Medical Specialties Commons^™

Non-Hodgkin And Hodgkin Lymphomas Select For Overexpression Of Bclw., Clare M. Adams, Ramkrishna Mitra, Jerald Z. Gong, Md, Christine M. Eischen

Department of Cancer Biology Faculty Papers

Purpose: B-cell lymphomas must acquire resistance to apoptosis during their development. We recently discovered BCLW, an antiapoptotic BCL2 family member thought only to contribute to spermatogenesis, was overexpressed in diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. To gain insight into the contribution of BCLW to B-cell lymphomas and its potential to confer resistance to BCL2 inhibitors, we investigated the expression of BCLW and the other antiapoptotic BCL2 family members in six different B-cell lymphomas. Experimental Design: We performed a large-scale gene expression analysis of datasets comprising approximately 2,300 lymphoma patient samples, including non-Hodgkin and Hodgkin lymphomas as well as …

Advancing Stroke Genomic Research In The Age Of Trans-Omics Big Data Science: Emerging Priorities And Opportunities, Mayowa Owolabi, Emmanuel Peprah, Huichun Xu, Rufus Akinyemi, Hemant K. Tiwari, Marguerite R. Irvin, Kolawole Wasiu Wahab, Donna K. Arnett, Bruce Ovbiagele

Epidemiology and Environmental Health Faculty Publications

Background—We systematically reviewed the genetic variants associated with stroke in genome-wide association studies (GWAS) and examined the emerging priorities and opportunities for rapidly advancing stroke research in the era of Trans-Omics science.

Methods—Using the PRISMA guideline, we searched PubMed and NHGRI- EBI GWAS catalog for stroke studies from 2007 till May 2017.

Results—We included 31 studies. The major challenge is that the few validated variants could not account for the full genetic risk of stroke and have not been translated for clinical use. None of the studies included continental Africans. Genomic study of stroke among Africans presents …

Top2a And Ezh2 Provide Early Detection Of An Aggressive Prostate Cancer Subgroup., David P. Labbé, Christopher J. Sweeney, Myles Brown, Phillip Galbo, Spencer Rosario, Kristine M. Wadosky, Sheng-Yu Ku, Martin Sjöström, Mohammed Alshalalfa, Nicholas Erho, Elai Davicioni, R. Jeffrey Karnes, Edward M. Schaeffer, Robert B. Jenkins, Robert B. Den, Ashley E. Ross, Michaela Bowden, Ying Huang, Kathryn P. Gray, Felix Y. Feng, Daniel E. Spratt, David W. Goodrich, Kevin H. Eng, Leigh Ellis

Department of Radiation Oncology Faculty Papers

Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer–associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient's progression to metastatic disease. Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess …

Reducing Symptom Distress In Patients With Advanced Cancer Using An E-Alert System For Caregivers: Pooled Analysis Of Two Randomized Clinical Trials, David H. Gustafson, Lori L. Dubenske, Amy K. Atwood, Ming-Yuan Chih, Roberta A. Johnson, Fiona Mctavish, Andrew Quanbeck, Roger L. Brown, James F. Cleary, Dhavan Shah

Health and Clinical Sciences Faculty Publications

Background: Symptom distress in patients toward the end of life can change rapidly. Family caregivers have the potential to help patients manage those symptoms, as well as their own stress, if they are equipped with the proper resources. Electronic health (eHealth) systems may be able to provide those resources. Very sick patients may not be able to use such systems themselves to report their symptoms but family caregivers could.

Objective: The aim of this paper was to assess the effects on cancer patient symptom distress of an eHealth system that alerts clinicians to significant changes in the patient’s symptoms, as …

Cancer-Associated Fibroblasts Neutralize The Anti-Tumor Effect Of Csf1 Receptor Blockade By Inducing Pmn-Mdsc Infiltration Of Tumors., Vinit Kumar, Laxminarasimha Donthireddy, Douglas Marvel, Thomas Condamine, Fang Wang, Sergio Lavilla-Alonso, Ayumi Hashimoto, Prashanthi Vonteddu, Reeti Behera, Marlee A. Goins, Charles Mulligan, Brian Nam, Neil Hockstein, Fred Denstman, Shanti Shakamuri, David W. Speicher, Ashani T. Weeraratna, Timothy Chao, Robert H. Vonderheide, Lucia R. Languino, Peter Ordentlich, Qin Liu, Xiaowei Xu, Albert Lo, Ellen Puré, Chunsheng Zhang, Andrey Loboda, Manuel A. Sepulveda, Linda A. Snyder, Dmitry I. Gabrilovich

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with …

Cardiovascular Health Is Associated With Physical Function Among Older Community Dwelling Men And Women., Yichen Jin, Toshiko Tanaka, Yan Ma, Stefania Bandinelli, Luigi Ferrucci, Sameera A Talegawkar

Exercise and Nutrition Sciences Faculty Publications

Background

Age related decline in physical function is a significant concern affecting the quality of life of older individuals.

Methods

We examined the associations between baseline overall cardiovascular health (CVH), its components, and physical function in 906 men and women from the InCHIANTI cohort. Physical function was assessed using the Short Performance Physical Battery and poor physical function was defined as an Short Performance Physical Battery score less than 10. Overall CVH score, ranging from 0 to 12 in the cohort, was operationalized using adherence to ideal levels for health behaviors including smoking status, physical activity, body mass index, and …

Precision Newborn Screening For Lysosomal Disorders, Melissa M. Minter Baerg, Stephanie D. Stoway, Jeremy Hart, Lea Mott, Dawn S. Peck, Stephanie L. Nett, Jason S. Eckerman, Jean M. Lacey, Coleman T. Turgeon, Dimitar Gavrilov, Devin Oglesbee, Kimiyo Raymond, Silvia Tortorelli, Dietrich Matern, Lars Mørkrid, Piero Rinaldo

Pathology and Laboratory Medicine Faculty Publications

Purpose: The implementation of newborn screening for lysosomal disorders has uncovered overall poor specificity, psychosocial harm experienced by caregivers, and costly follow-up testing of false-positive cases. We report an informatics solution proven to minimize these issues.

Methods: The Kentucky Department for Public Health outsourced testing for mucopolysaccharidosis type I (MPS I) and Pompe disease, conditions recently added to the recommended uniform screening panel, plus Krabbe disease, which was added by legislative mandate. A total of 55,161 specimens were collected from infants born over 1 year starting from February 2016. Testing by tandem mass spectrometry was integrated with multivariate pattern recognition …

Tumor Suppressor Pdcd4 Attenuates Sin1 Translation To Inhibit Invasion In Colon Carcinoma, Qing Wang, Jiang Zhu, Ya-Wen Wang, Yong Dai, Yanlei Wang, Chi Wang, Jinpeng Liu, Alyson Baker, Nancy H. Colburn, Hsin-Sheng Yang

Toxicology and Cancer Biology Faculty Publications

Programmed cell death 4 (Pdcd4), a tumor invasion suppressor, is frequently downregulated in colorectal cancer and other cancers. In this study, we find that loss of Pdcd4 increases the activity of mammalian target of rapamycin complex 2 (mTORC2) and thereby upregulates Snail expression. Examining the components of mTORC2 showed that Pdcd4 knockdown increased the protein but not mRNA level of stress-activated-protein kinase interacting protein 1 (Sin1), which resulted from enhanced Sin1 translation. To understand how Pdcd4 regulates Sin1 translation, the SIN1 5′ untranslated region (5′UTR) was fused with luciferase reporter and named as 5′Sin1-Luc. Pdcd4 knockdown/knockout significantly increased the translation …

Epigenetic Etiology Of Intellectual Disability., Shigeki Iwase, Nathalie G Bérubé, Zhaolan Zhou, Nael Nadif Kasri, Elena Battaglioli, Marilyn Scandaglia, Angel Barco

Paediatrics Publications

Intellectual disability (ID) is a prevailing neurodevelopmental condition associated with impaired cognitive and adaptive behaviors. Many chromatin-modifying enzymes and other epigenetic regulators have been genetically associated with ID disorders (IDDs). Here we review how alterations in the function of histone modifiers, chromatin remodelers, and methyl-DNA binding proteins contribute to neurodevelopmental defects and altered brain plasticity. We also discuss how progress in human genetics has led to the generation of mouse models that unveil the molecular etiology of ID, and outline the direction in which this field is moving to identify therapeutic strategies for IDDs. Importantly, because the chromatin regulators linked …

The Need For A Network To Establish And Validate Predictive Biomarkers In Cancer Immunotherapy., Giuseppe V Masucci, Alessandra Cesano, Alexander Eggermont, Bernard A Fox, Ena Wang, Francesco M Marincola, Gennaro Ciliberto, Kevin Dobbin, Igor Puzanov, Janis Taube, Jennifer Wargo, Lisa H Butterfield, Lisa Villabona, Magdalena Thurin, Michael A Postow, Paul M Sondel, Sandra Demaria, Sanjiv Agarwala, Paolo A Ascierto

Articles, Abstracts, and Reports

Immunotherapies have emerged as one of the most promising approaches to treat patients with cancer. Recently, the entire medical oncology field has been revolutionized by the introduction of immune checkpoints inhibitors. Despite success in a variety of malignancies, responses typically only occur in a small percentage of patients for any given histology or treatment regimen. There are also concerns that immunotherapies are associated with immune-related toxicity as well as high costs. As such, identifying biomarkers to determine which patients are likely to derive clinical benefit from which immunotherapy and/or be susceptible to adverse side effects is a compelling clinical and …

Moonlighting Newborn Screening Markers: The Incidental Discovery Of A Second-Tier Test For Pompe Disease, Silvia Tortorelli, Jason S. Eckerman, Joseph J. Orsini, Colleen Stevens, Jeremy Hart, Patricia L. Hall, John J. Alexander, Dimitar Gavrilov, Devin Oglesbee, Kimiyo Raymond, Dietrich Matern, Piero Rinaldo

Pathology and Laboratory Medicine Faculty Publications

Purpose: To describe a novel biochemical marker in dried blood spots suitable to improve the specificity of newborn screening for Pompe disease.

Methods: The new marker is a ratio calculated between the creatine/creatinine (Cre/Crn) ratio as the numerator and the activity of acid α-glucosidase (GAA) as the denominator. Using Collaborative Laboratory Integrated Reports (CLIR), the new marker was incorporated in a dual scatter plot that can achieve almost complete segregation between Pompe disease and false-positive cases.

Results: The (Cre/Crn)/GAA ratio was measured in residual dried blood spots of five Pompe cases and was found to be elevated (range 4.41–13.26; 99%ile …

Tumor And Microenvironment Evolution During Immunotherapy With Nivolumab., Nadeem Riaz, Jonathan J Havel, Vladimir Makarov, Alexis Desrichard, Walter Urba, Jennifer S Sims, F Stephen Hodi, Salvador Martín-Algarra, Rajarsi Mandal, William H Sharfman, Shailender Bhatia, Wen-Jen Hwu, Thomas F Gajewski, Craig L Slingluff, Diego Chowell, Sviatoslav M Kendall, Han Chang, Rachna Shah, Fengshen Kuo, Luc G T Morris, John-William Sidhom, Jonathan P Schneck, Christine E Horak, Nils Weinhold, Timothy A Chan

Articles, Abstracts, and Reports

The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific …

Differential Impact Of Serial Measurement Of Nonplatelet Thromboxane Generation On Long-Term Outcome After Cardiac Surgery., Nikolaos Kakouros, Tyler J Gluckman, John V Conte, Thomas S Kickler, Katherine Laws, Bruce A Barton, Jeffrey J Rade

Articles, Abstracts, and Reports

BACKGROUND: Systemic thromboxane generation, not suppressible by standard aspirin therapy and likely arising from nonplatelet sources, increases the risk of atherothrombosis and death in patients with cardiovascular disease. In the RIGOR (Reduction in Graft Occlusion Rates) study, greater nonplatelet thromboxane generation occurred early compared with late after coronary artery bypass graft surgery, although only the latter correlated with graft failure. We hypothesize that a similar differential association exists between nonplatelet thromboxane generation and long-term clinical outcome.

METHODS AND RESULTS: Five-year outcome data were analyzed for 290 RIGOR subjects taking aspirin with suppressed platelet thromboxane generation. Multivariable modeling was performed to …

Identification Of A Novel Synaptic Protein, Tmtc3, Involved In Periventricular Nodular Heterotopia With Intellectual Disability And Epilepsy, Sali M K Farhan, Kevin C J Nixon, Michelle Everest, Tara N Edwards, Shirley Long, Dmitri Segal, Maria J Knip, Heleen H Arts, Rana Chakrabarti, Jian Wang, John F Robinson, Donald Lee, Seyed M Mirsattari, C Anthony Rupar, Victoria M Siu, Forge Canada Consortium, Michael O Poulter, Robert A Hegele, Jamie M Kramer

Paediatrics Publications

Defects in neuronal migration cause brain malformations, which are associated with intellectual disability (ID) and epilepsy. Using exome sequencing, we identified compound heterozygous variants (p.Arg71His and p. Leu729ThrfsTer6) in TMTC3, encoding transmembrane and tetratricopeptide repeat containing 3, in four siblings with nocturnal seizures and ID. Three of the four siblings have periventricular nodular heterotopia (PVNH), a common brain malformation caused by failure of neurons to migrate from the ventricular zone to the cortex. Expression analysis using patient-derived cells confirmed reduced TMTC3 transcript levels and loss of the TMTC3 protein compared to parental and control cells. As TMTC3 function is currently …

Canadian Guidelines For Controlled Pediatric Donation After Circulatory Determination Of Death-Summary Report, Matthew J Weiss, Laura Hornby, Bram Rochwerg, Michael Van Manen, Sonny Dhanani, V Ben Sivarajan, Amber Appleby, Mary Bennett, Daniel Buchman, Catherine Farrell, Aviva Goldberg, Rebecca Greenberg, Ram Singh, Thomas A Nakagawa, William Witteman, Jill Barter, Allon Beck, Kevin Coughlin, Alf Conradi, Cynthia Cupido, Rosanne Dawson, Anne Dipchand, Darren Freed, Karen Hornby, Valerie Langlois, Cheryl Mack, Meagan Mahoney, Deepak Manhas, Christopher Tomlinson, Samara Zavalkoff, Sam D Shemie

Paediatrics Publications

OBJECTIVES: Create trustworthy, rigorous, national clinical practice guidelines for the practice of pediatric donation after circulatory determination of death in Canada.

METHODS: We followed a process of clinical practice guideline development based on World Health Organization and Canadian Medical Association methods. This included application of Grading of Recommendations Assessment, Development, and Evaluation methodology. Questions requiring recommendations were generated based on 1) 2006 Canadian donation after circulatory determination of death guidelines (not pediatric specific), 2) a multidisciplinary symposium of national and international pediatric donation after circulatory determination of death leaders, and 3) a scoping review of the pediatric donation after circulatory …

Disparities In Rate, Triggers, And Management In Pediatric And Adult Cases Of Suspected Drug-Induced Anaphylaxis In Canada, Sofianne Gabrielli, Ann E Clarke, Harley Eisman, Judy Morris, Lawrence Joseph, Sebastien La Vieille, Peter Small, Rodrick Lim, Paul Enarson, Michal Zelcer, Edmond S Chan, Chris Mill, Moshe Ben-Shoshan

Paediatrics Publications

Introduction

Data is sparse on drug-induced anaphylaxis (DIA) and there have not been studies assessing the differences in clinical characteristics and management of DIA between adults and children.

Objective

We assessed the percentage, diagnosis, and management of DIA among all anaphylaxis visits in three pediatric and one adult emergency departments (ED) across Canada.

Methods

Children presenting to the Montreal Children's Hospital (MCH), British Columbia Children's Hospital (BCCH), and Children's Hospital at London Health Sciences Center and adults presenting to Hôpital du Sacré-Coeur with anaphylaxis were recruited as part of the Cross-Canada Anaphylaxis Registry. A standardized data form documenting the reaction …

Efficacy And Safety Of Pembrolizumab In Patients Enrolled In Keynote-030 In The United States: An Expanded Access Program., Tara C Gangadhar, Wen-Jen Hwu, Michael A Postow, Omid Hamid, Adil Daud, Roxana Dronca, Richard Joseph, Steven J O'Day, F S Hodi, Anna C Pavlick, Harriet Kluger, Romina P Oxborough, Aiming Yang, Mihaela Gazdoiu, Debra A Kush, Scot Ebbinghaus, April K S Salama

Articles, Abstracts, and Reports

KEYNOTE-030 (ClinicalTrials.gov ID, NCT02083484) was a global expanded access program that allowed access to pembrolizumab, an antiprogrammed death 1 antibody, for patients with advanced melanoma before its regulatory approval. Patients with unresectable stage III/IV melanoma that progressed after standard-of-care therapy, including ipilimumab and, if BRAF mutant, a BRAF inhibitor, were eligible to receive pembrolizumab 2 mg/kg every 3 weeks. Response was assessed by immune-related response criteria by investigator review. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. In the United States, 979 patients enrolled between April and September 2014. …

Predictors Of Sleepiness In Obstructive Sleep Apnoea At Baseline And After 6 Months Of Continuous Positive Airway Pressure Therapy., Rohit Budhiraja, Clete A Kushida, Deborah A Nichols, James K Walsh, Richard D Simon, Daniel J Gottlieb, Stuart F Quan

Articles, Abstracts, and Reports

We evaluated factors associated with subjective and objective sleepiness at baseline and after 6 months of continuous positive airway pressure (CPAP) therapy in patients with obstructive sleep apnoea (OSA).We analysed data from the Apnoea Positive Pressure Long-term Efficacy Study (APPLES), a prospective 6-month multicentre randomised controlled trial with 1105 subjects with OSA, 558 of who were randomised to active CPAP. Epworth sleepiness scale (ESS) scores and the mean sleep latency (MSL) on the maintenance of wakefulness test at baseline and after 6 months of CPAP therapy were recorded.Excessive sleepiness (ESS score >10) was present in 543 (49.1%) participants. Younger age, …

Second Primary Malignant Neoplasms And Survival In Adolescent And Young Adult Cancer Survivors., Theresa H M Keegan, Archie Bleyer, Aaron S Rosenberg, Qian Li, Melanie Goldfarb

Articles, Abstracts, and Reports

Importance: Although the increased incidence of second primary malignant neoplasms (SPMs) is a well-known late effect after cancer, few studies have compared survival after an SPM to survival of the same cancer occurring as first primary malignant neoplasm (PM) by age.

Objective: To assess the survival impact of SPMs in adolescents and young adults (AYAs) (15-39 years) compared with that of pediatric (<15 >years) and older adult (≥40 years) patients with the same SPMs.

Design, Setting, and Participants: This was a population-based, retrospective cohort study of patients with cancer in 13 Surveillance, Epidemiology and End Results regions in the United …

Characteristics Associated With Requests By Pathologists For Second Opinions On Breast Biopsies., Berta M Geller, Heidi D Nelson, Donald L Weaver, Paul D Frederick, Kimberly H Allison, Tracy Onega, Patricia A Carney, Anna N A Tosteson, Joann G Elmore

Articles, Abstracts, and Reports

AIMS: Second opinions in pathology improve patient safety by reducing diagnostic errors, leading to more appropriate clinical treatment decisions. Little objective data are available regarding the factors triggering a request for second opinion despite second opinion consultations being part of the diagnostic system of pathology. Therefore we sought to assess breast biopsy cases and interpreting pathologists characteristics associated with second opinion requests.

METHODS: Collected pathologist surveys and their interpretations of 60 test set cases were used to explore the relationships between case characteristics, pathologist characteristics and case perceptions, and requests for second opinions. Data were evaluated by logistic regression and …

Rapid Rest/Stress Regadenoson Ungated Perfusion Cmr For Detection Of Coronary Artery Disease In Patients With Atrial Fibrillation., Erik T Bieging, I Haider, G Adluru, L Chang, P Suksaranjit, D Likhite, A Shaaban, L Jensen, B D Wilson, C J Mcgann, E Dibella

Articles, Abstracts, and Reports

Cardiovascular magnetic resonance (CMR) perfusion has been established as a useful imaging modality for the detection of coronary artery disease (CAD). However, there are several limitations when applying standard, ECG-gated stress/rest perfusion CMR to patients with atrial fibrillation (AF). In this study we investigate an approach with no ECG gating and a rapid rest/stress perfusion protocol to determine its accuracy for detection of CAD in patients with AF. 26 patients with AF underwent a rapid rest/regadenoson stress CMR perfusion imaging protocol, and all patients had X-ray coronary angiography. An ungated radial myocardial perfusion sequence was used. Imaging protocol included: rest …

Multisite Evaluation Of The Bd Max Extended Enteric Bacterial Panel For Detection Of Yersinia Enterocolitica, Enterotoxigenic Escherichia Coli, Vibrio, And Plesiomonas Shigelloides From Stool Specimens., Patricia J Simner, Margret Oethinger, Kathleen A Stellrecht, Dylan R Pillai, Ram Yogev, Helene Leblond, Joel Mortensen

Articles, Abstracts, and Reports

The purpose of this study was to perform a multisite evaluation to establish the performance characteristics of the BD Max extended enteric bacterial panel (xEBP) assay directly from unpreserved or Cary-Blair-preserved stool specimens for the detection of Yersinia enterocolitica, enterotoxigenic Escherichia coli (ETEC), Vibrio, and Plesiomonas shigelloides The study included prospective, retrospective, and prepared contrived specimens from 6 clinical sites. BD Max xEBP results were compared to the reference method, which included standard culture techniques coupled with alternate PCR and sequencing, except for ETEC, for which the reference method was two alternate PCRs and sequencing. Alternate PCR was …

Secukinumab Sustains Improvement In Signs And Symptoms Of Psoriatic Arthritis: 2 Year Results From The Phase 3 Future 2 Study., Iain B Mcinnes, Philip Mease, Christopher T Ritchlin, Proton Rahman, Alice B Gottlieb, Bruce Kirkham, Radhika Kajekar, Eumorphia-Maria Delicha, Luminita Pricop, Shephard Mpofu

Articles, Abstracts, and Reports

Objectives: To assess long-term efficacy, safety and tolerability of secukinumab up to 104 weeks in patients with active PsA.

Methods: Patients with PsA (n = 397) were randomized to s.c. secukinumab 300, 150 or 75 mg or placebo at baseline, weeks 1, 2, 3 and 4 and every 4 weeks thereafter. Placebo-treated patients were re-randomized to receive secukinumab 300 or 150 mg s.c. from week 16 (placebo non-responders) or week 24 (placebo responders). Exploratory endpoints at week 104 included 20, 50 and 70% improvement in ACR criteria (ACR20, 50, 70); 75 and 90% improvement in the Psoriasis Area Severity Index, …

Agenda For Translating Physical Activity, Nutrition, And Weight Management Interventions For Cancer Survivors Into Clinical And Community Practice., Karen Basen-Engquist, Catherine M Alfano, Melissa Maitin-Shepard, Cynthia A Thomson, Kathryn H Schmitz, Bernardine M Pinto, Kevin Stein, David S Zucker, Karen L Syrjala, Elizabeth Fallon, Colleen Doyle, Wendy Demark-Wahnefried

Articles, Abstracts, and Reports

Evidence supporting physical activity, diet, and weight management for cancer survivors has grown, leading to the development of guidelines and interventions. The next step is to identify necessary practice and policy changes and to develop a research agenda to inform how interventions can be delivered to survivors most effectively and efficiently in health care settings and by community-based organizations. Here, an agenda is proposed for research, practice, and policy that incorporates recommendations for a range of programming options, a patient-centered, tailored screening and referral approach, and training needs for survivorship care providers and providers of exercise, nutrition, and weight management …

The Isb Cancer Genomics Cloud: A Flexible Cloud-Based Platform For Cancer Genomics Research., Sheila M Reynolds, Michael Miller, Phyliss Lee, Kalle Leinonen, Suzanne M Paquette, Zack Rodebaugh, Abigail Hahn, David L Gibbs, Joseph Slagel, William J Longabaugh, Varsha Dhankani, Madelyn Reyes, Todd Pihl, Mark Backus, Matthew Bookman, Nicole Deflaux, Jonathan Bingham, David Pot, Ilya Shmulevich

Articles, Abstracts, and Reports

The ISB Cancer Genomics Cloud (ISB-CGC) is one of three pilot projects funded by the National Cancer Institute to explore new approaches to computing on large cancer datasets in a cloud environment. With a focus on Data as a Service, the ISB-CGC offers multiple avenues for accessing and analyzing The Cancer Genome Atlas, TARGET, and other important references such as GENCODE and COSMIC using the Google Cloud Platform. The open approach allows researchers to choose approaches best suited to the task at hand: from analyzing terabytes of data using complex workflows to developing new analysis methods in common languages such …

Smarcb1 Is Required For Widespread Baf Complex-Mediated Activation Of Enhancers And Bivalent Promoters., Robert T Nakayama, John L Pulice, Alfredo M Valencia, Matthew J Mcbride, Zachary M Mckenzie, Mark A Gillespie, Wai Lim Ku, Mingxiang Teng, Kairong Cui, Robert T Williams, Seth H Cassel, He Qing, Christian J Widmer, George D Demetri, Rafael A Irizarry, Keji Zhao, Jeffrey A Ranish, Cigall Kadoch

Articles, Abstracts, and Reports

Perturbations to mammalian SWI/SNF (mSWI/SNF or BAF) complexes contribute to more than 20% of human cancers, with driving roles first identified in malignant rhabdoid tumor, an aggressive pediatric cancer characterized by biallelic inactivation of the core BAF complex subunit SMARCB1 (BAF47). However, the mechanism by which this alteration contributes to tumorigenesis remains poorly understood. We find that BAF47 loss destabilizes BAF complexes on chromatin, absent significant changes in complex assembly or integrity. Rescue of BAF47 in BAF47-deficient sarcoma cell lines results in increased genome-wide BAF complex occupancy, facilitating widespread enhancer activation and opposition of Polycomb-mediated repression at bivalent promoters. We …

Chronic Traumatic Encephalopathy-Integration Of Canonical Traumatic Brain Injury Secondary Injury Mechanisms With Tau Pathology, Jacqueline R. Kulbe, Edward D. Hall

Spinal Cord and Brain Injury Research Center Faculty Publications

In recent years, a new neurodegenerative tauopathy labeled Chronic Traumatic Encephalopathy (CTE), has been identified that is believed to be primarily a sequela of repeated mild traumatic brain injury (TBI), often referred to as concussion, that occurs in athletes participating in contact sports (e.g. boxing, football, football, rugby, soccer, ice hockey) or in military combatants, especially after blast-induced injuries. Since the identification of CTE, and its neuropathological finding of deposits of hyperphosphorylated tau protein, mechanistic attention has been on lumping the disorder together with various other non-traumatic neurodegenerative tauopathies. Indeed, brains from suspected CTE cases that have come to autopsy …

Linking Tuberous Sclerosis Complex, Excessive Mtor Signaling, And Age-Related Neurodegeneration: A New Association Between Tsc1 Mutation And Frontotemporal Dementia, Nicholas T. Olney, Carolina Alquezar, Eliana Marisa Ramos, Alissa L. Nana, Jamie C. Fong, Anna M. Karydas, Joanne B Taylor, Melanie L. Stephens, Andrea R. Argouarch, Victoria A. Van Berlo, Deepika R. Dokuru, Elliott H. Sherr, Gregory A. Jicha, William P. Dillon, Rahul S. Desikan, Mary De May, William W. Seeley, Giovanni Coppola, Bruce L. Miller, Aimee W. Kao

Neurology Faculty Publications

No abstract provided.

Understanding The Patient Experience With Carcinoid Syndrome: Exit Interviews From A Randomized, Placebo-Controlled Study Of Telotristat Ethyl, Lowell B. Anthony, Claire Ervin, Pablo Lapuerta, Matthew H. Kulke, Pamela Kunz, Emily Bergsland, Dieter Hörsch, David C. Metz, Janice Pasieka, Nick Pavlakis, Marianne Pavel, Martyn Caplin, Kjell Öberg, John Ramage, Emily Evans, Qi Melissa Yang, Shanna Jackson, Karie Arnold, Linda Law, Dana B. Dibenedetti

Markey Cancer Center Faculty Publications

Purpose: Telotristat ethyl, an oral tryptophan hydroxylase inhibitor, is intended to treat carcinoid syndrome by reducing serotonin production. Telotristat ethyl was evaluated in TELESTAR, a Phase III study for patients who had carcinoid syndrome with at least 4 bowel movements (BMs) per day and who were receiving somatostatin analogue therapy. This interview substudy was conducted to provide insight into the patient experience in TELESTAR and to help understand whether reductions in BM frequency (the primary end point) and other symptoms were clinically meaningful.

Methods: Participating sites were asked to invite (before randomization) all eligible patients to telephone interviews scheduled at …

Pro-Inflammatory Chemokines And Cytokines Dominate The Blister Fluid Molecular Signature In Patients With Epidermolysis Bullosa And Affect Leukocyte And Stem Cell Migration., Vitali Alexeev, Julio Cesar Salas-Alanis, Francis Palisson, Lila Mukhtarzada, Giulio Fortuna, Jouni Uitto, Andrew P. South, Olga Igoucheva

Department of Dermatology and Cutaneous Biology Faculty Papers

Hereditary epidermolysis bullosa (EB) is associated with skin blistering and the development of chronic nonhealing wounds. Although clinical studies have shown that cell-based therapies improve wound healing, the recruitment of therapeutic cells to blistering skin and to more advanced skin lesions remains a challenge. Here, we analyzed cytokines and chemokines in blister fluids of patients affected by dystrophic, junctional, and simplex EB. Our analysis revealed high levels of CXCR1, CXCR2, CCR2, and CCR4 ligands, particularly dominant in dystrophic and junctional EB. In vitro migration assays demonstrated the preferential recruitment of CCR4⁺ lymphocytes and CXCR1⁺, CXCR2⁺, …