Medicine and Health Sciences Commons^™

Chronic Muscle Weakness And Mitochondrial Dysfunction In The Absence Of Sustained Atrophy In A Preclinical Sepsis Model, Allison M. Owen, Samir P. Patel, Jeffrey D. Smith, Beverly K. Balasuriya, Stephanie F. Mori, Gregory S. Hawk, Arnold J. Stromberg, Naohide Kuriyama, Masao Kaneki, Alexander G. Rabchevsky, Timothy A. Butterfield, Karyn A. Esser, Charlotte A. Peterson, Marlene E. Starr, Hiroshi Saito

Physiology Faculty Publications

Chronic critical illness is a global clinical issue affecting millions of sepsis survivors annually. Survivors report chronic skeletal muscle weakness and development of new functional limitations that persist for years. To delineate mechanisms of sepsis-induced chronic weakness, we first surpassed a critical barrier by establishing a murine model of sepsis with ICU-like interventions that allows for the study of survivors. We show that sepsis survivors have profound weakness for at least 1 month, even after recovery of muscle mass. Abnormal mitochondrial ultrastructure, impaired respiration and electron transport chain activities, and persistent protein oxidative damage were evident in the muscle of …

Gilteritinib Or Chemotherapy For Relapsed Or Refractory Flt3-Mutated Aml, Alexander E. Perl, Giovanni Martinelli, Jorge E. Cortes, Andreas Neubauer, Ellin Berman, Stefania Paolini, Pau Montesinos, Maria R. Baer, Richard A. Larson, Celalettin Ustun, Francesco Fabbiano, Harry P. Erba, Antonio Di Stasi, Robert Stuart, Rebecca Olin, Margaret Kasner, Fabio Ciceri, Wen-Chien Chou, Nikolai Podoltsev, Christian Recher, Hisayuki Yokoyama, Naoko Hosono, Sung-Soo Yoon, Je-Hwan Lee, Timothy Pardee, Amir T. Fathi, Chaofeng Liu, Nahla Hasabou, Xuan Liu, Erkut Bahceci, Mark J. Levis

Department of Medical Oncology Faculty Papers

BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML.

METHODS: In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3-mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission …

Multiple Sclerosis Outcomes After Cancer Immunotherapy, Catherine R. Garcia, Rani Jayswal, Val R. Adams, Lowell B. Anthony, John L. Villano

Markey Cancer Center Faculty Publications

INTRODUCTION: Neurological immune-related adverse events are a rare but potentially deadly complication after immune checkpoint inhibitor (ICI) treatment. As multiple sclerosis (MS) is an immune-mediated disease, it is unknown how ICI treatment may affect outcomes.

METHODS: We analyzed the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for pembrolizumab, atezolizumab, nivolumab, ipilimumab, avelumab, and durvalumab 2 years prior their FDA approval until December 31, 2017, to include all cases with confirmed diagnosis/relapse of MS. We also included cases reported in the literature and a patient from our institution.

RESULTS: We identified 14 cases of MS …

Low-Cost, High-Resolution Imaging For Detecting Cervical Precancer In Medically-Underserved Areas Of Texas, Sonia G Parra, Ana M Rodriguez, Katelin D Cherry, Richard A Schwarz, Rose M Gowen, Laura B Guerra, Andrea M Milbourne, Paul A Toscano, Susan P Fisher-Hoch, Kathleen M Schmeler, Rebecca R Richards-Kortum

Journal Articles

OBJECTIVE: Cervical cancer rates in the United States have declined since the 1940's, however, cervical cancer incidence remains elevated in medically-underserved areas, especially in the Rio Grande Valley (RGV) along the Texas-Mexico border. High-resolution microendoscopy (HRME) is a low-cost, in vivo imaging technique that can identify high-grade precancerous cervical lesions (CIN2+) at the point-of-care. The goal of this study was to evaluate the performance of HRME in medically-underserved areas in Texas, comparing results to a tertiary academic medical center.

METHODS: HRME was evaluated in five different outpatient clinical settings, two in Houston and three in the RGV, with medical providers …

Advances In Gene Ontology Utilization Improve Statistical Power Of Annotation Enrichment, Eugene Waverly Hinderer Iii, Robert M. Flight, Rashmi Dubey, James N. Macleod, Hunter N. B. Moseley

Maxwell H. Gluck Equine Research Center Faculty Publications

Gene-annotation enrichment is a common method for utilizing ontology-based annotations in gene and gene-product centric knowledgebases. Effective utilization of these annotations requires inferring semantic linkages by tracing paths through edges in the ontological graph, referred to as relations. However, some relations are semantically problematic with respect to scope, necessitating their omission or modification lest erroneous term mappings occur. To address these issues, we created the Gene Ontology Categorization Suite, or GOcats—a novel tool that organizes the Gene Ontology into subgraphs representing user-defined concepts, while ensuring that all appropriate relations are congruent with respect to scoping semantics. Here, we demonstrate the …

Cancer Cell Population Growth Kinetics At Low Densities Deviate From The Exponential Growth Model And Suggest An Allee Effect., Kaitlyn E Johnson, Grant Howard, William Mo, Michael K Strasser, Ernesto A B F Lima, Sui Huang, Amy Brock

Articles, Abstracts, and Reports

Most models of cancer cell population expansion assume exponential growth kinetics at low cell densities, with deviations to account for observed slowing of growth rate only at higher densities due to limited resources such as space and nutrients. However, recent preclinical and clinical observations of tumor initiation or recurrence indicate the presence of tumor growth kinetics in which growth rates scale positively with cell numbers. These observations are analogous to the cooperative behavior of species in an ecosystem described by the ecological principle of the Allee effect. In preclinical and clinical models, however, tumor growth data are limited by the …

Diagnosis Of Non-Small Cell Lung Cancer For Early Stage Asymptomatic Patients., Cherylle Goebel, Christopher L Louden, Robert Mckenna, Osita Onugha, Andrew Wachtel, Thomas Long

Articles, Abstracts, and Reports

BACKGROUND/AIM: In 2016 in the United States, 7 of 10 patients were estimated to die following lung cancer diagnosis. This is due to a lack of a reliable screening method that detects early-stage lung cancer. Our aim is to accurately detect early stage lung cancer using algorithms and protein biomarkers.

PATIENTS AND METHODS: A total of 1,479 human plasma samples were processed using a multiplex immunoassay platform. 82 biomarkers and 6 algorithms were explored. There were 351 NSCLC samples (90.3% Stage I, 2.3% Stage II, and 7.4% Stage III/IV).

RESULTS: We identified 33 protein biomarkers and developed a classifier using …

The Current State Of Molecular Testing In The Treatment Of Patients With Solid Tumors, 2019., Wafik S El-Deiry, Richard M Goldberg, Heinz-Josef Lenz, Anthony F Shields, Geoffrey T Gibney, Antoinette R Tan, Jubilee Brown, Burton Eisenberg, Elisabeth I Heath, Surasak Phuphanich, Edward Kim, Andrew J Brenner, John L Marshall

Articles, Abstracts, and Reports

The world of molecular profiling has undergone revolutionary changes over the last few years as knowledge, technology, and even standard clinical practice have evolved. Broad molecular profiling is now nearly essential for all patients with metastatic solid tumors. New agents have been approved based on molecular testing instead of tumor site of origin. Molecular profiling methodologies have likewise changed such that tests that were performed on patients a few years ago are no longer complete and possibly inaccurate today. As with all rapid change, medical providers can quickly fall behind or struggle to find up-to-date sources to ensure he or …

Real-World Treatment Patterns And Adverse Events In Metastatic Renal Cell Carcinoma From A Large Us Claims Database., Sumanta Pal, Jun Gong, Shivani K Mhatre, Shih-Wen Lin, Andy Surinach, Sarika Ogale, Rini Vohra, Herschel Wallen, Daniel George

Articles, Abstracts, and Reports

BACKGROUND: Vascular endothelial growth factor (VEGF), tyrosine kinase (TK) and mechanistic target of rapamycin kinase (mTOR) inhibitors are common first-line (1 L) treatments for metastatic renal cell carcinoma (mRCC). Despite treatment availability, the 5-year survival rate in patients diagnosed at the metastatic stage is only ≈ 10%. To gain contemporary insights into RCC treatment trends that may inform clinical, scientific and payer considerations, treatment patterns and adverse events (AEs) associated with 1 L therapy were examined in a retrospective, longitudinal, population-based, observational study of patients with mRCC.

METHODS: US administrative claims data (Truven Health MarketScan Commercial Databases) were used to …

Initial Management Of Meningiomas: Analysis Of The National Cancer Database, Catherine R. Garcia, Stacey A. Slone, Monica Chau, Janna H. Neltner, Thomas A. Pittman, John L. Villano

Neurology Faculty Publications

BACKGROUND: Meningiomas are the most common central nervous system tumor. We describe current trends in treatment and survival using the largest cancer dataset in the United States.

METHODS: We analyzed the National Cancer Database from 2004 to 2014, for all patients with diagnosis of meningioma.

RESULTS: 201,765 cases were analyzed. Patients were most commonly White (81.9%) females (73.2%) with a median age of 64 years. Fifty percent of patients were diagnosed by imaging. Patients were reported as grade I (24.9%), grade II (5.0%), grade III (0.7%), or unknown WHO grade (69.4%). Patients diagnosed by imaging were older, received treatment in …

Tumor Heterogeneity As A Predictor Of Response To Neoadjuvant Chemotherapy In Locally Advanced Rectal Cancer, Alissa Greenbaum, David R. Martin, Therese J. Bocklage, Ji-Hyun Lee, Scott A. Ness, Ashwani Rajput

Pathology and Laboratory Medicine Faculty Publications

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) is the standard of care for locally advanced adenocarcinoma of the rectum, but it is currently unknown which patients have disease that will respond. This study tested the correlation between response to nCRT and intratumoral heterogeneity using next-generation sequencing assays.

PATIENTS AND METHODS: DNA was extracted from formalin-fixed, paraffin-embedded biopsy samples from a cohort of patients with locally advanced rectal adenocarcinoma (T3/4 or N1/2 disease) who received nCRT. High read-depth sequencing of > 400 cancer-relevant genes was performed. Tumor mutations and variant allele frequencies were used to calculate mutant-allele tumor heterogeneity (MATH) scores as measures of intratumoral …

Downregulation Of Cenpf Remodels Prostate Cancer Cells And Alters Cellular Metabolism., Muhammad Shahid, Minhyung Kim, Min Young Lee, Austin Yeon, Sungyong You, Hyung L Kim, Jayoung Kim

Articles, Abstracts, and Reports

Metabolic alterations in prostate cancer (PC) are associated with progression and aggressiveness. However, the underlying mechanisms behind PC metabolic functions are unknown. The authors' group recently reported on the important role of centromere protein F (CENPF), a protein associated with the centromere-kinetochore complex and chromosomal segregation during mitosis, in PC MRI visibility. This study focuses on discerning the role of CENPF in metabolic perturbation in human PC3 cells. A series of bioinformatics analyses shows that CENPF is one gene that is strongly associated with aggressive PC and that its expression is positively correlated with metastasis. By identifying and reconstructing the …

Abcb1 Snp Predicts Outcome In Patients With Acute Myeloid Leukemia Treated With Gemtuzumab Ozogamicin: A Report From Children's Oncology Group Aaml0531 Trial., Roya Rafiee, Lata Chauhan, Todd A. Alonzo, Yi-Cheng Wang, Ahlam Elmasry, Michael R. Loken, Jessica Pollard, Richard Aplenc, Susana Raimondi, Betsy A. Hirsch, Irwin D. Bernstein, A S. Gamis, Soheil Meshinchi, Jatinder K. Lamba

Manuscripts, Articles, Book Chapters and Other Papers

Gemtuzumab-ozogamicin (GO), a humanized-anti-CD33 antibody linked with the toxin-calicheamicin-γ is a reemerging and promising drug for AML. Calicheamicin a key element of GO, induces DNA-damage and cell-death once the linked CD33-antibody facilitates its uptake. Calicheamicin efflux by the drug-transporter PgP-1 have been implicated in GO response thus in this study, we evaluated impact of ABCB1-SNPs on GO response. Genomic-DNA samples from 942 patients randomized to receive standard therapy with or without addition of GO (COG-AAML0531) were genotyped for ABCB1-SNPs. Our most interesting results show that for rs1045642, patients with minor-T-allele (CT/TT) had better outcome as compared to patients with CC …

Daratumumab, Bortezomib, Cyclophosphamide And Dexamethasone In Newly Diagnosed And Relapsed Multiple Myeloma: Lyra Study., Habte Yimer, Jason Melear, Edward Faber, William Bensinger, John M Burke, Mohit Narang, Don Stevens, Sriya Gunawardena, Yana Lutska, Keqin Qi, Jon Ukropec, Ming Qi, Thomas S Lin, Robert M Rifkin

Articles, Abstracts, and Reports

This United States community study evaluated the combination of daratumumab, bortezomib, cyclophosphamide and dexamethasone (D-VCd) in newly diagnosed multiple myeloma (NDMM) and relapsed multiple myeloma (RMM). Patients received 4-8 induction cycles of bortezomib 1·5 mg/m2 , cyclophosphamide 300 mg/m2 and dexamethasone 40 mg weekly. Intravenous daratumumab 16 mg/kg was administered as approved except for a split-first dose in Cycle 1. Eligible patients underwent autologous stem cell transplantation. All patients received ≤12 daratumumab maintenance doses monthly. Eighty-six NDMM and 14 RMM patients received ≥1 treatment dose. In NDMM patients, very good partial response or better (≥VGPR) and overall response rates after …

Evaluating The Effectiveness And Implementation Of Evidence-Based Treatment: A Multisite Hybrid Design., Jamile A Ashmore, Kirk W Ditterich, Claire C Conley, Melissa R Wright, Peggy S Howland, Kelly L Huggins, Jena Cooreman, Priscilla S Andrews, Donald R Nicholas, Lind Roberts, Larissa Hewitt, Joan N Scales, Jenny K Delap, Christine A Gray, Lynelle A Tyler, Charlotte Collins, Catherine M Whiting, Brittany M Brothers, Marlena M Ryba, Barbara L Andersen

Articles, Abstracts, and Reports

The gap between treatment development and efficacy testing to scaled up implementations of evidence-based treatment (EBT) is an estimated 20 years, and hybrid research designs aim to reduce the gap. One was used for a multisite study in cancer control, testing coprimary aims: (a) determine the feasibility and utility of a flexible EBT implementation strategy and (b) determine the clinical effectiveness of an EBT as implemented by newly trained providers. Therapists from 15 diverse sites implemented the biobehavioral intervention (BBI) for cancer patients (N = 158) as part of standard care. For implementation, therapists determined treatment format, number of …

Tisagenlecleucel Model-Based Cellular Kinetic Analysis Of Chimeric Antigen Receptor-T Cells., Andrew M. Stein, Stephan A. Grupp, John E. Levine, Theodore W. Laetsch, Michael A. Pulsipher, Michael W. Boyer, Keith August, Bruce L. Levine, Lori Tomassian, Sweta Shah, Mimi Leung, Pai-Hsi Huang, Rakesh Awasthi, Karen Thudium Mueller, Patricia A. Wood, Carl H. June

Manuscripts, Articles, Book Chapters and Other Papers

Tisagenlecleucel is a chimeric antigen receptor-T cell therapy that facilitates the killing of CD19+ B cells. A model was developed for the kinetics of tisagenlecleucel and the impact of therapies for treating cytokine release syndrome (tocilizumab and corticosteroids) on expansion. Data from two phase II studies in pediatric and young adult relapsed/refractory B cell acute lymphoblastic leukemia were pooled to evaluate this model and evaluate extrinsic and intrinsic factors that may impact the extent of tisagenlecleucel expansion. The doubling time, initial decline half-life, and terminal half-life for tisagenlecleucel were 0.78, 4.3, and 220 days, respectively. No impact of tocilizumab or …

Comparative Effectiveness Of Intensity Modulated Radiation Therapy To 3-Dimensional Conformal Radiation In Locally Advanced Lung Cancer: Pathological And Clinical Outcomes., Sarit Appel, Jair Bar, Alon Ben-Nun, Marina Perelman, Dror Alezra, Damien Urban, Maoz Ben-Ayun, Nir Honig, Efrat Ofek, Tamar Katzman, Amir Onn, Sumit Chatterji, Sergey Dubinski, Lev Tsvang, Shira Felder, Judith Kraitman, Ory Haisraely, Tatiana Rabin Alezra, Sivan Lieberman, Edith M. Marom, Nir Golan, David Simansky, Zvi Symon, Yaacov Richard Lawrence

Department of Radiation Oncology Faculty Papers

OBJECTIVE: Intensity-modulated radiotherapy (IMRT) has better normal-tissue sparing compared with 3-dimensional conformal radiation (3DCRT). We sought to assess the impact of radiation technique on pathological and clinical outcomes in locally advanced non-small cell lung cancer (LANSCLC) treated with a trimodality strategy.

METHODS: Retrospective review of LANSCLC patients treated from August 2012 to August 2018 at Sheba Medical Center, Israel. The trimodality strategy consisted of concomitant chemoradiation to 60 Gray (Gy) followed by completion surgery. The planning target volume (PTV) was defined by co-registered PET/CT. Here we compare the pathological regression, surgical margin status, local control rates (LC), disease free (DFS) …

Commonly Integrated Epigenetic Modifications Of Differentially Expressed Genes Lead To Adaptive Resistance In Cancer., Abdullah Al Emran, Diego M Marzese, Dinoop R Menon, Heinz Hammerlindl, Farzana Ahmed, Erika Richtig, Pascal Duijf, Dave Hoon, Helmut Schaider

Articles, Abstracts, and Reports

Aim: To investigate the integrated epigenetic regulation of acquired drug resistance in cancer. Materials & methods: Our gene expression data of five induced drug-tolerant cell models, one resistant cell line and one publicly available drug-resistant dataset were integrated to identify common differentially expressed genes and pathways. ChIP-seq and DNA methylation by HM450K beadchip were used to study the epigenetic profile of differential expressed genes. Results & conclusion: Integrated transcriptomic analysis identified a common 'viral mimicry' related gene signature in induced drug-tolerant cells and the resistant state. Analysis of the epigenetic regulation revealed a common set of down-regulated genes, which are …

Incorporating Pathway Information Into Feature Selection Towards Better Performed Gene Signatures, Suyan Tian, Chi Wang, Bing Wang

Biostatistics Faculty Publications

To analyze gene expression data with sophisticated grouping structures and to extract hidden patterns from such data, feature selection is of critical importance. It is well known that genes do not function in isolation but rather work together within various metabolic, regulatory, and signaling pathways. If the biological knowledge contained within these pathways is taken into account, the resulting method is a pathway-based algorithm. Studies have demonstrated that a pathway-based method usually outperforms its gene-based counterpart in which no biological knowledge is considered. In this article, a pathway-based feature selection is firstly divided into three major categories, namely, pathway-level selection, …

Inotuzumab Ozogamicin In Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia., Deepa Bhojwani, Richard Sposto, Nirali N. Shah, Vilmarie Rodriguez, Constance Yuan, Maryalice Stetler-Stevenson, Maureen M. O'Brien, Jennifer L. Mcneer, Amrana Quereshi, Aurelie Cabannes, Paul Schlegel, Claudia Rossig, Luciano Dalla-Pozza, Keith August, Sarah Alexander, Jean-Pierre Bourquin, Michel Zwaan, Elizabeth A. Raetz, Mignon L. Loh, Susan R. Rheingold

Manuscripts, Articles, Book Chapters and Other Papers

Although inotuzumab ozogamicin (InO) is recognized as an effective agent in relapsed acute lymphoblastic leukemia (ALL) in adults, data on safety and efficacy in pediatric patients are scarce. We report the use of InO in 51 children with relapsed/refractory ALL treated in the compassionate use program. In this heavily pretreated cohort, complete remission was achieved in 67% of patients with overt marrow disease. The majority (71%) of responders were negative for minimal residual disease. Responses were observed irrespective of cytogenetic subtype or number or type of prior treatment regimens. InO was well-tolerated; grade 3 hepatic transaminitis or hyperbilirubinemia were noted …

A Clinician's Guide To Next Generation Imaging In Patients With Advanced Prostate Cancer (Radar Iii)., E. David Crawford, Phillip J. Koo, Neal Shore, Susan F. Slovin, Raoul S. Concepcion, Stephen J. Freedland, Leonard G. Gomella, Lawrence Karsh, Thomas E. Keane, Paul Maroni, David Penson, Daniel P. Petrylak, Ashley Ross, Vlad Mouraviev, Robert E. Reiter, Chaitanya Divgi, Evan Y. Yu

Department of Urology Faculty Papers

PURPOSE: The advanced prostate cancer therapeutic landscape has changed dramatically in the last several years, resulting in improved overall survival of patients with castration naïve and castration resistant disease. The evolution and development of novel next generation imaging techniques will affect diagnostic and therapeutic decision making. Clinicians must navigate when and which next generation imaging techniques to use and how to adjust treatment strategies based on the results, often in the absence of correlative therapeutic data. Therefore, guidance is needed based on best available information and current clinical experience.

MATERIALS AND METHODS: The RADAR (Radiographic Assessments for Detection of Advanced …

Buparlisib In Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase Ii Trial., Patrick Y Wen, Mehdi Touat, Brian M Alexander, Ingo K Mellinghoff, Shakti Ramkissoon, Christine S Mccluskey, Kristine Pelton, Sam Haidar, Sankha S Basu, Sarah C Gaffey, Loreal E Brown, Juan Emmanuel Martinez-Ledesma, Shaofang Wu, Jungwoo Kim, Wei Wei, Mi-Ae Park, Jason T Huse, John G Kuhn, Mikael L Rinne, Howard Colman, Nathalie Y R Agar, Antonio M Omuro, Lisa M Deangelis, Mark R Gilbert, John F De Groot, Timothy F Cloughesy, Andrew S Chi, Thomas M Roberts, Jean J Zhao, Eudocia Q Lee, Lakshmi Nayak, James R Heath, Laura L Horky, Tracy T Batchelor, Rameen Beroukhim, Susan M Chang, Azra H Ligon, Ian F Dunn, Dimpy Koul, Geoffrey S Young, Michael D Prados, David A Reardon, W K Alfred Yung, Keith L Ligon

Articles, Abstracts, and Reports

PURPOSE: Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation.

METHODS: This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once …

Stress-Induced Epinephrine Enhances Lactate Dehydrogenase A And Promotes Breast Cancer Stem-Like Cells, Bai Cui, Yuanyuan Luo, Pengfei Tian, Fei Peng, Jinxin Lu, Yongliang Yang, Qitong Su, Bing Liu, Jiachuan Yu, Xi Luo, Liu Yin, Wei Cheng, Fan An, Bin He, Dapeng Liang, Sijin Wu, Peng Chu, Luyao Song, Xinyu Liu, Huandong Luo, Binhua P. Zhou

Molecular and Cellular Biochemistry Faculty Publications

Chronic stress triggers activation of the sympathetic nervous system and drives malignancy. Using an immunodeficient murine system, we showed that chronic stress–induced epinephrine promoted breast cancer stem-like properties via lactate dehydrogenase A–dependent (LDHA-dependent) metabolic rewiring. Chronic stress–induced epinephrine activated LDHA to generate lactate, and the adjusted pH directed USP28-mediated deubiquitination and stabilization of MYC. The SLUG promoter was then activated by MYC, which promoted development of breast cancer stem-like traits. Using a drug screen that targeted LDHA, we found that a chronic stress–induced cancer stem-like phenotype could be reversed by vitamin C. These findings demonstrated the critical importance of psychological …

Neoantigen Screening Identifies Broad Tp53 Mutant Immunogenicity In Patients With Epithelial Cancers., Parisa Malekzadeh, Anna Pasetto, Paul F Robbins, Maria R Parkhurst, Biman C Paria, Li Jia, Jared J Gartner, Victoria Hill, Zhiya Yu, Nicholas P Restifo, Abraham Sachs, Eric Tran, Winifred Lo, Robert Pt Somerville, Steven A Rosenberg, Drew C Deniger

Articles, Abstracts, and Reports

No abstract provided.

Shared Heritability And Functional Enrichment Across Six Solid Cancers., Xia Jiang, Hilary K Finucane, Fredrick R Schumacher, Stephanie L Schmit, Jonathan P Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B Kuchenbaecker, Joe Dennis, David V Conti, Graham Casey, Mia M Gaudet, Jeroen R Huyghe, Demetrius Albanes, Melinda C Aldrich, Angeline S Andrew, Irene L Andrulis, Hoda Anton-Culver, Antonis C Antoniou, Natalia N Antonenkova, Susanne M Arnold, Kristan J Aronson, Banu K Arun, Elisa V Bandera, Rosa B Barkardottir, Daniel R Barnes, Jyotsna Batra, Matthias W Beckmann, Javier Benitez, Sara Benlloch, Andrew Berchuck, Sonja I Berndt, Heike Bickeböller, Stephanie A Bien, Carl Blomqvist, Stefania Boccia, Natalia V Bogdanova, Stig E Bojesen, Manjeet K Bolla, Hiltrud Brauch, Hermann Brenner, James D Brenton, Mark N Brook, Joan Brunet, Hans Brunnström, Daniel D Buchanan, Barbara Burwinkel, Ralf Butzow, Gabriella Cadoni, Trinidad Caldés, Maria A Caligo, Ian Campbell, Peter T Campbell, Géraldine Cancel-Tassin, Lisa Cannon-Albright, Daniele Campa, Neil Caporaso, André L Carvalho, Andrew T Chan, Jenny Chang-Claude, Stephen J Chanock, Chu Chen, David C Christiani, Kathleen B M Claes, Frank Claessens, Judith Clements, J Margriet Collée, Marcia Cruz Correa, Fergus J Couch, Angela Cox, Julie M Cunningham, Cezary Cybulski, Kamila Czene, Mary B Daly, Anna Defazio, Peter Devilee, Orland Diez, Manuela Gago-Dominguez, Jenny L Donovan, Thilo Dörk, Eric J Duell, Alison M Dunning, Miriam Dwek, Diana M Eccles, Christopher K Edlund, Digna R Velez Edwards, Carolina Ellberg, D Gareth Evans, Peter A Fasching, Robert L Ferris, Triantafillos Liloglou, Jane C Figueiredo, Olivia Fletcher, Renée T Fortner, Florentia Fostira, Silvia Franceschi, Eitan Friedman, Steven J Gallinger, Patricia A Ganz, Judy Garber, José A García-Sáenz, Simon A Gayther, Graham G Giles, Andrew K Godwin, Mark S Goldberg, David E Goldgar, Ellen L Goode, Marc T Goodman, Gary E Goodman, Kjell Grankvist, Mark H Greene, Henrik Gronberg, Jacek Gronwald, Pascal Guénel, Niclas Håkansson, Per Hall, Ute Hamann, Freddie C Hamdy, Robert J Hamilton, Jochen Hampe, Aage Haugen, Florian Heitz, Rolando Herrero, Peter Hillemanns, Michael Hoffmeister, Estrid Høgdall, Yun-Chul Hong, John L Hopper, Richard Houlston, Peter J Hulick, David J Hunter, David G Huntsman, Gregory Idos, Evgeny N Imyanitov, Sue Ann Ingles, Claudine Isaacs, Anna Jakubowska, Paul James, Mark A Jenkins, Mattias Johansson, Mikael Johansson, Esther M John, Amit D Joshi, Radka Kaneva, Beth Y Karlan, Linda E Kelemen, Tabea Kühl, Kay-Tee Khaw, Elza Khusnutdinova, Adam S Kibel, Lambertus A Kiemeney, Jeri Kim, Susanne K Kjaer, Julia A Knight, Manolis Kogevinas, Zsofia Kote-Jarai, Stella Koutros, Vessela N Kristensen, Jolanta Kupryjanczyk, Martin Lacko, Stephan Lam, Diether Lambrechts, Maria Teresa Landi, Philip Lazarus, Nhu D Le, Eunjung Lee, Flavio Lejbkowicz, Heinz-Josef Lenz, Goska Leslie, Davor Lessel, Jenny Lester, Douglas A Levine, Li Li, Christopher I Li, Annika Lindblom, Noralane M Lindor, Geoffrey Liu, Fotios Loupakis, Jan Lubiński, Lovise Maehle, Christiane Maier, Arto Mannermaa, Loic Le Marchand, Sara Margolin, Taymaa May, Lesley Mcguffog, Alfons Meindl, Pooja Middha, Austin Miller, Roger L Milne, Robert J Macinnis, Francesmary Modugno, Marco Montagna, Victor Moreno, Kirsten B Moysich, Lorelei Mucci, Kenneth Muir, Anna Marie Mulligan, Katherine L Nathanson, David E Neal, Andrew R Ness, Susan L Neuhausen, Heli Nevanlinna, Polly A Newcomb, Lisa F Newcomb, Finn Cilius Nielsen, Liene Nikitina-Zake, Børge G Nordestgaard, Robert L Nussbaum, Kenneth Offit, Edith Olah, Ali Amin Al Olama, Olufunmilayo I Olopade, Andrew F Olshan, Håkan Olsson, Ana Osorio, Hardev Pandha, Jong Y Park, Nora Pashayan, Michael T Parsons, Tanja Pejovic, Kathryn L Penney, Wilbert H M Peters, Catherine M Phelan, Amanda I Phipps, Dijana Plaseska-Karanfilska, Miranda Pring, Darya Prokofyeva, Paolo Radice, Kari Stefansson, Susan J Ramus, Leon Raskin, Gad Rennert, Hedy S Rennert, Elizabeth J Van Rensburg, Marjorie J Riggan, Harvey A Risch, Angela Risch, Monique J Roobol, Barry S Rosenstein, Mary Anne Rossing, Kim De Ruyck, Emmanouil Saloustros, Dale P Sandler, Elinor J Sawyer, Matthew B Schabath, Johanna Schleutker, Marjanka K Schmidt, V Wendy Setiawan, Hongbing Shen, Erin M Siegel, Weiva Sieh, Christian F Singer, Martha L Slattery, Karina Dalsgaard Sorensen, Melissa C Southey, Amanda B Spurdle, Janet L Stanford, Victoria L Stevens, Sebastian Stintzing, Jennifer Stone, Karin Sundfeldt, Rebecca Sutphen, Anthony J Swerdlow, Eloiza H Tajara, Catherine M Tangen, Adonina Tardon, Jack A Taylor, M Dawn Teare, Manuel R Teixeira, Mary Beth Terry, Kathryn L Terry, Stephen N Thibodeau, Mads Thomassen, Line Bjørge, Marc Tischkowitz, Amanda E Toland, Diana Torres, Paul A Townsend, Ruth C Travis, Nadine Tung, Shelley S Tworoger, Cornelia M Ulrich, Nawaid Usmani, Celine M Vachon, Els Van Nieuwenhuysen, Ana Vega, Miguel Elías Aguado-Barrera, Qin Wang, Penelope M Webb, Clarice R Weinberg, Stephanie Weinstein, Mark C Weissler, Jeffrey N Weitzel, Catharine M L West, Emily White, Alice S Whittemore, H-Erich Wichmann, Fredrik Wiklund, Robert Winqvist, Alicja Wolk, Penella Woll, Michael Woods, Anna H Wu, Xifeng Wu, Drakoulis Yannoukakos, Wei Zheng, Shanbeh Zienolddiny, Argyrios Ziogas, Kristin K Zorn, Jacqueline M Lane, Richa Saxena, Duncan Thomas, Rayjean J Hung, Brenda Diergaarde, James Mckay, Ulrike Peters, Li Hsu, Montserrat García-Closas, Rosalind A Eeles, Georgia Chenevix-Trench, Paul J Brennan, Christopher A Haiman, Jacques Simard, Douglas F Easton, Stephen B Gruber, Paul D P Pharoah, Alkes L Price, Bogdan Pasaniuc, Christopher I Amos, Peter Kraft, Sara Lindström

Articles, Abstracts, and Reports

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r

Quality Assurance Guidelines For Interstitial Hyperthermia., H. Dobšíček Trefná, M. Schmidt, G. C. Van Rhoon, H. P. Kok, S. S. Gordeyev, U. Lamprecht, D. Marder, J. Nadobny, P. Ghadjar, S Abdel-Rahman, A. M. Kukiełka, V. Strnad, M. D. Hurwitz, Z. Vujaskovic, C. J. Diederich, P. R. Stauffer, J. Crezee

Department of Radiation Oncology Faculty Papers

Quality assurance (QA) guidelines are essential to provide uniform execution of clinical hyperthermia treatments and trials. This document outlines the clinical and technical consequences of the specific properties of interstitial heat delivery and specifies recommendations for hyperthermia administration with interstitial techniques. Interstitial hyperthermia aims at tumor temperatures in the 40-44 °C range as an adjunct to radiation or chemotherapy. The clinical part of this document imparts specific clinical experience of interstitial heat delivery to various tumor sites as well as recommended interstitial hyperthermia workflow and procedures. The second part describes technical requirements for quality assurance of current interstitial heating equipment …

Star-Related Lipid Transfer Protein 10 (Stard10): A Novel Key Player In Alcohol-Induced Breast Cancer Progression, Andrea Floris, Jia Luo, Jacqueline A. Frank, Jennifer Zhou, Sandro Orrù, Michela Biancolella, Sabina Pucci, Augusto Orlandi, Paolo Campagna, Antonella Balzano, Komal Ramani, Maria Lauda Tomasi

Pharmacology and Nutritional Sciences Faculty Publications

Background: Ethanol abuse promotes breast cancer development, metastasis and recurrence stimulating mammary tumorigenesis by mechanisms that remain unclear. Normally, 35% of breast cancer is Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2)-positive that predisposes to poor prognosis and relapse, while ethanol drinking leads to invasion of their ERBB2 positive cells triggering the phosphorylation status of mitogen-activated protein kinase. StAR-related lipid transfer protein 10 (STARD10) is a lipid transporter of phosphatidylcholine (PC) and phosphatidylethanolamine (PE); changes on membrane composition of PC and PE occur before the morphological tumorigenic events. Interestingly, STARD10 has been described to be highly expressed in 35–40% of ERBB2-positive breast …

The Mitochondrial Deoxyguanosine Kinase Is Required For Cancer Cell Stemness In Lung Adenocarcinoma, Shengchen Lin, Chongbiao Huang, Jianwei Sun, Oana Bollt, Xiuchao Wang, Eric Martine, Jiaxin Kang, Matthew D. Taylor, Bin Fang, Pankaj K. Singh, John Koomen, Jihui Hao, Shengyu Yang

Journal Articles: Eppley Institute

The mitochondrial deoxynucleotide triphosphate (dNTP) is maintained by the mitochondrial deoxynucleoside salvage pathway and dedicated for the mtDNA homeostasis, and the mitochondrial deoxyguanosine kinase (DGUOK) is a rate-limiting enzyme in this pathway. Here, we investigated the role of the DGUOK in the self-renewal of lung cancer stem-like cells (CSC). Our data support that DGUOK overexpression strongly correlates with cancer progression and patient survival. The depletion of DGUOK robustly inhibited lung adenocarcinoma tumor growth, metastasis, and CSC self-renewal. Mechanistically, DGUOK is required for the biogenesis of respiratory complex I and mitochondrial OXPHOS, which in turn regulates CSC self-renewal through AMPK-YAP1 signaling. …

Human Islet Response To Selected Type 1 Diabetes-Associated Bacteria: A Transcriptome-Based Study, Ahmed M. Abdellatif, Heather Jensen Smith, Robert Z. Harms, Nora Sarvetnick

Journal Articles: Eppley Institute

Type 1 diabetes (T1D) is a chronic autoimmune disease that results from destruction of pancreatic β-cells. T1D subjects were recently shown to harbor distinct intestinal microbiome profiles. Based on these findings, the role of gut bacteria in T1D is being intensively investigated. The mechanism connecting intestinal microbial homeostasis with the development of T1D is unknown. Specific gut bacteria such as Bacteroides dorei (BD) and Ruminococcus gnavus (RG) show markedly increased abundance prior to the development of autoimmunity. One hypothesis is that these bacteria might traverse the damaged gut barrier, and their constituents elicit a response from human islets that causes …

Inhibition Of Geranylgeranyl Diphosphate Synthase Is A Novel Therapeutic Strategy For Pancreatic Ductal Adenocarcinoma, Staci L. Haney, Michelle L. Varney, Yashpal S. Chhonker, Simon Shin, Kamiya Mehla, Ayrianne J. Crawford, Heather Jensen Smith, Lynette M. Smith, Daryl J. Murry, Michael A. Hollingsworth, Sarah A. Holstein

Journal Articles: Eppley Institute

Rab proteins play an essential role in regulating intracellular membrane trafficking processes. Rab activity is dependent upon geranylgeranylation, a post-translational modification that involves the addition of 20-carbon isoprenoid chains via the enzyme geranylgeranyl transferase (GGTase) II. We have focused on the development of inhibitors against geranylgeranyl diphosphate synthase (GGDPS), which generates the isoprenoid donor (GGPP), as anti-Rab agents. Pancreatic ductal adenocarcinoma (PDAC) is characterized by abnormal mucin production and these mucins play important roles in tumor development, metastasis and chemo-resistance. We hypothesized that GGDPS inhibitor (GGDPSi) treatment would induce PDAC cell death by disrupting mucin trafficking, thereby inducing the unfolded …