Medicine and Health Sciences Commons^™

Rare But Recurrent Ros1 Fusions Resulting From Chromosome 6q22 Microdeletions Are Targetable Oncogenes In Glioma., Monika A Davare, Jacob J Henderson, Anupriya Agarwal, Jacob P Wagner, Sudarshan R Iyer, Nameeta Shah, Randy Woltjer, Romel Somwar, Stephen W Gilheeney, Ana Decarvalo, Tom Mikkelson, Erwin G Van Meir, Marc Ladanyi, Brian J Druker

Articles, Abstracts, and Reports

PURPOSE: Gliomas, a genetically heterogeneous group of primary central nervous system tumors, continue to pose a significant clinical challenge. Discovery of chromosomal rearrangements involving kinase genes has enabled precision therapy, and improved outcomes in several malignancies.

EXPERIMENTAL DESIGN: Positing that similar benefit could be accomplished for patients with brain cancer, we evaluated The Cancer Genome Atlas (TCGA) glioblastoma dataset. Functional validation of the oncogenic potential and inhibitory sensitivity of discovered ROS1 fusions was performed using three independent cell-based model systems, and an

RESULTS:

CONCLUSIONS: Our findings highlight that CNS tumors should be specifically interrogated for these rare intrachromosomal 6q22 microdeletion …

Clinical Pharmacology Of Tisagenlecleucel In B-Cell Acute Lymphoblastic Leukemia., Karen Thudium Mueller, Edward Waldron, Stephan A. Grupp, John E. Levine, Theodore W. Laetsch, Michael A. Pulsipher, Michael W. Boyer, Keith August, Jason Hamilton, Rakesh Awasthi, Andrew M. Stein, Denise Sickert, Abhijit Chakraborty, Bruce L. Levine, Carl H. June, Lori Tomassian, Sweta S. Shah, Mimi Leung, Tetiana Taran, Patricia A. Wood, Shannon L. Maude

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL).

PATIENTS AND METHODS: We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across two studies in pediatric B-ALL (ELIANA and ENSIGN).

RESULTS: Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders (N = 62) had ≈2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders ( …

Targeting The Brd4/Foxo3a/Cdk6 Axis Sensitizes Akt Inhibition In Luminal Breast Cancer, Jingyi Liu, Weijie Guo, Zhibing Duan, Lei Zeng, Yadi Wu, Yule Chen, Fang Tai, Yifan Wang, Yiwei Lin, Qiang Zhang, Yanling He, Jiong Deng, Rachel L. Stewart, Chi Wang, Pengnian Charles Lin, Saghi Ghaffari, B. Mark Evers, Suling Liu, Ming-Ming Zhou, Binhua P. Zhou, Jian Shi

Molecular and Cellular Biochemistry Faculty Publications

BRD4 assembles transcriptional machinery at gene super-enhancer regions and governs the expression of genes that are critical for cancer progression. However, it remains unclear whether BRD4-mediated gene transcription is required for tumor cells to develop drug resistance. Our data show that prolonged treatment of luminal breast cancer cells with AKT inhibitors induces FOXO3a dephosphorylation, nuclear translocation, and disrupts its association with SirT6, eventually leading to FOXO3a acetylation as well as BRD4 recognition. Acetylated FOXO3a recognizes the BD2 domain of BRD4, recruits the BRD4/RNAPII complex to the CDK6 gene promoter, and induces its transcription. Pharmacological inhibition of either BRD4/FOXO3a association or …

Collagen Prolyl 4-Hydroxylase 1 Is Essential For Hif-1Α Stabilization And Tnbc Chemoresistance, Gaofeng Xiong, Rachel L. Stewart, Jie Chen, Tianyan Gao, Timothy L. Scott, Luis M. Samayoa, Kathleen L. O'Connor, Andrew N. Lane, Ren Xu

Markey Cancer Center Faculty Publications

Collagen prolyl 4-hydroxylase (P4H) expression and collagen hydroxylation in cancer cells are necessary for breast cancer progression. Here, we show that P4H alpha 1 subunit (P4HA1) protein expression is induced in triple-negative breast cancer (TNBC) and HER2 positive breast cancer. By modulating alpha ketoglutarate (α-KG) and succinate levels P4HA1 expression reduces proline hydroxylation on hypoxia-inducible factor (HIF) 1α, enhancing its stability in cancer cells. Activation of the P4HA/HIF-1 axis enhances cancer cell stemness, accompanied by decreased oxidative phosphorylation and reactive oxygen species (ROS) levels. Inhibition of P4HA1 sensitizes TNBC to the chemotherapeutic agent docetaxel and doxorubicin in xenografts and patient-derived …

Control Of Ccnd1 Ubiquitylation By The Catalytic Saga Subunit Usp22 Is Essential For Cell Cycle Progression Through G1 In Cancer Cells., Victoria J. Gennaro, Timothy J. Stanek, Amy R. Peck, Yunguang Sun, Feng Wang, Shuo Qie, Karen E. Knudsen, Hallgeir Rui, Tauseef Butt, J. Alan Diehl, Steven B. Mcmahon

Department of Biochemistry and Molecular Biology Faculty Papers

Overexpression of the deubiquitylase ubiquitin-specific peptidase 22 (USP22) is a marker of aggressive cancer phenotypes like metastasis, therapy resistance, and poor survival. Functionally, this overexpression of USP22 actively contributes to tumorigenesis, as USP22 depletion blocks cancer cell cycle progression in vitro, and inhibits tumor progression in animal models of lung, breast, bladder, ovarian, and liver cancer, among others. Current models suggest that USP22 mediates these biological effects via its role in epigenetic regulation as a subunit of the Spt-Ada-Gcn5-acetyltransferase (SAGA) transcriptional cofactor complex. Challenging the dogma, we report here a nontranscriptional role for USP22 via a direct effect on the …

A Brief Report Of Immunohistochemical Markers To Identify Aggressive Hepatoblastoma., Vivekanand Singh, Michelle Manalang, Meenal Singh, Udayan Apte

Manuscripts, Articles, Book Chapters and Other Papers

Hepatoblastoma (HB) is the most common malignant liver tumor in children. Although survival of patients has improved significantly over the last 2 decades, a significant number of patients do not respond to standard chemotherapy. We conducted a pilot study to understand if there was immunophenotypic difference between tumors that respond well to chemotherapy versus that do not. We selected 10 cases of HB from children presenting at our hospital. All patients had initial tissue diagnosis, underwent chemotherapy followed by surgical resection. The cases were divided into 2 groups: aggressive group with 5 cases (all of which had a poor response …

Country-Level Macroeconomic Indicators Predict Early Post-Allogeneic Hematopoietic Cell Transplantation Survival In Acute Lymphoblastic Leukemia: A Cibmtr Analysis., William A. Wood, Ruta Brazauskas, Zhen-Huan Hu, Hisham Abdel-Azim, Ibrahim A. Ahmed, Mahmoud Aljurf, Sherif Badawy, Amer Beitinjaneh, Biju George, David Buchbinder, Jan Cerny, Laurence Dedeken, Miguel Angel Diaz, Cesar O. Freytes, Siddhartha Ganguly, Usama Gergis, David Gomez Almaguer, Ashish Gupta, Gregory Hale, Shahrukh K. Hashmi, Yoshihiro Inamoto, Rammurti T. Kamble, Kehinde Adekola, Tamila Kindwall-Keller, Jennifer Knight, Lalit Kumar, Yachiyo Kuwatsuka, Jason Law, Hillard M. Lazarus, Charles Lemaistre, Richard F. Olsson, Michael A. Pulsipher, Bipin N. Savani, Kirk R. Schultz, Ayman A. Saad, Matthew Seftel, Sachiko Seo, Thomas C. Shea, Amir Steinberg, Keith Sullivan, David Szwajcer, Baldeep Wirk, Jean Yared, Agnes Yong, Jignesh Dalal, Theresa Hahn, Nandita Khera, Carmem Bonfim, Yoshiko Atsuta, Wael Saber

Manuscripts, Articles, Book Chapters and Other Papers

For patients with acute lymphoblastic leukemia (ALL), allogeneic hematopoietic cell transplantation (alloHCT) offers a potential cure. Life-threatening complications can arise from alloHCT that require the application of sophisticated health care delivery. The impact of country-level economic conditions on post-transplantation outcomes is not known. Our objective was to assess whether these variables were associated with outcomes for patients transplanted for ALL. Using data from the Center for Blood and Marrow Transplant Research, we included 11,261 patients who received a first alloHCT for ALL from 303 centers across 38 countries between the years of 2005 and 2013. Cox regression models were constructed …

Identification Of Susceptibility Pathways For The Role Of Chromosome 15q25.1 In Modifying Lung Cancer Risk, Xuemei Ji, Yohan Bossé, Maria Teresa Landi, Jiang Gui, Xiangjun Xiao, David Qian, Philippe Joubert Joubert, Maxime Lamontagne, Yafang Li, Ivan Gorlov, Mariella De Biasi, Younghun Han, Olga Gorlova, Rayjean J. Hung, Xifeng Wu, James Mckay, Xuchen Zong, Robert Carreras-Torres, David C. Christiani, Neil Caporaso, Mattias Johansson, Geoffrey Liu, Stig E. Bojesen, Loic Le Marchand, Demetrios Albanes, Heike Bickeböller, Melinda C. Aldrich, William S. Bush, Adonina Tardon, Gad Rennert, Susanne M. Arnold

Markey Cancer Center Faculty Publications

Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated …

Identification Of Susceptibility Pathways For The Role Of Chromosome 15q25.1 In Modifying Lung Cancer Risk., Xuemei Ji, Yohan Bossé, Maria Teresa Landi, Jiang Gui, Xiangjun Xiao, David Qian, Philippe Joubert, Maxime Lamontagne, Yafang Li, Ivan Gorlov, Mariella De Biasi, Younghun Han, Olga Gorlova, Rayjean J Hung, Xifeng Wu, James Mckay, Xuchen Zong, Robert Carreras-Torres, David C Christiani, Neil Caporaso, Mattias Johansson, Geoffrey Liu, Stig E Bojesen, Loic Le Marchand, Demetrios Albanes, Heike Bickeböller, Melinda C Aldrich, William S Bush, Adonina Tardon, Gad Rennert, Chu Chen, M Dawn Teare, John K Field, Lambertus A Kiemeney, Philip Lazarus, Aage Haugen, Stephen Lam, Matthew B Schabath, Angeline S Andrew, Hongbing Shen, Yun-Chul Hong, Jian-Min Yuan, Pier A Bertazzi, Angela C Pesatori, Yuanqing Ye, Nancy Diao, Li Su, Ruyang Zhang, Yonathan Brhane, Natasha Leighl, Jakob S Johansen, Anders Mellemgaard, Walid Saliba, Christopher Haiman, Lynne Wilkens, Ana Fernandez-Somoano, Guillermo Fernandez-Tardon, Erik H F M Van Der Heijden, Jin Hee Kim, Juncheng Dai, Zhibin Hu, Michael P A Davies, Michael W Marcus, Hans Brunnström, Jonas Manjer, Olle Melander, David C Muller, Kim Overvad, Antonia Trichopoulou, Rosario Tumino, Jennifer Doherty, Gary E Goodman, Angela Cox, Fiona Taylor, Penella Woll, Irene Brüske, Judith Manz, Thomas Muley, Angela Risch, Albert Rosenberger, Kjell Grankvist, Mikael Johansson, Frances Shepherd, Ming-Sound Tsao, Susanne M Arnold, Eric B Haura, Ciprian Bolca, Ivana Holcatova, Vladimir Janout, Milica Kontic, Jolanta Lissowska, Anush Mukeria, Simona Ognjanovic, Tadeusz M Orlowski, Ghislaine Scelo, Beata Swiatkowska, David Zaridze, Per Bakke, Vidar Skaug, Shanbeh Zienolddiny, Eric J Duell, Lesley M Butler, Woon-Puay Koh, Yu-Tang Gao, Richard Houlston, John Mclaughlin, Victoria Stevens, David C Nickle, Ma'en Obeidat, Wim Timens, Bin Zhu, Lei Song, María Soler Artigas, Martin D Tobin, Louise V Wain, Fangyi Gu, Jinyoung Byun, Ahsan Kamal, Dakai Zhu, Rachel F Tyndale, Wei-Qi Wei, Stephen Chanock, Paul Brennan, Christopher I Amos

Articles, Abstracts, and Reports

Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated …

Cogstate Computerized Memory Tests In Patients With Brain Metastases: Secondary Endpoint Results Of Nrg Oncology Rtog 0933., Chip Caine, Snehal Deshmukh, Vinai Gondi, Minesh Mehta, Wolfgang Tomé, Benjamin W. Corn, Andrew Kanner, Howard Rowley, Vijayananda Kundapur, Albert Denittis, Jeffrey Noah Greenspoon, Andre A. Konski, Glenn S. Bauman, Adam Raben, Wenyin Shi, Merideth Wendland, Lisa Kachnic

Minesh Mehta

Whole brain radiotherapy (WBRT) is associated with memory dysfunction. As part of NRG Oncology RTOG 0933, a phase II study of WBRT for brain metastases that conformally avoided the hippocampal stem cell compartment (HA-WBRT), memory was assessed pre- and post-HA-WBRT using both traditional and computerized memory tests. We examined whether the computerized tests yielded similar findings and might serve as possible alternatives for assessment of memory in multi-institution clinical trials. Adult patients with brain metastases received HA-WBRT to 30 Gy in ten fractions and completed Hopkins Verbal Learning Test-Revised (HVLT-R), CogState International Shopping List Test (ISLT) and One Card Learning …

Co-Expression Of Cd39 And Cd103 Identifies Tumor-Reactive Cd8 T Cells In Human Solid Tumors., Thomas Duhen, Rebekka Duhen, Ryan Montler, Jake Moses, Tarsem Moudgil, Noel F De Miranda, Cheri P Goodall, Tiffany C Blair, Bernard A Fox, Jason E Mcdermott, Shu-Ching Chang, Gary Grunkemeier, Rom Leidner, Richard Bryan Bell, Andrew D Weinberg

Shu-Ching Chang, PhD, MS

Identifying tumor antigen-specific T cells from cancer patients has important implications for immunotherapy diagnostics and therapeutics. Here, we show that CD103+CD39+ tumor-infiltrating CD8 T cells (CD8 TIL) are enriched for tumor-reactive cells both in primary and metastatic tumors. This CD8 TIL subset is found across six different malignancies and displays an exhausted tissue-resident memory phenotype. CD103+CD39+ CD8 TILs have a distinct T-cell receptor (TCR) repertoire, with T-cell clones expanded in the tumor but present at low frequencies in the periphery. CD103+CD39+ CD8 TILs also efficiently kill autologous tumor cells in a MHC-class I-dependent manner. Finally, higher frequencies of CD103+CD39+ CD8 …

Co-Expression Of Cd39 And Cd103 Identifies Tumor-Reactive Cd8 T Cells In Human Solid Tumors., Thomas Duhen, Rebekka Duhen, Ryan Montler, Jake Moses, Tarsem Moudgil, Noel F De Miranda, Cheri P Goodall, Tiffany C Blair, Bernard A Fox, Jason E Mcdermott, Shu-Ching Chang, Gary Grunkemeier, Rom Leidner, Richard Bryan Bell, Andrew D Weinberg

Articles, Abstracts, and Reports

Identifying tumor antigen-specific T cells from cancer patients has important implications for immunotherapy diagnostics and therapeutics. Here, we show that CD103+CD39+ tumor-infiltrating CD8 T cells (CD8 TIL) are enriched for tumor-reactive cells both in primary and metastatic tumors. This CD8 TIL subset is found across six different malignancies and displays an exhausted tissue-resident memory phenotype. CD103+CD39+ CD8 TILs have a distinct T-cell receptor (TCR) repertoire, with T-cell clones expanded in the tumor but present at low frequencies in the periphery. CD103+CD39+ CD8 TILs also efficiently kill autologous tumor cells in a MHC-class I-dependent manner. Finally, higher frequencies of CD103+CD39+ CD8 …

Recurrent Tumor-Specific Regulation Of Alternative Polyadenylation Of Cancer-Related Genes., Zhuyi Xue, René L Warren, Ewan A Gibb, Daniel Macmillan, Johnathan Wong, Readman Chiu, S Austin Hammond, Chen Yang, Ka Ming Nip, Catherine A Ennis, Abigail Hahn, Sheila Reynolds, Inanc Birol

Articles, Abstracts, and Reports

BACKGROUND: Alternative polyadenylation (APA) results in messenger RNA molecules with different 3' untranslated regions (3' UTRs), affecting the molecules' stability, localization, and translation. APA is pervasive and implicated in cancer. Earlier reports on APA focused on 3' UTR length modifications and commonly characterized APA events as 3' UTR shortening or lengthening. However, such characterization oversimplifies the processing of 3' ends of transcripts and fails to adequately describe the various scenarios we observe.

RESULTS: We built a cloud-based targeted de novo transcript assembly and analysis pipeline that incorporates our previously developed cleavage site prediction tool, KLEAT. We applied this pipeline to …

Age Adjusted Hematopoietic Stem Cell Transplant Comorbidity Index Predicts Survival In A T-Cell Depleted Cohort, Hayder Saeed, Swati Yalamanchi, Meng Liu, Emily Van Meter, Zartash Gul, Gregory Monohan, Dianna Howard, Gerhard C. Hildebrandt, Roger Herzig

Markey Cancer Center Faculty Publications

Objectives: Allogeneic hematopoietic stem cell transplant (HCT) continues to evolve with the treatment in higher risk patient population. This practice mandates stringent update and validation of risk stratification prior to undergoing such a complex and potentially fatal procedure. We examined the adoption of the new comorbidity index (HCT-CI/Age) proposed by the Seattle group after the addition of age variable and compared it to the pre-transplant assessment of mortality (PAM) that already incorporates age as part of its evaluation criteria.

Methods: A retrospective analysis of adult patients who underwent HCT at our institution from January 2010 through August 2014 was …

Potent Immune Modulation By Medi6383, An Engineered Human Ox40 Ligand Igg4p Fc Fusion Protein., Michael D Oberst, Catherine Augé, Chad Morris, Stacy Kentner, Kathy Mulgrew, Kelly Mcglinchey, James Hair, Shino Hanabuchi, Qun Du, Melissa Damschroder, Hui Feng, Steven Eck, Nicholas Buss, Lolke De Haan, Andrew J Pierce, Haesun Park, Andrew Sylwester, Michael K Axthelm, Louis Picker, Nicholas P Morris, Andrew D Weinberg, Scott A Hammond

Articles, Abstracts, and Reports

Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution-phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcγRs) on the surface of adjacent cells. The resulting costimulation of OX40 on T cells induced NFκB promoter activity in OX40-expressing T cells and induced …

Digitizing Omics Profiles By Divergence From A Baseline., Wikum Dinalankara, Qian Ke, Yiran Xu, Lanlan Ji, Nicole Pagane, Anching Lien, Tejasvi Matam, Elana J Fertig, Nathan D Price, Laurent Younes, Luigi Marchionni, Donald Geman

Articles, Abstracts, and Reports

Data collected from omics technologies have revealed pervasive heterogeneity and stochasticity of molecular states within and between phenotypes. A prominent example of such heterogeneity occurs between genome-wide mRNA, microRNA, and methylation profiles from one individual tumor to another, even within a cancer subtype. However, current methods in bioinformatics, such as detecting differentially expressed genes or CpG sites, are population-based and therefore do not effectively model intersample diversity. Here we introduce a unified theory to quantify sample-level heterogeneity that is applicable to a single omics profile. Specifically, we simplify an omics profile to a digital representation based on the omics profiles …

Benchmarking Rectal Cancer Care: Institutional Compliance With A Longitudinal Checklist., William C. Chapman, Pamela Choi, Alexander T. Hawkins, Steven R. Hunt, Matthew L. Silviera, Paul E. Wise, Matthew G. Mutch, Sean C. Glasgow

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: In 2012, the American Society of Colon and Rectal Surgeons published the Rectal Cancer Surgery Checklist, a consensus document listing 25 essential elements of care for all patients undergoing radical surgery for rectal cancer. The authors herein examine checklist adherence in a mature, multisurgeon specialty academic practice.

MATERIALS AND METHODS: A retrospective medical record review of patients undergoing elective radical resection for rectal adenocarcinoma over a 23-mo period was conducted. Checklists were completed post hoc for each patient, and these results were tabulated to determine levels of compliance. Subgroup analyses by compliance and experience levels of the treating surgeon …

Analysis Of Clinical Data To Determine The Minimum Number Of Sensors Required For Adequate Skin Temperature Monitoring Of Superficial Hyperthermia Treatments., Akke Bakker, Rebecca Holman, Dario B. Rodrigues, Hana Dobšíček Trefná, Paul R. Stauffer, Geertjan Van Tienhoven, Coen R.N. Rasch, Hans Crezee

Department of Radiation Oncology Faculty Papers

PURPOSE: Tumor response and treatment toxicity are related to minimum and maximum tissue temperatures during hyperthermia, respectively. Using a large set of clinical data, we analyzed the number of sensors required to adequately monitor skin temperature during superficial hyperthermia treatment of breast cancer patients.

METHODS: Hyperthermia treatments monitored with >60 stationary temperature sensors were selected from a database of patients with recurrent breast cancer treated with re-irradiation (23 × 2 Gy) and hyperthermia using single 434 MHz applicators (effective field size 351-396 cm²). Reduced temperature monitoring schemes involved randomly selected subsets of stationary skin sensors, and another subset …

Human Cancer And Platelet Interaction, A Potential Therapeutic Target, Shike Wang, Zhenyu Li, Ren Xu

Markey Cancer Center Faculty Publications

Cancer patients experience a four-fold increase in thrombosis risk, indicating that cancer development and progression are associated with platelet activation. Xenograft experiments and transgenic mouse models further demonstrate that platelet activation and platelet-cancer cell interaction are crucial for cancer metastasis. Direct or indirect interaction of platelets induces cancer cell plasticity and enhances survival and extravasation of circulating cancer cells during dissemination. In vivo and in vitro experiments also demonstrate that cancer cells induce platelet aggregation, suggesting that platelet-cancer interaction is bidirectional. Therefore, understanding how platelets crosstalk with cancer cells may identify potential strategies to inhibit cancer metastasis and to reduce …

Menopausal-Related Symptoms In Women One Year After Breast Cancer Surgery., Melissa Mazor, Kathryn Lee, Anand Dhruva, Janine K Cataldo, Steven M Paul, Michelle Melisko, Betty J Smoot, Jon D Levine, Charles Elboim, Yvette P Conley, Christine Miaskowksi

Articles, Abstracts, and Reports

CONTEXT: Approximately 60% to 100% of women with breast cancer experience at least one menopausal-related symptom. Little is known about associations between menopausal status and symptoms in women 12 months after breast cancer surgery.

OBJECTIVES: The purpose of this study was to evaluate for differences in occurrence, severity, and distress of symptoms between pre- and postmenopausal women 12 months after breast cancer surgery.

METHODS: Women with breast cancer (n = 327) completed the Menopausal Symptoms Scale, which evaluated the occurrence, severity, and distress of 46 common menopausal-related symptoms. Regression analyses were used to evaluate between-group differences in the seven symptoms …

Cyclin D1-Mediated Microrna Expression Signature Predicts Breast Cancer Outcome, Guangxue Wang, Michael Gormley, Jing Qiao, Qian Zhao, Min Wang, Gabriele Disante, Shengqiong Deng, Lin Dong, Timothy G. Pestell, Xiaoming Ju, Mathew C. Casimiro, Sankar Addya, Adam Ertel, Ayden Tozeren, Qinchuan Li, Zuoren Yu, Richard G. Pestell

Department of Cancer Biology Faculty Papers

Background: Genetic classification of breast cancer based on the coding mRNA suggests the evolution of distinct subtypes. Whether the non-coding genome is altered concordantly with the coding genome and the mechanism by which the cell cycle directly controls the non-coding genome is poorly understood.

Methods: Herein, the miRNA signature maintained by endogenous cyclin D1 in human breast cancer cells was defined. In order to determine the clinical significance of the cyclin D1-mediated miRNA signature, we defined a miRNA expression superset from 459 breast cancer samples. We compared the coding and non-coding genome of breast cancer subtypes.

Results: Hierarchical clustering of …

In-Hospital Mortality And Post-Surgical Complications Among Cancer Patients With Metabolic Syndrome, Tomi Akinyemiju, Swati Sakhuja, Neomi Vin-Raviv

Epidemiology and Environmental Health Faculty Publications

Background

Metabolic syndrome (MetS) is an important etiologic and prognostic factor for cancer, but few studies have assessed hospitalization outcomes among patients with both conditions.

Methods

Data was obtained from the Healthcare Cost and Utilization project Nationwide Inpatient Sample (HCUP-NIS). Study variables were assessed using ICD-9 codes on adults aged 40 years and over admitted to a US hospital between 2007 and 2011 with primary diagnosis of either breast, colorectal, or prostate cancer. We examined in-hospital mortality, post-surgical complications, and discharge disposition among cancer patients with MetS and compared with non-MetS patients.

Results

Hospitalized breast (OR: 0.31, 95% CI: 0.20–0.46), …

Demographic, Presentation, And Treatment Factors And Racial Disparities In Ovarian Cancer Hospitalization Outcomes, Tomi F. Akinyemiju, Gurudatta Naik, Kemi Ogunsina, Daniel T. Dibaba, Neomi Vin-Raviv

Epidemiology and Environmental Health Faculty Publications

BACKGROUND: This study examines whether racial disparities in hospitalization outcomes persist between African-American and White women with ovarian cancer after matching on demographic, presentation, and treatment factors.

METHODS: Using data from the Nationwide Inpatient Sample database, 5,164 African-American ovarian cancer patients were sequentially matched with White patients on demographic (e.g., age, income), presentation (e.g., stage, comorbidities), and treatment (e.g., surgery, radiation) factors. Racial differences in-hospital length of stay, post-operative complications, and in-hospital mortality were evaluated using conditional logistic regression models.

RESULTS: White ovarian cancer patients had relatively higher odds of post-operative complications when matched on demographics (OR 1.35, 95% CI …

First Report Of Nrg Oncology/Radiation Therapy Oncology Group 0622: A Phase 2 Trial Of Samarium-153 Followed By Salvage Prostatic Fossa Irradiation In High-Risk Clinically Nonmetastatic Prostate Cancer After Radical Prostatectomy., Richard K. Valicenti, Stephanie L. Pugh, Edouard J. Trabulsi, Oliver Sartor, Eric C. Ko, Michael R. Girvigian, Seth A. Rosenthal, Mark E. Shaves, Jean Hoffman-Censits, John Schallenkamp, Howard M. Sandler

Department of Urology Faculty Papers

PURPOSE: To investigate the utility of ¹⁵³Sm lexidronam (Quadramet) in the setting of men with prostate cancer status post radical prostatectomy who develop biochemical failure with no clinical evidence of osseous metastases.

PATIENTS AND METHODS: Trial NRG Oncology RTOG 0622 is a single-arm phase 2 trial that enrolled men with pT2-T4, N0-1, M0 prostate cancer status post radical prostatectomy, who meet at least 1 of these biochemical failure criteria: (1) prostate-specific antigen (PSA) > 1.0 ng/mL; (2) PSA > 0.2 ng/mL if Gleason score 9 to 10; or (3) PSA > 0.2 ng/mL if N1. Patients received ¹⁵³Sm (2.0 mCi/kg intravenously …

Applying Genomics In Heart Transplantation., Brendan J Keating, Alexandre C Pereira, Michael Snyder, Brian D. Piening

Articles, Abstracts, and Reports

While advances in patient care and immunosuppressive pharmacotherapies have increased the lifespan of heart allograft recipients, there are still significant comorbidities post-transplantation and 5-year survival rates are still significant, at approximately 70%. The last decade has seen massive strides in genomics and other omics fields, including transcriptomics, with many of these advances now starting to impact heart transplant clinical care. This review summarizes a number of the key advances in genomics which are relevant for heart transplant outcomes, and we highlight the translational potential that such knowledge may bring to patient care within the next decade.

Neurotensin Receptor 3/Sortilin Contributes To Tumorigenesis Of Neuroendocrine Tumors Through Augmentation Of Cell Adhesion And Migration, Ji Tae Kim, Dana L. Napier, Heidi L. Weiss, Eun Y. Lee, Courtney M. Townsend, B. Mark Evers

Markey Cancer Center Faculty Publications

Neurotensin (NTS), a 13–amino acid peptide which is distributed predominantly along gastrointestinal tract, has multiple physiologic and pathologic functions, and its effects are mediated by three distinct NTS receptors (NTSRs). Overexpression and activation of NTS signaling components, especially NTS and/or NTSR1, are closely linked with cancer progression and metastasis in various types of cancers including neuroendocrine tumors (NETs). Although deregulation of NTSR3/sortilin has been implicated in a variety of human diseases, the expression and role of NTSR3/sortilin in NETs have not been elucidated. In this study, we investigated the expression and oncogenic effect of NTSR3/sortilin in NETs. Increased protein levels …

Beta-Catenin Cleavage Enhances Transcriptional Activation, Tatiana Goretsky, Emily M. Bradford, Qing Ye, Olivia F. Lamping, Tomas Vanagunas, Mary Pat Moyer, Patrick C. Keller, Preetika Sinh, Josep M. Llovet, Tianyan Gao, Qing-Bai She, Linheng Li, Terrence A. Barrett

Internal Medicine Faculty Publications

Nuclear activation of Wnt/β-catenin signaling is required for cell proliferation in inflammation and cancer. Studies from our group indicate that β-catenin activation in colitis and colorectal cancer (CRC) correlates with increased nuclear levels of β-catenin phosphorylated at serine 552 (pβ-Cat⁵⁵²). Biochemical analysis of nuclear extracts from cancer biopsies revealed the existence of low molecular weight (LMW) pβ-Cat⁵⁵², increased to the exclusion of full size (FS) forms of β-catenin. LMW β-catenin lacks both termini, leaving residues in the armadillo repeat intact. Further experiments showed that TCF4 predominantly binds LMW pβ-Cat⁵⁵² in the nucleus of inflamed and …

Microscale Gene Expression Analysis Of Tumor-Associated Macrophages, Kuldeep S. Attri, Kamiya Mehla, Surendra K. Shukla, Pankaj K. Singh

Journal Articles: Eppley Institute

Macrophages, apart from being the key effector cells of the innate immune system, also play critical roles during the development and progression of various complex diseases, including cancer. Tumor-associated macrophages, infiltrate tumors during different stages of cancer progression to regulate motility, invasion, and intravasation to metastatic sites. Macrophages can exist in different polarization states associated with unique function in tumors. Since tumor-associated macrophages constitute a very small proportion of tumor cells, analysis of gene expression pattern using normal extraction buffer-based methods remains a challenging task. Therefore, it is imperative to develop low-throughput strategies to investigate transcriptional regulations from a small …

Met Receptor Inhibitor Su11274 Localizes In The Endoplasmic Reticulum, Edwin J. Wiest, Heather Jensen Smith, Michael A. Hollingsworth

Journal Articles: Eppley Institute

We discovered that SU11274, a class I c-Met inhibitor, fluoresces when excited by 488 nm laser light and showed rapid specific accumulation in distinct subcellular compartments. Given that SU11274 reduces cancer cell viability, we exploited these newly identified spectral properties to determine SU11274 intracellular distribution and accumulation in human pancreatic cancer cells. The aim of the studies reported here was to identify organelle(s) to which SU11274 is trafficked. We conclude that SU11274 rapidly and predominantly accumulates in the endoplasmic reticulum.

Cetuximab Plus Carboplatin And Paclitaxel With Or Without Bevacizumab Versus Carboplatin And Paclitaxel With Or Without Bevacizumab In Advanced Nsclc (Swog S0819): A Randomised, Phase 3 Study, Roy S. Herbst, Mary W. Redman, Edward S. Kim, Thomas J. Semrad, Lyudmila Bazhenova, Gregory Masters, Kurt Oettel, Perry Guaglianone, Christopher Reynolds, Anand Karnad, Susanne M. Arnold, Marileila Varella-Garcia, James Moon, Philip C. Mack, Charles D. Blanke, Fred R. Hirsch, Karen Kelly, David R. Gandara

Markey Cancer Center Faculty Publications

Background

EGFR antibodies have shown promise in patients with advanced non-small-cell lung cancer (NSCLC), particularly with squamous cell histology. We hypothesised that EGFR copy number by fluorescence in-situ hybridisation (FISH) can identify patients most likely to benefit from these drugs combined with chemotherapy and we aimed to explore the activity of cetuximab with chemotherapy in patients with advanced NSCLC who are EGFR FISH-positive.

Methods

We did this open-label, phase 3 study (SWOG S0819) at 277 sites in the USA and Mexico. We randomly assigned (1:1) eligible patients with treatment-naive stage IV NSCLC to receive paclitaxel (200 mg/m ²; every …