Medicine and Health Sciences Commons^™

Vamorolone, A Dissociative Steroidal Compound, Reduces Pro-Inflammatory Cytokine Expression In Glioma Cells And Increases Activity And Survival In A Murine Model Of Cortical Tumor., Elizabeth Wells, Madhuri Kambhampati, Jesse M Damsker, Heather Gordish-Dressman, Sridevi Yadavilli, Oren J Becher, Jamila Gittens, Mojca Stampar, Roger J. Packer, Javad Nazarian

Genomics and Precision Medicine Faculty Publications

Corticosteroids, such as dexamethasone, are routinely used as palliative care in neuro-oncology for their anti-inflammatory benefits, however many patients experience dose limiting side effects caused by glucocorticoid response element (GRE)-mediated transcription. The purpose of this study was to use a murine model to investigate a new steroid alternative, vamorolone, which promises to reduce side effects through dissociating GRE-mediated transcription and NF-κB -mediated anti-inflammatory actions. To compare vamorolone to dexamethasone in reducing pro-inflammatory signals in vitro, murine glioma cells were treated with dexamethasone, vamorolone or vehicle control. Changes in mRNA expression were assessed using the nanostring inflammatory platform. Furthermore, drug …

Photothermal Therapy Improves The Efficacy Of A Mek Inhibitor In Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors., Elizabeth E. Sweeney, Rachel A. Burga, Chaoyang Li, Yuan Zhu, Rohan Fernandes

Pediatrics Faculty Publications

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors with low survival rates and the leading cause of death in neurofibromatosis type 1 (NF1) patients under 40 years old. Surgical resection is the standard of care for MPNSTs, but is often incomplete and can generate loss of function, necessitating the development of novel treatment methods for this patient population. Here, we describe a novel combination therapy comprising MEK inhibition and nanoparticle-based photothermal therapy (PTT) for MPNSTs. MEK inhibitors block activity driven by Ras, an oncogene constitutively activated in NF1-associated MPNSTs, while PTT serves as a minimally invasive method to ablate …

A Proteogenomic Approach To Understanding Myc Function In Metastatic Medulloblastoma Tumors., Jerome A Staal, Yanxin Pei, Brian R. Rood

Pediatrics Faculty Publications

Brain tumors are the leading cause of cancer-related deaths in children, and medulloblastoma is the most prevalent malignant childhood/pediatric brain tumor. Providing effective treatment for these cancers, with minimal damage to the still-developing brain, remains one of the greatest challenges faced by clinicians. Understanding the diverse events driving tumor formation, maintenance, progression, and recurrence is necessary for identifying novel targeted therapeutics and improving survival of patients with this disease. Genomic copy number alteration data, together with clinical studies, identifies c-MYC amplification as an important risk factor associated with the most aggressive forms of medulloblastoma with marked metastatic potential. Yet despite …

Inhibition Of Nuclear Factor-Kappa B Enhances The Tumor Growth Of Ovarian Cancer Cell Line Derived From A Low-Grade Papillary Serous Carcinoma In P53-Independent Pathway, Xue Xiao, Gong Yang, Peng Bai, Shunping Gui, Tri M. Bui Nguyen, +8 Additional Authors

Biochemistry and Molecular Medicine Faculty Publications

Background: NF-kB can function as an oncogene or tumor suppressor depending on cancer types. The role of NF-kB in low-grade serous ovarian cancer, however, has never been tested. We sought to elucidate the function of NF-kB in the low-grade serous ovarian cancer.

Methods: The ovarian cancer cell line, HOC-7, derived from a low-grade papillary serous carcinoma. Introduction of a dominant negative mutant, IkBαM, which resulted in decrease of NF-kB function in ovarian cancer cell lines. The transcription ability, tumorigenesis, cell proliferation and apoptosis were observed in derivative cell lines in comparison with parental cells.

Results: Western blot analysis indicated increased …

Differences In The Carcinogenic Evaluation Of Glyphosate Between The International Agency For Research On Cancer (Iarc) And The European Food Safety Authority (Efsa)., C. J. Portier, B. Armstrong, B. Baguley, X. Baur, I. Belyaev, Melissa J. Perry, +Several Additional Authors

Environmental and Occupational Health Faculty Publications

No abstract provided.

Histological And Molecular Analysis Of A Progressive Diffuse Intrinsic Pontine Glioma And Synchronous Metastatic Lesions: A Case Report., Javad Nazarian, Gary E Mason, Cheng Ying Ho, Eshini Panditharatna, Madhuri Kambhampati, Louis Gilbert Vezina, Roger J. Packer, Eugene I Hwang

Genomics and Precision Medicine Faculty Publications

There is no curative treatment for patients with diffuse intrinsic pontine glioma (DIPG). However, with the recent availability of biopsy and autopsy tissue, new data regarding the biologic behavior of this tumor have emerged, allowing greater molecular characterization and leading to investigations which may result in improved therapeutic options. Treatment strategies must address both primary disease sites as well as any metastatic deposits, which may be variably sensitive to a particular approach.In this case report, we present a patient with DIPG treated with irradiation and serial investigational agents. The clinical, pathological and molecular phenotypes of both the progressive primary tumor …

Nitrate From Drinking Water And Diet And Bladder Cancer Among Postmenopausal Women In Iowa., Rena R Jones, Peter J Weyer, Curt T Dellavalle, Maki Inoue-Choi, Kristin E Anderson, Kenneth P Cantor, Stuart Krasner, Kim Robien, Laura E Beane Freeman, Debra T Silverman, Mary H Ward

Exercise and Nutrition Sciences Faculty Publications

BACKGROUND: Nitrate is a drinking water contaminant arising from agricultural sources and a precursor in the endogenous formation of N-nitroso compounds (NOC), which are possible bladder carcinogens.

OBJECTIVES: To investigate the ingestion of nitrate and nitrite from drinking water and diet and bladder cancer risk in women.

METHODS: We identified incident bladder cancers among a cohort of 34,708 postmenopausal women in Iowa (1986-2010). Dietary nitrate and nitrite intakes were estimated from a baseline food frequency questionnaire. Drinking water source and duration were assessed in a 1989 follow-up. For women using public water supplies (PWS) >10 years (N=15,577), we estimated average …

Identification Of Genes That Are Essential To Restrict Genome Duplication To Once Per Cell Division., Alex Vassilev, Chrissie Y. Lee, Boris Vassilev, Wenge Zhu, Pinar Ormanoglu, Scott E. Martin, Melvin L. Depamphilis

Biochemistry and Molecular Medicine Faculty Publications

Nuclear genome duplication is normally restricted to once per cell division, but aberrant events that allow excess DNA replication (EDR) promote genomic instability and aneuploidy, both of which are characteristics of cancer development. Here we provide the first comprehensive identification of genes that are essential to restrict genome duplication to once per cell division. An siRNA library of 21,584 human genes was screened for those that prevent EDR in cancer cells with undetectable chromosomal instability. Candidates were validated by testing multiple siRNAs and chemical inhibitors on both TP53+ and TP53- cells to reveal the relevance of this ubiquitous tumor suppressor …

Urethral Solitary Fibrous Tumor: A Rare Pathologic Diagnosis Of A Periurethral Mass, Gaby N. Moawad, Elias Abi Khalil, Cheryl Silverbrook, Stephanie Barak, Alice Semerjian, Michael Phillips

Obstetrics and Gynecology Faculty Publications

Solitary fibrous tumors (SFTs) may occur at any site in the body. SFTs can only be conclusively diagnosed based on histopathologic and immunohistochemical characteristics of the tumor. The presence of SFTs in the abdomen and pelvis is extremely rare. To our knowledge no cases of urethral solitary fibrous tumor in the literature have been reported so far. We present a case of a solitary fibrous tumor arising from the urethra in a twenty-three-year-old female presenting with vaginal mass.

Genetic Association Of Deleted In Colorectal Carcinoma Variants With Breast Cancer Risk: A Case-Control Study., Xinghan Liu, Xijing Wang, Sidney W. Fu, Zhijun Dai, + 9 More

Medicine Faculty Publications

Deleted in colorectal carcinoma (DCC), a netrin-1 dependence receptor, is correlated with cell progression, migration, and adhesion. Evidence indicated that DCC was frequently down-regulated in many cancers. However, the association of DCC with breast cancer remains uncertain. We conducted a case-control study to investigate the impact of three DCC gene variants (rs2229080, rs7504990, and rs4078288) on breast cancer susceptibility in Chinese women. This study included 560 breast cancer patients and 583 age-matched healthy controls from Northwest China. The three gene variants were genotyped via Sequenom MassARRAY. Odds ratios (ORs) and 95% confidence intervals (CIs) were utilized to evaluate …

A Mir-200c/141-Bmi1 Autoregulatory Loop Regulates Oncogenic Activity Of Bmi1 In Cancer Cells., Mingu Kang, Manjari Dimri, Goberdhan P. Dimri

Biochemistry and Molecular Medicine Faculty Publications

MicroRNAs (miRNAs) are known to function as oncomiRs or tumor suppressors and are important noncoding RNA regulators of oncogenesis. The miR-200c/141 locus on chromosome 12 encodes miR-200c and miR-141, two members of the miR-200 family, which have been shown to function as tumor suppressive miRNAs by targeting multiple oncogenic factors such as polycomb group protein BMI1. Here, we show that BMI1 reciprocally functions as a transcriptional repressor of the miR-200c/141 cluster and that BMI1 inhibitors upregulate expression of miR-200c and miR-141. Our data suggest that BMI1 binds to the miR-200c/141 promoter and regulates it through transcription factor binding motifs E-box …

Single-Nucleotide Polymorphisms In Psca And The Risk Of Breast Cancer In A Chinese Population., Meng Wang, Xijing Wang, Sidney W. Fu, Zhijun Dai, Tianbo Jin, + 10 Additional Authors

Medicine Faculty Publications

This study explored the associations between common PSCA single-nucleotide polymorphisms (rs2294008, rs2978974, and rs2976392) and breast cancer among 560 breast cancer cases and 583 controls (Chinese Han women). We found rs2294008 was significantly associated with a high risk of breast cancer (homozygote model, odds ratio [OR]: 1.67, 95% confidence interval [CI]: 1.06–2.59; recessive, OR: 1.64, 95% CI: 1.06–2.53). And stratification by menopausal status revealed an association of the minor allele of rs2294008 with breast cancer risk among premenopausal (homozygote model, OR: 2.41, 95% CI: 1.03–5.66; recessive, OR: 2.80, 95 % CI: 1.21–6.47) and postmenopausal women (allele model, OR: 1.29, 95% …

Is The Force Awakened? Publication Trends In Oncology Big Data As Phase Ii Cancerlinq Is Launched, Hind Rafei, Benjamin Viernes, Angelike P. Liappis, Dalia Abdelaziz Mobarek

GW Research Days 2016 - 2020

Background: The American Society of Clinical Oncology launched CancerLinQ project in 2010 to provide real-time data collection, mining and visualization, clinical decision support, and quality feedback. Creation of a big data software platform is currently underway to power the CancerLinQ in the phase II of the project. This would allow for evidence driven practice and rapid learning for cancer care providers. Additionally, adequate knowledge about the utility of Big Data to encourage provider utilization in high Impact Factor (IF) journals is needed. We aimed to assess trends and quality of Big Data published in Oncology.

Methods: Peer-reviewed English …

Circulating Mirna Biomarkers In Early Breast Cancer Detection Following Mammography, Alexa Lean, Jialu Lucy Yang, Xiaohui Tan, Christine B. Teal, Rachel F. Brem, Sidney W. Fu

GW Research Days 2016 - 2020

The currently accepted stepwise model of breast tumorigenesis assumes a gradual transition from normal breast epithelial cells to atypical ductal hyperplasia (ADH), to ductal carcinoma in situ (DCIS) and then to invasive ductal carcinoma (IDC). Percutaneous core needle biopsy (CNB) is the standard technique following an abnormal mammographic finding. However, CNB is less reliable in differentiating simple ADH (sADH) from ADH component coexisted with advanced lesions such as DCIS and/or IDC (cADH). Therefore, to identify and validate novel reliable molecular biomarkers is essential in order to improve the efficiency of therapeutic recommendations, as well as to minimize anxiety and unnecessary …

Identifying Venous Thromboembolism In Cancer Patients Using Veterans Affairs Administrative Data, Noah Ravenborg, Najeebah A. Bade, Dalia Abdelaziz Mobarek

GW Research Days 2016 - 2020

Identifying Venous Thromboembolism in Cancer Patients Using Veterans Affairs Administrative Data

Noah Ravenborg1, Najeebah A. Bade, M.D.2, Dalia Abdelaziz Mobarek, M.D.1, 2, 3

1 George Washington University School of Medicine and Health Sciences, Washington, D.C. 2 Department of Medicine, Section of Hematology, Veterans Affairs Medical Center, Washington, D.C., 3 Department of Medicine, Section of Hematology & Medical Oncology, George Washington University Medical Center, Washington, D.C. Noah Ravenborg Cell phone: (310)-804-0848, Email: nravenborg@gwu.edu, MS2

IMPORTANCE: The validity of administrative data in identifying diagnoses within the Veterans Affairs (VA) database, including viral hepatitis, cirrhosis, H. pylori, and cancer metastasis has been reported. …

Distinct Lymphocyte Antigens 6 (Ly6) Family Members Ly6d, Ly6e, Ly6k And Ly6h Drive Tumorigenesis And Clinical Outcome., Linlin Luo, Peter Mcgarvey, Subha Madhavan, Rakesh Kumar, Yuriy Gusev, Geeta Upadhyay

Biochemistry and Molecular Medicine Faculty Publications

Stem cell antigen-1 (Sca-1) is used to isolate and characterize tumor initiating cell populations from tumors of various murine models [1]. Sca-1 induced disruption of TGF-β signaling is required in vivo tumorigenesis in breast cancer models [2, 3-5]. The role of human Ly6 gene family is only beginning to be appreciated in recent literature [6-9]. To study the significance of Ly6 gene family members, we have visualized one hundred thirty gene expression omnibus (GEO) dataset using Oncomine (Invitrogen) and Georgetown Database of Cancer (G-DOC). This analysis showed that four different members Ly6D, Ly6E, Ly6H or Ly6K have increased gene expressed …

The Role Of Ng2 Proteoglycan In Glioma., Sridevi Yadavilli, Eugene I Hwang, Roger J. Packer, Javad Nazarian

Neurology Faculty Publications

Neuron glia antigen-2 ((NG2), also known as chondroitin sulphate proteoglycan 4, or melanoma-associated chondroitin sulfate proteoglycan) is a type-1 membrane protein expressed by many central nervous system (CNS) cells during development and differentiation and plays a critical role in proliferation and angiogenesis. 'NG2' often references either the protein itself or the highly proliferative and undifferentiated glial cells expressing high levels of NG2 protein. NG2 glia represent the fourth major type of neuroglia in the mammalian nervous system and are classified as oligodendrocyte progenitor cells by virtue of their committed oligodendrocyte generation in developing and adult brain. Here, we discuss NG2 …

Mir-671-5p Inhibits Epithelial-To-Mesenchymal Transition By Downregulating Foxm1 Expression In Breast Cancer., Xiaohui Tan, Yebo Fu, Liang Chen, Woojin Lee, Yinglei Lai, M. Katayoon Rezaei, Sana Tabbara, Patricia Latham, Christine B Teal, Yan-Gao Man, Robert S. Siegel, Rachel F. Brem, Sidney W. Fu

Medicine Faculty Publications

MicroRNA (miRNA) dysfunction is associated with a variety of human diseases, including cancer. Our previous study showed that miR-671-5p was deregulated throughout breast cancer progression. Here, we report for the first time that miR-671-5p is a tumor-suppressor miRNA in breast tumorigenesis. We found that expression of miR-671-5p was decreased significantly in invasive ductal carcinoma (IDC) compared to normal in microdissected formalin-fixed, paraffin-embedded (FFPE) tissues. Forkhead Box M1 (FOXM1), an oncogenic transcription factor, was predicted as one of the direct targets of miR-671-5p, which was subsequently confirmed by luciferase assays. Forced expression of miR-671-5p in breast cancer cell lines downregulated FOXM1 …

Mutational Profiles Reveal An Aberrant Tgf-Β-Cea Regulated Pathway In Colon Adenomas., Jian Chen, Gottumukkala S Raju, Wilma Jogunoori, Shoujun Gu, Lopa Mishra, + 27 More

Surgery Faculty Publications

Mutational processes and signatures that drive early tumorigenesis are centrally important for early cancer prevention. Yet, to date, biomarkers and risk factors for polyps (adenomas) that inordinately and rapidly develop into colon cancer remain poorly defined. Here, we describe surprisingly high mutational profiles through whole-genome sequence (WGS) analysis in 2 of 4 pairs of benign colorectal adenoma tissue samples. Unsupervised hierarchical clustered transcriptomic analysis of a further 7 pairs of adenomas reveals distinct mutational signatures regardless of adenoma size. Transitional single nucleotide substitutions of C:G>T:A predominate in the adenoma mutational spectrum. Strikingly, we observe mutations in the TGF-β pathway …

Vitamin D Deficiency Promotes Liver Tumor Growth In Transforming Growth Factor-Β/Smad3-Deficient Mice Through Wnt And Toll-Like Receptor 7 Pathway Modulation., Jian Chen, Lior H Katz, Nina M Muñoz, Shoujun Gu, Ji-Hyun Shin, Lopa Mishra, +13 Additional Authors

Surgery Faculty Publications

Disruption of the TGF-β pathway is associated with liver fibrosis and suppression of liver tumorigenesis, conditions associated with low Vitamin D (VD) levels. However, potential contributions of VD to liver tumor progression in the context of TGF-β signaling remain unexplored. Our analyses of VD deprivation (VDD) in in vivo models of liver tumor formation revealed striking three-fold increases in tumor burden in Smad3(+/-) mice, with a three-fold increase in TLR7 expression compared to controls. ChIP and transcriptional assays confirm Smad3 binding at two TLR7 promoter SBE sites. Molecular interactions between TGF-β pathway and VDD were validated clinically, where an absence …

Importance Of Hereditary And Selected Environmental Risk Factors In The Etiology Of Inflammatory Breast Cancer: A Case-Comparison Study., Roxana Moslehi, Elizabeth Freedman, Nur Zeinomar, Carmela Veneroso, Paul H. Levine

Epidemiology Faculty Publications

BACKGROUND: To assess the importance of heredity in the etiology of inflammatory breast cancer (IBC), we compared IBC patients to several carefully chosen comparison groups with respect to the prevalence of first-degree family history of breast cancer.

METHODS: IBC cases (n = 141) were compared to non-inflammatory breast cancer cases (n = 178) ascertained through George Washington University (GWU) with respect to the prevalence of first-degree family history of breast cancer and selected environmental/lifestyle risk factors for breast cancer. Similar comparisons were conducted with subjects from three case-control studies: breast cancer cases (n = 1145) and unaffected controls (n = …

Spatial And Temporal Homogeneity Of Driver Mutations In Diffuse Intrinsic Pontine Glioma., Hamid Nikbakht, Eshini Panditharatna, Leonie G Mikael, Rui Li, Tenzin Gayden, Alan Siu, Javad Nazarian, + 17 More

Neurological Surgery Faculty Publications

Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly paediatric brain tumours where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, here we analyse 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3) K27M-including H3.2K27M-mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). Later oncogenic alterations arise in sub-clones and often …

Mirnas As Potential Biomarkers In Early Breast Cancer Detection Following Mammography, Sidney W. Fu, Woojin Lee, Caitrin M. Coffey, Alexa Lea, Xiaoling Wu, Xiaohui Tan, Yan-Gao Man, Rachel F. Brem

Medicine Faculty Publications

Breast cancer is the most common cancer among American women, except for skin cancers. About 12 % women in the United States will develop invasive breast cancer during their lifetime. Currently one of the most accepted model/theories is that ductal breast cancer (most common type of breast cancer) follows a linear progression: from normal breast epithelial cells to ductal hyperplasia to atypical ductal hyperplasia (ADH) to ductal carcinoma in situ (DCIS), and finally to invasive ductal carcinoma (IDC). Distinguishing pure ADH diagnosis from DCIS and/or IDC on mammography, and even combined with follow-up core needle biopsy (CNB) is still a …

Vertebral Metastasis As The Initial Manifestation Of Colon Cancer, Tushina Jain, Renee Williams, Benjamin Liechty, Lea Ann Chen

Medicine Faculty Publications

Oncology guidelines currently recommend against performing colonoscopies in the workup of adenocarcinoma of unknown primary unless colonic malignancy is otherwise suggested by clinical signs or symptoms. We present 2 cases of metastatic colonic adenocarcinoma that presented only with neurologic symptoms from vertebral metastasis. Although bony metastases are a rare presentation of colon cancer and colonoscopy is not warranted in the initial workup of adenocarcinoma of unknown primary, we describe these cases as a reminder that bony metastases do not rule out a colon cancer diagnosis.