Medicine and Health Sciences Commons^™

Amino Acids, Microbiota-Related Metabolites, And The Risk Of Incident Diabetes Among Normoglycemic Chinese Adults: Findings From The 4c Study, Shuangyuan Wang, Mian Li, Hong Lin, Guixia Wang, Yu Xu, Xinjie Zhao, Chunyan Hu, Yi Zhang, Ruizhi Zheng, Ruying Hu, Lixin Shi, Rui Du, Qing Su, Jiqiu Wang, Yuhong Chen, Xuefeng Yu, Li Yan, Tiange Wang, Zhiyun Zhao, Ruixin Liu, Xiaolin Wang, Qi Li, Guijun Qin, Qin Wan, Gang Chen, Min Xu, Meng Dai, Di Zhang, Xulei Tang, Zhengnan Gao, Feixia Shen, Zuojie Luo, Yingfen Qin, Li Chen, Yanan Huo, Qiang Li, Zhen Ye, Yinfei Zhang, Chao Liu, Youmin Wang, Shengli Wu, Tao Yang, Huacong Deng, Jiajun Zhao, Shenghan Lai, Yiming Mu, Lulu Chen, Donghui Li, Guowang Xu, Guang Ning, Weiqing Wang, Yufang Bi, Jieli Lu

Faculty, Staff and Student Publications

Although previous studies suggest that amino acids (AAs) and microbiota-related metabolites (MRMs) are associated with type 2 diabetes mellitus (T2DM), the results remain unclear among normoglycemic populations. We test 28 serum AAs and 22 MRMs in 3,414 subjects with incident diabetes and matched normoglycemic controls from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. In fully adjusted logistic regression models, per SD increment of branched-chain AAs, aromatic AAs, asparagine, alanine, glutamic acid, homoserine, 2-aminoadipic acid, histidine, methionine, and proline are positively associated with incident T2DM. In the MRM panel, serum carnitines, N-acetyltryptophan, and uric acid are positively associated with …

Overlapping And Distinct Functions Of The Paralogous Pagr Regulators Of Bacillus Anthracis, Ileana D Corsi, Theresa M Koehler

Faculty, Staff and Student Publications

The Bacillus anthracis pagA gene, encoding the protective antigen component of anthrax toxin, is part of a bicistronic operon on pXO1 that codes for its own repressor, PagR1. In addition to the pagAR1 operon, PagR1 regulates sap and eag, two chromosome genes encoding components of the surface layer, a mounting structure for surface proteins involved in virulence. Genomic studies have revealed a PagR1 paralog, PagR2, encoded by a gene on pXO2. The amino acid sequences of the paralogues are 71% identical and show similarity to the ArsR family of transcription regulators. We determined that the expression of either rPagR1 …

Racial Disparities In Diabetes Mellitus Prevalence In Prostate Cancer Patients On Androgen Deprivation Therapy, Sameh Gomaa, William Kelly, Do, Grace Lu-Yao, Phd, Edith Mitchell, Md, Tingting Zhan, Phd, Kuang-Yi Wen, Phd

Department of Medical Oncology Posters

Intro/Background

• Androgen deprivation therapy (ADT) is successfully used in patients with advanced prostate cancer.
• ADT has show to prolong survival.
• The use of ADT is associated with many side effects, most notably an increase in diabetes incidence for patients on ADT.
• African American men have higher prevalence and mortality rates from prostate cancer than White men.
• It is unclear how prostate cancer treatment such as ADT affects these disparities.
• This study examines racial differences in the prevalence of diabetes mellitus in prostate cancer patients based on their ADT status in the US.

An International Working Group Consensus Report For The Prioritization Of Molecular Biomarkers For Ewing Sarcoma, David S Shulman, Sarah B Whittle, Didier Surdez, Kelly M Bailey, Enrique De Álava, Jason T Yustein, Adam Shlien, Masanori Hayashi, Alexander J R Bishop, Brian D Crompton, Steven G Dubois, Neerav Shukla, Patrick J Leavey, Stephen L Lessnick, Heinrich Kovar, Olivier Delattre, Thomas G P Grünewald, Cristina R Antonescu, Ryan D Roberts, Jeffrey A Toretsky, Franck Tirode, Richard Gorlick, Katherine A Janeway, Damon Reed, Elizabeth R Lawlor, Patrick J Grohar

Faculty, Staff and Students Publications

The advent of dose intensified interval compressed therapy has improved event-free survival for patients with localized Ewing sarcoma (EwS) to 78% at 5 years. However, nearly a quarter of patients with localized tumors and 60-80% of patients with metastatic tumors suffer relapse and die of disease. In addition, those who survive are often left with debilitating late effects. Clinical features aside from stage have proven inadequate to meaningfully classify patients for risk-stratified therapy. Therefore, there is a critical need to develop approaches to risk stratify patients with EwS based on molecular features. Over the past decade, new technology has enabled …

Overcoming The Cardiac Toxicities Of Cancer Therapy Immune Checkpoint Inhibitors, Omoruyi Credit Irabor, Nicolas Nelson, Yash Shah, Muneeb Khan Niazi, Spencer Poiset, Eugene Storozynsky, Dinender K Singla, D. Craig Hooper, Bo Lu

Division of Cardiology Faculty Papers

Immune checkpoint inhibitors (ICIs) have led recent advances in the field of cancer immunotherapy improving overall survival in multiple malignancies with abysmal prognoses prior to their introduction. The remarkable efficacy of ICIs is however limited by their potential for systemic and organ specific immune-related adverse events (irAEs), most of which present with mild to moderate symptoms that can resolve spontaneously, with discontinuation of therapy or glucocorticoid therapy. Cardiac irAEs however are potentially fatal. The understanding of autoimmune cardiotoxicity remains limited due to its rareness. In this paper, we provide an updated review of the literature on the pathologic mechanisms, diagnosis, …

A Small Molecule Antagonist Of Smn Disrupts The Interaction Between Smn And Rnap Ii, Yanli Liu, Aman Iqbal, Weiguo Li, Zuyao Ni, Yalong Wang, Jurupula Ramprasad, Karan Joshua Abraham, Mengmeng Zhang, Dorothy Yanling Zhao, Su Qin, Peter Loppnau, Honglv Jiang, Xinghua Guo, Peter J Brown, Xuechu Zhen, Guoqiang Xu, Karim Mekhail, Xingyue Ji, Mark T Bedford, Jack F Greenblatt, Jinrong Min

Faculty, Staff and Student Publications

Survival of motor neuron (SMN) functions in diverse biological pathways via recognition of symmetric dimethylarginine (Rme2s) on proteins by its Tudor domain, and deficiency of SMN leads to spinal muscular atrophy. Here we report a potent and selective antagonist with a 4-iminopyridine scaffold targeting the Tudor domain of SMN. Our structural and mutagenesis studies indicate that both the aromatic ring and imino groups of compound 1 contribute to its selective binding to SMN. Various on-target engagement assays support that compound 1 specifically recognizes SMN in a cellular context and prevents the interaction of SMN with the R1810me2s of RNA polymerase …

Association Between Abnormal Lipid Profile And Inflammation And Progression Of Myelodysplastic Syndrome To Acute Leukemia, Wei Qiao, Elliana Young, Chun Feng, Suyu Liu, Jeff Jin, Laila Noor, Cristhiam M Rojas Hernandez, Gautam Borthakur, Olga Gorlova, Vahid Afshar-Kharghan

Faculty, Staff and Student Publications

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with a small risk of developing hematologic malignancies and a higher risk of cardiovascular diseases (CVD). We asked whether the reverse correlation exists and cardiometabolic risk factors have an impact on the progression of myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). We investigated the association between abnormal lipid profiles and inflammation in MDS, which shares many genetic mutations with CHIP, and the risk of developing acute leukemia. We examined the medical records of 11071 MDS patients. Among them, 5422 had at least one lipid profile or C-reactive protein (CRP) measurement. In …

Epigenetic Dysregulations In Arsenic-Induced Carcinogenesis, Ranakul Islam, Lei Zhao, Yifang Wang, Grace Lu-Yao, Ling-Zhi Liu

Department of Medical Oncology Faculty Papers

Arsenic is a crucial environmental metalloid whose high toxicity levels negatively impact human health. It poses significant health concerns to millions of people in developed and developing countries such as the USA, Canada, Bangladesh, India, China, and Mexico by enhancing sensitivity to various types of diseases, including cancers. However, how arsenic causes changes in gene expression that results in heinous conditions remains elusive. One of the proposed essential mechanisms that still has seen limited research with regard to causing disease upon arsenic exposure is the dysregulation of epigenetic components. In this review, we have extensively summarized current discoveries in arsenic-induced …

Targeting Ras Mutant Colorectal Cancer With Dual Inhibition Of Mek And Cdk4/6, Alexey V Sorokin, Preeti Kanikarla Marie, Lea Bitner, Muddassir Syed, Melanie Woods, Ganiraju Manyam, Lawrence N Kwong, Benny Johnson, Van K Morris, Philip Jones, David G Menter, Michael S Lee, Scott Kopetz

Faculty, Staff and Student Publications

UNLABELLED: KRAS and NRAS mutations occur in 45% of colorectal cancers, with combined MAPK pathway and CDK4/6 inhibition identified as a potential therapeutic strategy. In the current study, this combinatorial treatment approach was evaluated in a co-clinical trial in patient-derived xenografts (PDX), and safety was established in a clinical trial of binimetinib and palbociclib in patients with metastatic colorectal cancer with RAS mutations. Across 18 PDX models undergoing dual inhibition of MEK and CDK4/6, 60% of tumors regressed, meeting the co-clinical trial primary endpoint. Prolonged duration of response occurred predominantly in TP53 wild-type models. Clinical evaluation of binimetinib and palbociclib …

Mri-Based Digital Models Forecast Patient-Specific Treatment Responses To Neoadjuvant Chemotherapy In Triple-Negative Breast Cancer, Chengyue Wu, Angela M Jarrett, Zijian Zhou, Nabil Elshafeey, Beatriz E Adrada, Rosalind P Candelaria, Rania M M Mohamed, Medine Boge, Lei Huo, Jason B White, Debu Tripathy, Vicente Valero, Jennifer K Litton, Clinton Yam, Jong Bum Son, Jingfei Ma, Gaiane M Rauch, Thomas E Yankeelov

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) is persistently refractory to therapy, and methods to improve targeting and evaluation of responses to therapy in this disease are needed. Here, we integrate quantitative MRI data with biologically based mathematical modeling to accurately predict the response of TNBC to neoadjuvant systemic therapy (NAST) on an individual basis. Specifically, 56 patients with TNBC enrolled in the ARTEMIS trial (NCT02276443) underwent standard-of-care doxorubicin/cyclophosphamide (A/C) and then paclitaxel for NAST, where dynamic contrast-enhanced MRI and diffusion-weighted MRI were acquired before treatment and after two and four cycles of A/C. A biologically based model was established to …

Protocol For Establishing A Protein-Protein Interaction Network Using Tandem Affinity Purification Followed By Mass Spectrometry In Mammalian Cells, Weixiang Bian, Hua Jiang, Shan Feng, Junjie Chen, Wenqi Wang, Xu Li

Faculty, Staff and Student Publications

Identification of protein interactors is fundamental to understanding their functions. Here, we describe a modified protocol for tandem affinity purification coupled with mass spectrometry (TAP/MS), which includes two-step purification. We detail the S-, 2×FLAG-, and Streptavidin-Binding Peptide (SBP)- tandem tags (SFB-tag) system for protein purification. This protocol can be used to identify protein interactors and establish a high-confidence protein-protein interaction network based on computational models. This is particularly useful for identifying

Serologic Versus Molecular Testing For Screening For Hepatitis C Virus Infection In Patients With Hematologic Malignancies, Harrys A Torres, Georgios Angelidakis, Ying Jiang, Minas Economides, Khalis Mustafayev, Marcel Yibirin, Robert Orlowski, Richard Champlin, Srdan Verstovsek, Issam Raad

Faculty, Staff and Student Publications

Testing for antibody against hepatitis C virus (anti-HCV) is a low-cost diagnostic method worldwide; however, an optimal screening test for HCV in patients with cancer has not been established. We sought to identify an appropriate screening test for HCV infection in patients with hematologic malignancies and/or hematopoietic cell transplants (HCT). Patients in our center were simultaneously screened using serological (anti-HCV) and molecular (HCV RNA) assays (February 2019-November 2019). In total, 214 patients were enrolled in this study. Three patients (1.4%) were positive for anti-HCV, and 2 (0.9%) were positive for HCV RNA. The overall percentage agreement was 99.5% (95% CI: …

Association Between Abnormal Lipid Profile And Inflammation And Progression Of Myelodysplastic Syndrome To Acute Leukemia, Wei Qiao, Elliana Young, Chun Feng, Suyu Liu, Jeff Jin, Laila Noor, Cristhiam M Rojas Hernandez, Gautam Borthakur, Olga Gorlova, Vahid Afshar-Kharghan

Faculty, Staff and Student Publications

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with a small risk of developing hematologic malignancies and a higher risk of cardiovascular diseases (CVD). We asked whether the reverse correlation exists and cardiometabolic risk factors have an impact on the progression of myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). We investigated the association between abnormal lipid profiles and inflammation in MDS, which shares many genetic mutations with CHIP, and the risk of developing acute leukemia. We examined the medical records of 11071 MDS patients. Among them, 5422 had at least one lipid profile or C-reactive protein (CRP) measurement. In …

“Stripe” Transcription Factors Provide Accessibility To Co-Binding Partners In Mammalian Genomes, Yongbing Zhao, Supriya V Vartak, Andrea Conte, Xiang Wang, David A Garcia, Evan Stevens, Seol Kyoung Jung, Kyong-Rim Kieffer-Kwon, Laura Vian, Timothy Stodola, Francisco Moris, Laura Chopp, Silvia Preite, Pamela L Schwartzberg, Joseph M Kulinski, Ana Olivera, Christelle Harly, Avinash Bhandoola, Elisabeth F Heuston, David M Bodine, Raul Urrutia, Arpita Upadhyaya, Matthew T Weirauch, Gordon Hager, Rafael Casellas

Faculty, Staff and Student Publications

Regulatory elements activate promoters by recruiting transcription factors (TFs) to specific motifs. Notably, TF-DNA interactions often depend on cooperativity with colocalized partners, suggesting an underlying cis-regulatory syntax. To explore TF cooperativity in mammals, we analyze ∼500 mouse and human primary cells by combining an atlas of TF motifs, footprints, ChIP-seq, transcriptomes, and accessibility. We uncover two TF groups that colocalize with most expressed factors, forming stripes in hierarchical clustering maps. The first group includes lineage-determining factors that occupy DNA elements broadly, consistent with their key role in tissue-specific transcription. The second one, dubbed universal stripe factors (USFs), comprises ∼30 SP, …

Remission Of Liquid Tumors And Sars-Cov-2 Infection: A Literature Review, Dong Ho Shin, Andrew Gillard, Arie Van Wieren, Candelaria Gomez-Manzano, Juan Fueyo

Faculty, Staff and Student Publications

The coronavirus disease 2019 (COVID-19) pandemic has produced a new global challenge for patients with cancer. The disease and the immunosuppression induced by cancer therapies have generated a perfect storm of conditions to increase the severity of the symptoms and worsen the prognosis. However, a few clinical reports showcased the power of viruses to induce remission in some patients suffering from liquid tumors. Here, we reviewed six cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that resulted in cancer remission, simultaneously highlighting the strengths and the unique challenges of oncolytic virotherapy. Virotherapy has become a special case of cancer …

Lats1/2 Control Tgfb-Directed Epithelial-To-Mesenchymal Transition In The Murine Dorsal Cranial Neuroepithelium Through Yap Regulation, Idaliz M Martínez Traverso, Jeffrey D Steimle, Xiaolei Zhao, Jun Wang, James F Martin

Faculty, Staff and Student Publications

Hippo signaling, an evolutionarily conserved kinase cascade involved in organ size control, plays key roles in various tissue developmental processes, but its role in craniofacial development remains poorly understood. Using the transgenic Wnt1-Cre2 driver, we inactivated the Hippo signaling components Lats1 and Lats2 in the cranial neuroepithelium of mouse embryos and found that the double conditional knockout (DCKO) of Lats1/2 resulted in neural tube and craniofacial defects. Lats1/2 DCKO mutant embryos had microcephaly with delayed and defective neural tube closure. Furthermore, neuroepithelial cell shape and architecture were disrupted within the cranial neural tube in Lats1/2 DCKO mutants. RNA sequencing of …

Transcranial Magnetic Stimulation (Tms) Seeded Tractography Provides Superior Prediction Of Eloquence Compared To Anatomic Seeded Tractography, Matthew Muir, Sarah Prinsloo, Hayley Michener, Arya Shetty, Dhiego Chaves De Almeida Bastos, Jeffrey Traylor, Chibawanye Ene, Sudhakar Tummala, Vinodh A Kumar, Sujit S Prabhu

Faculty, Staff and Student Publications

BACKGROUND: For patients with brain tumors, maximizing the extent of resection while minimizing postoperative neurological morbidity requires accurate preoperative identification of eloquent structures. Recent studies have provided evidence that anatomy may not always predict eloquence. In this study, we directly compare transcranial magnetic stimulation (TMS) data combined with tractography to traditional anatomic grading criteria for predicting permanent deficits in patients with motor eloquent gliomas.

METHODS: We selected a cohort of 42 glioma patients with perirolandic tumors who underwent preoperative TMS mapping with subsequent resection and intraoperative mapping. We collected clinical outcome data from their chart with the primary outcome being …

Inhibition Of Uba6 By Inosine Augments Tumour Immunogenicity And Responses, Lei Zhang, Li Jiang, Liang Yu, Qin Li, Xiangjun Tian, Jingquan He, Ling Zeng, Yuqin Yang, Chaoran Wang, Yuhan Wei, Xiaoyue Jiang, Jing Li, Xiaolu Ge, Qisheng Gu, Jikun Li, Di Wu, Anthony J Sadler, Di Yu, Dakang Xu, Yue Gao, Xiangliang Yuan, Baokun He

Faculty, Staff and Student Publications

Anti-cancer immunity and response to immune therapy is influenced by the metabolic states of the tumours. Immune checkpoint blockade therapy (ICB) is known to involve metabolic adaptation, however, the mechanism is not fully known. Here we show, by metabolic profiling of plasma samples from melanoma-bearing mice undergoing anti-PD1 and anti-CTLA4 combination therapy, that higher levels of purine metabolites, including inosine, mark ICB sensitivity. Metabolic profiles of ICB-treated human cancers confirm the association between inosine levels and ICB sensitivity. In mouse models, inosine supplementation sensitizes tumours to ICB, even if they are intrinsically ICB resistant, by enhancing T cell-mediated cytotoxicity and …

International Consensus Classification Of Myeloid Neoplasms And Acute Leukemias: Integrating Morphologic, Clinical, And Genomic Data, Daniel A Arber, Attilio Orazi, Robert P Hasserjian, Michael J Borowitz, Katherine R Calvo, Hans-Michael Kvasnicka, Sa A Wang, Adam Bagg, Tiziano Barbui, Susan Branford, Carlos E Bueso-Ramos, Jorge E Cortes, Paola Dal Cin, Courtney D Dinardo, Hervé Dombret, Eric J Duncavage, Benjamin L Ebert, Elihu H Estey, Fabio Facchetti, Kathryn Foucar, Naseema Gangat, Umberto Gianelli, Lucy A Godley, Nicola Gökbuget, Jason Gotlib, Eva Hellström-Lindberg, Gabriela S Hobbs, Ronald Hoffman, Elias J Jabbour, Jean-Jacques Kiladjian, Richard A Larson, Michelle M Le Beau, Mignon L-C Loh, Bob Löwenberg, Elizabeth Macintyre, Luca Malcovati, Charles G Mullighan, Charlotte Niemeyer, Olatoyosi M Odenike, Seishi Ogawa, Alberto Orfao, Elli Papaemmanuil, Francesco Passamonti, Kimmo Porkka, Ching-Hon Pui, Jerald P Radich, Andreas Reiter, Maria Rozman, Martina Rudelius, Michael R Savona, Charles A Schiffer, Annette Schmitt-Graeff, Akiko Shimamura, Jorge Sierra, Wendy A Stock, Richard M Stone, Martin S Tallman, Jürgen Thiele, Hwei-Fang Tien, Alexandar Tzankov, Alessandro M Vannucchi, Paresh Vyas, Andrew H Wei, Olga K Weinberg, Agnieszka Wierzbowska, Mario Cazzola, Hartmut Döhner, Ayalew Tefferi

Faculty, Staff and Student Publications

The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As …

Clinical Activity Of Checkpoint Inhibitors In Angiosarcoma: A Retrospective Cohort Study, Vinod Ravi, Aparna Subramaniam, Jing Zheng, Behrang Amini, Van A Trinh, Jocelyn Joseph, Robert G Mennel, Andrew J Bishop, Erich M Sturgis, Ryan P Goepfert, Sudha Yalamanchili, Gilberto Botello, Bettzy Stephen, Sarina A Piha-Paul, Anisha B Patel, Alexander J Lazar, Anthony P Conley, Robert S Benjamin, Shreyaskumar R Patel, Phillip A Futreal, Neeta Somaiah, Aung Naing

Faculty, Staff and Student Publications

Background: Systemic treatments for angiosarcoma remains an area of unmet clinical need. The authors conducted this retrospective study to assess the clinical activity of checkpoint inhibitors in patients with angiosarcoma. The primary objective was to assess the objective response rate, and the secondary objective was to assess the progression-free and overall survival durations and disease control rate.

Methods: Patient data were obtained using The University of Texas MD Anderson Cancer Center Tumor Registry database. The final study population was refined to only include patients who had undergone pembrolizumab monotherapy. The objective response rate was evaluated using RECIST/irRECIST version 1.1. Progression-free …

Risk And Incidence Of Head And Neck Cancers In Veterans Living With Hiv And Matched Hiv-Negative Veterans, Angela L Mazul, Christine M Hartman, Yvonne M Mowery, Jennifer R Kramer, Donna L White, Kathryn E Royse, Suchismita Raychaudhury, Vlad C Sandulache, Sarah T Ahmed, Jose P Zevallos, Peter A Richardson, Andrew G Sikora, Elizabeth Y Chiao

Faculty, Staff and Students Publications

BACKGROUND: Persons living with HIV/AIDS have a higher incidence of virus-related and tobacco/alcohol-related cancers. This study is the first to estimate the effect of HIV versus HIV-negative veterans on the risk of head and neck squamous cell carcinoma incidence in a large retrospective cohort study.

METHODS: The authors constructed a retrospective cohort study using patient data from 1999 to 2016 from the National Veterans Administration Corporate Data Warehouse and the VA Central Cancer Registry. This cohort study included 45,052 veterans living with HIV/AIDS and 162,486 HIV-negative patients matched by age, sex, and index visit (i.e., HIV diagnosis date or clinic …

Cancer Patient Beliefs And Attitudes Regarding Immune Checkpoint Inhibitor Therapy, Nedal Darwish, Delaney C. Stuhr, Haily M. Datz, Halima Bakillah, Tenzin Tseky, Mohamed Manaa, Serge Dauphin

Advances in Clinical Medical Research and Healthcare Delivery

The development and widespread use of immune checkpoint inhibitors (ICIs) have advanced the field of oncology in a short period of time. Despite this, patient perception regarding this new medication class has not been adequately assessed, which may affect treatment decisions and adherence. The Belief about Medicines Questionnaire (BMQ) is a validated survey composed of 18 questions which analyzes patient’s beliefs about the necessity of prescribed medication and concern about the potential adverse events caused by the medication. General medication overuse and harm are also determined. This is the first study to utilize the BMQ for patients on ICI therapy.

Bet Inhibition Induces Vulnerability To Mcl1 Targeting Through Upregulation Of Fatty Acid Synthesis Pathway In Breast Cancer, Gonghong Yan, Augustin Luna, Heping Wang, Behnaz Bozorgui, Xubin Li, Maga Sanchez, Zeynep Dereli, Nermin Kahraman, Goknur Kara, Xiaohua Chen, Caishang Zheng, Daniel Mcgrail, Nidhi Sahni, Yiling Lu, Ozgun Babur, Murat Cokol, Bora Lim, Bulent Ozpolat, Chris Sander, Gordon B Mills, Anil Korkut

Faculty, Staff and Student Publications

Therapeutic options for treatment of basal-like breast cancers remain limited. Here, we demonstrate that bromodomain and extra-terminal (BET) inhibition induces an adaptive response leading to MCL1 protein-driven evasion of apoptosis in breast cancer cells. Consequently, co-targeting MCL1 and BET is highly synergistic in breast cancer models. The mechanism of adaptive response to BET inhibition involves the upregulation of lipid synthesis enzymes including the rate-limiting stearoyl-coenzyme A (CoA) desaturase. Changes in lipid synthesis pathway are associated with increases in cell motility and membrane fluidity as well as re-localization and activation of HER2/EGFR. In turn, the HER2/EGFR signaling results in the accumulation …

Openkbp-Opt: An International And Reproducible Evaluation Of 76 Knowledge-Based Planning Pipelines, Aaron Babier, Rafid Mahmood, Binghao Zhang, Victor G L Alves, Ana Maria Barragán-Montero, Joel Beaudry, Carlos E Cardenas, Yankui Chang, Zijie Chen, Jaehee Chun, Kelly Diaz, Harold David Eraso, Erik Faustmann, Sibaji Gaj, Skylar Gay, Mary Gronberg, Bingqi Guo, Junjun He, Gerd Heilemann, Sanchit Hira, Yuliang Huang, Fuxin Ji, Dashan Jiang, Jean Carlo Jimenez Giraldo, Hoyeon Lee, Jun Lian, Shuolin Liu, Keng-Chi Liu, José Marrugo, Kentaro Miki, Kunio Nakamura, Tucker Netherton, Dan Nguyen, Hamidreza Nourzadeh, Alexander F I Osman, Zhao Peng, José Darío Quinto Muñoz, Christian Ramsl, Dong Joo Rhee, Juan David Rodriguez, Hongming Shan, Jeffrey V Siebers, Mumtaz H Soomro, Kay Sun, Andrés Usuga Hoyos, Carlos Valderrama, Rob Verbeek, Enpei Wang, Siri Willems, Qi Wu, Xuanang Xu, Sen Yang, Lulin Yuan, Simeng Zhu, Lukas Zimmermann, Kevin L Moore, Thomas G Purdie, Andrea L Mcniven, Timothy C Y Chan

Faculty, Staff and Student Publications

Objective.To establish an open framework for developing plan optimization models for knowledge-based planning (KBP).

Approach.Our framework includes radiotherapy treatment data (i.e. reference plans) for 100 patients with head-and-neck cancer who were treated with intensity-modulated radiotherapy. That data also includes high-quality dose predictions from 19 KBP models that were developed by different research groups using out-of-sample data during the OpenKBP Grand Challenge. The dose predictions were input to four fluence-based dose mimicking models to form 76 unique KBP pipelines that generated 7600 plans (76 pipelines × 100 patients). The predictions and KBP-generated plans were compared to the reference …

A Rare Case Of Pembrolizumab Associated Encephalopathy, Sijan Basnet, Rajanbir Singh, Biswaraj Tharu, Tushar Pawar, Garima Basnet

Journal of Community Hospital Internal Medicine Perspectives

We present a unique case of a 55-year-old man with confusion thought to be due to pembrolizumab which he was receiving for renal cell carcinoma. His workup for other possible etiologies for encephalopathy was negative. He was treated with high dose intravenous methylprednisolone followed by prednisone taper and intravenous immunoglobulin with gradual improvement in his mentation.

Mutations In Bcor, A Co-Repressor Of Crx/Otx2, Are Associated With Early-Onset Retinal Degeneration, Maéva Langouët, Christine Jolicoeur, Awais Javed, Pierre Mattar, Micah D Gearhart, Stephen P Daiger, Mette Bertelsen, Lisbeth Tranebjærg, Nanna D Rendtorff, Karen Grønskov, Catherine Jespersgaard, Rui Chen, Zixi Sun, Hui Li, Najmeh Alirezaie, Jacek Majewski, Vivian J Bardwell, Ruifang Sui, Robert K Koenekoop, Michel Cayouette

Faculty, Staff and Student Publications

Many transcription factors regulating the production, survival, and function of photoreceptor cells have been identified, but little is known about transcriptional co-regulators in retinal health and disease. Here, we show that BCL6 co-repressor (BCOR), a Polycomb repressive complex 1 factor mutated in various cancers, is involved in photoreceptor degenerative diseases. Using proteomics and transcription assays, we report that BCOR interacts with the transcription factors CRX and OTX2 and reduces their ability to activate the promoters of photoreceptor-specific genes. CUT&RUN sequencing further shows that BCOR shares genome-wide binding profiles with CRX/OTX2, consistent with a general co-repression activity. We also identify missense …

Coexistence Of Cutaneous Squamous Cell Carcinoma And Basal Cell Carcinoma In A Renal Transplant Recipient: A Case Report., Diana Voloshyna, Tanveer Ahamad Shaik, Sunita Shrestha, Ajmat Ansari, Faraz Saleem, Muhammad Abu Zar Ghaffari

Faculty and Staff Scholarship

In solid organ transplant patients, non-melanoma skin cancer remains a leading cause of mortality. The most common skin malignancies in solid organ transplant patients are squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In organ transplant patients, SCC is 100 times more prevalent, and BCC is 10 times more prevalent than in the general population. Many risk factors for developing such malignancies are equivalent to those in the general population. However, in the transplant population, such cancers occur at an earlier age, act more aggressively, and often appear at multiple locations. Thus, assiduousness on the patient's part and healthcare …

Characterization Of The Plastic Scintillator Detector System Exradin W2 In A High Dose Rate Flattening-Filter-Free Photon Beam, Sara Thrower, Surendra Prajapati, Shannon Holmes, Emil Schüler, Sam Beddar

Faculty, Staff and Student Publications

(1) Background: The Exradin W2 is a commercially available scintillator detector designed for reference and relative dosimetry in small fields. In this work, we investigated the performance of the W2 scintillator in a 10 MV flattening-filter-free photon beam and compared it to the performance of ion chambers designed for small field measurements. (2) Methods: We measured beam profiles and percent depth dose curves with each detector and investigated the linearity of each system based on dose per pulse (DPP) and pulse repetition frequency. (3) Results: We found excellent agreement between the W2 scintillator and the ion chambers for beam profiles …

Turning Nonselective Inhibitors Of Type I Protein Arginine Methyltransferases Into Potent And Selective Inhibitors Of Protein Arginine Methyltransferase 4 Through A Deconstruction-Reconstruction And Fragment-Growing Approach, Giulia Iannelli, Ciro Milite, Nils Marechal, Vincent Cura, Luc Bonnefond, Nathalie Troffer-Charlier, Alessandra Feoli, Donatella Rescigno, Yalong Wang, Alessandra Cipriano, Monica Viviano, Mark T Bedford, Jean Cavarelli, Sabrina Castellano, Gianluca Sbardella

Faculty, Staff and Student Publications

Protein arginine methyltransferases (PRMTs) are important therapeutic targets, playing a crucial role in the regulation of many cellular processes and being linked to many diseases. Yet, there is still much to be understood regarding their functions and the biological pathways in which they are involved, as well as on the structural requirements that could drive the development of selective modulators of PRMT activity. Here we report a deconstruction-reconstruction approach that, starting from a series of type I PRMT inhibitors previously identified by us, allowed for the identification of potent and selective inhibitors of PRMT4, which regardless of the low cell …

Modelling Aggressive Prostate Cancers Of Young Men In Immune-Competent Mice, Driven By Isogenic Trp53 Alterations And Pten Loss, Javier Octavio Mejía-Hernández, Simon P Keam, Reem Saleh, Fenella Muntz, Stephen B Fox, David Byrne, Arielle Kogan, Lokman Pang, Jennifer Huynh, Cassandra Litchfield, Franco Caramia, Guillermina Lozano, Hua He, James M You, Shahneen Sandhu, Scott G Williams, Ygal Haupt, Sue Haupt

Faculty, Staff and Student Publications

Understanding prostate cancer onset and progression in order to rationally treat this disease has been critically limited by a dire lack of relevant pre-clinical animal models. We have generated a set of genetically engineered mice that mimic human prostate cancer, initiated from the gland epithelia. We chose driver gene mutations that are specifically relevant to cancers of young men, where aggressive disease poses accentuated survival risks. An outstanding advantage of our models are their intact repertoires of immune cells. These mice provide invaluable insight into the importance of immune responses in prostate cancer and offer scope for studying treatments, including …