Acid ,Genetics ,Animals ,Humans ,Smad3 Protein ,Enhancer ,Biology ,Transcription factor ,030304 developmental biology ,Sp1 transcription factor ,Base Sequence ,lcsh:R ,Computational Biology ,Mice, Inbred C57BL ,CCAAT-Binding Factor ,Transcription Factor AP-2 ,CCAAT-Enhancer-Binding Proteins ,biology.protein ,lcsh:Q ,Sequence Alignment - Abstract
The urea cycle converts toxic ammonia to urea within the liver of mammals. At least 6 enzymes are required for ureagenesis, which correlates with dietary protein intake. The transcription of urea cycle genes is, at least in part, regulated by glucocorticoid and glucagon hormone signaling pathways. N-acetylglutamate synthase (NAGS) produces a unique cofactor, N-acetylglutamate (NAG), that is essential for the catalytic function of the first and rate-limiting enzyme of ureagenesis, carbamyl phosphate synthetase 1 (CPS1). However, despite the important role of NAGS in ammonia removal, little is known about the mechanisms of its regulation. We identified two regions of high conservation upstream of the translation start of the NAGS gene. Reporter assays confirmed that these regions represent promoter and enhancer and that the enhancer is tissue specific. Within the promoter, we identified multiple transcription start sites that differed between liver and small intestine. Several transcription factor binding motifs were conserved within the promoter and enhancer regions while a TATA-box motif was absent. DNA-protein pull-down assays and chromatin immunoprecipitation confirmed binding of Sp1 and CREB, but not C/EBP in the promoter and HNF-1 and NF-Y, but not SMAD3 or AP-2 in the enhancer. The functional importance of these motifs was demonstrated by decreased transcription of reporter constructs following mutagenesis of each motif. The presented data strongly suggest that Sp1, CREB, HNF-1, and NF-Y, that are known to be responsive to hormones and diet, regulate NAGS transcription. This provides molecular mechanism of regulation of ureagenesis in response to hormonal and dietary changes. more...
- Published
- 2012
- Full Text
- View/download PDF
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