Digital Commons Network^™

Case Report: Durable Response Of Gliomatosis Cerebri With Concurrent Tumor-Treating Fields (Ttfields) And Chemoradiotherapy Treatment, Alex M. Desjarlais, Ryan C. Miller, Ayesha S. Ali, Muneeb Z. Niazi, Louis Cappelli, Jon Glass, Christopher J. Farrell, Wenyin Shi

Department of Radiation Oncology Faculty Papers

Background: Gliomatosis cerebri (GC) is a rare and aggressive form of widely disseminated glioma infiltrating at least 3 lobes of the brain. It is a diffuse pattern of growth seen in glioma rather than a distinct pathological diagnosis based on new Word Health Organization (WHO) classification. Despite this, it is associated with worse prognosis than equally graded gliomas. Tumor treating fields (TTFields) treatment is a more recent advancement in glioma treatment delivered through low energy, intermediate frequency (200 kHz) electromagnetic fields, with multi-modal mechanisms of action. It is Food and Drug Administration (FDA) approved for newly diagnosed and recurrent glioblastoma …

Nurse Initiated Standing Orders: A Process Improvement At An Emergency Department In Interior Alaska, Justin D. Melberg

Capstone Experience: Master of Public Health

Emergency Departments (EDs) are a valuable and limited public health resource. In addition to treating acute medical emergencies, EDs bridge the gaps in urgent care and primary care accessibility, operating twenty-four hours a day, seven days a week, providing care regardless of an individual’s ability to pay. EDs across the country operate at or above capacity regularly, and overcrowding is projected to increase due to decreased facilities and available inpatient beds. Innovative measures are necessary to increase patient throughput and decrease length of stay while maintaining quality care. Nurse initiated standing orders, also known as nurse driven protocols, standing orders, …

Neural Damage Following Francisella Tularensis Infection, Anahis Tena

Open Access Theses & Dissertations

This dissertation investigates the impact of Francisella tularensis infection on the brain, focusing on its anatomical localization, effects on synaptic health, and behavioral and cognitive consequences in mice. Employing a combination of fluorescent tagging, confocal and light sheet microscopy, the study first maps bacterial foci within the brain, anticipating a concentration in the limbic system, particularly the hippocampus. Subsequently, it examines synaptic function post-infection using calcium imaging in various neuronal cultures, expecting a decrease in calcium signaling indicative of synaptic impairment. Finally, behavioral assays like the forced swim test, object recognition test, and Morris Water Maze assess the cognitive and …

Evaluation Of The Efficacy Of Synthetic Glycovaccines Against Both Murine Acute Chagas Disease And Cutaneous Leishmaniasis, Colin D. Knight

Open Access Theses & Dissertations

Chagas disease (CD) and cutaneous leishmaniasis (CL) are neglected tropical diseases caused by the protozoan trypanosomatids, Trypanosoma cruzi and Leishmania spp., respectively. There are approximately 6-8 million people infected with T. cruzi worldwide and ~300,000 people in the US. Between 700,000 and 1.2 million new cases of CL occur worldwide yearly. The approved chemotherapies for both diseases are partially effective and may cause serious adverse events, resulting in premature treatment interruption. Moreover, no effective vaccine for either disease is available. Therefore, developing a vaccine that would provide effective cross-protection against both diseases would provide a cost-effective alternative to the existing …

Revolutionizing Fracture Fixation In Diabetic And Non-Diabetic Rats: High Mobility Group Box 1-Based Coating For Enhanced Osseointegration, Alexandra Arteaga, Cláudia Cristina Biguetti, Bhuvana Lakkasetter Chandrashekar, Javier La Fontaine, Danieli C. Rodrigues

School of Podiatric Medicine Publications

Chronic inflammation and hyperglycemia in diabetic patients increase the risk of implant failure and impaired fracture healing. We previously developed and characterized a titanium (Ti) coating strategy using an imidazolium-based ionic liquid (IonL) with a fully reduced, non-oxidizable High Mobility Group Box 1 (HMGB1) isoform (Ti-IonL-HMGB1) to immunomodulate tissue healing. In this study, we used an open reduction fracture fixation (ORIF) model in non-diabetic (ND) and diabetic (D) rats to further investigate the effectiveness of this Ti-IonL-HMGB1 coating on orthopedic applications. Ninety male Lewis rats (12–15 weeks) were divided into D (n = 45) and ND (n = …

Hyperoxidized Prdx3 As A Specific Ferroptosis Marker, Yuelong Yan, Boyi Gan

Faculty, Staff and Student Publications

The lack of a reliable and specific marker for ferroptosis has hindered the advancement of treatments related to this cell death mechanism toward clinical application. A recent study published in Molecular Cell has identified hyperoxidized peroxiredoxin 3 (PRDX3) as a promising marker for ferroptosis, opening up new avenues for monitoring and targeting ferroptosis in disease treatment.

Pathomic Features Reveal Immune And Molecular Evolution From Lung Preneoplasia To Invasive Adenocarcinoma, Pingjun Chen, Frank R Rojas, Xin Hu, Alejandra Serrano, Bo Zhu, Hong Chen, Lingzhi Hong, Rukhmini Bandyoyadhyay, Muhammad Aminu, Neda Kalhor, J Jack Lee, Siba El Hussein, Joseph D Khoury, Harvey I Pass, Andre L Moreira, Vamsidhar Velcheti, Daniel H Sterman, Junya Fukuoka, Kazuhiro Tabata, Dan Su, Lisha Ying, Don L Gibbons, John V Heymach, Ignacio I Wistuba, Junya Fujimoto, Luisa M Solis Soto, Jianjun Zhang, Jia Wu

Faculty, Staff and Student Publications

Recent statistics on lung cancer, including the steady decline of advanced diseases and the dramatically increasing detection of early-stage diseases and indeterminate pulmonary nodules, mark the significance of a comprehensive understanding of early lung carcinogenesis. Lung adenocarcinoma (ADC) is the most common histologic subtype of lung cancer, and atypical adenomatous hyperplasia is the only recognized preneoplasia to ADC, which may progress to adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) and eventually to invasive ADC. Although molecular evolution during early lung carcinogenesis has been explored in recent years, the progress has been significantly hindered, largely due to insufficient materials …

Atm Mutations Associate With Distinct Co-Mutational Patterns And Therapeutic Vulnerabilities In Nsclc, Natalie I Vokes, Ana Galan Cobo, Margarita Fernandez-Chas, David Molkentine, Santiago Treviño, Vitaly Druker, Yu Qian, Sonia Patel, Stephanie Schmidt, Lingzhi Hong, Jeff Lewis, Waree Rinsurongkawong, Vadeerat Rinsurongkawong, J Jack Lee, Marcelo V Negrao, Don L Gibbons, Ara Vaporciyan, Xiuning Le, Jia Wu, Jianjun Zhang, Una Rigney, Sonia Iyer, Emma Dean, John V Heymach

Faculty, Staff and Student Publications

PURPOSE: Ataxia-telangiectasia mutated (ATM) is the most frequently mutated DNA damage repair gene in non-small cell lung cancer (NSCLC). However, the molecular correlates of ATM mutations and their clinical implications have not been fully elucidated.

EXPERIMENTAL DESIGN: Clinicopathologic and genomic data from 26,587 patients with NSCLC from MD Anderson, public databases, and a de-identified nationwide (US-based) NSCLC clinicogenomic database (CGDB) were used to assess the co-mutation landscape, protein expression, and mutational processes in ATM-mutant tumors. We used the CGDB to evaluate ATM-associated outcomes in patients treated with immune checkpoint inhibitors (ICI) with or without chemotherapy, and assessed the effect of …

Systematic Review And Meta-Analysis Of Immune Checkpoint Inhibitors As Single Agent Or In Combination With Chemotherapy In Early-Stage Non-Small Cell Lung Cancer: Impact Of Clinicopathological Factors And Indirect Comparison Between Treatment Strategies, Antonio Nuccio, Giuseppe Viscardi, Fabio Salomone, Alberto Servetto, Francesco Maria Venanzi, Silvia Teresa Riva, Sara Oresti, Francesca Rita Ogliari, Mariagrazia Viganò, Alessandra Bulotta, Robert Cameron, Alessandra Esposito, Jacobi Hines, Roberto Bianco, Michele Reni, Tina Cascone, Marina Chiara Garassino, Valter Torri, Giulia Veronesi, Michela Cinquini, Roberto Ferrara

Faculty, Staff and Student Publications

Background: In non-small cell lung cancer (NSCLC), the immune checkpoint inhibitors (ICI) revolution is rapidly moving from metastatic to early-stage, however, the impact of clinicopathological variables and optimal treatment sequencing remain unclear.

Methods: Randomized controlled trials (RCTs) in patients with early-stage NSCLC treated with ICI as single agent or in combination with platinum-based chemotherapy (PCT) were included. Primary outcomes were pathological complete response (pCR), event free survival (EFS) (neoadjuvant/perioperative), and disease-free survival (DFS) (adjuvant). Secondary outcomes were major pathological response (MPR), overall survival (OS), toxicity, surgical outcomes (neoadjuvant/perioperative); OS and toxicity (adjuvant). An additional secondary endpoint was to compare EFS …

Competing Engagement Of Β-Arrestin Isoforms Balances Igf1r/P53 Signaling And Controls Melanoma Cell Chemotherapeutic Responsiveness, Sonia Cismas, Sylvya Pasca, Caitrin Crudden, Iara Trocoli Drakensjo, Naida Suleymanova, Simin Zhang, Benjamin Gebhard, Dawei Song, Shiyong Neo, Takashi Shibano, Terry J Smith, George A Calin, Ada Girnita, Leonard Girnita

Faculty, Staff and Student Publications

Constraints on the p53 tumor suppressor pathway have long been associated with the progression, therapeutic resistance, and poor prognosis of melanoma, the most aggressive form of skin cancer. Likewise, the insulin-like growth factor type 1 receptor (IGF1R) is recognized as an essential coordinator of transformation, proliferation, survival, and migration of melanoma cells. Given that β-arrestin (β-arr) system critically governs the anti/pro-tumorigenic p53/IGF1R signaling pathways through their common E3 ubiquitin-protein ligase MDM2, we explore whether unbalancing this system downstream of IGF1R can enhance the response of melanoma cells to chemotherapy. Altering β-arr expression demonstrated that both β-arr1-silencing and β-arr2-overexpression (-β-arr1/+β-arr2) facilitated …

Acute Myeloid Leukemia With Mutated Tp53: Is This Newly Proposed Entity Oversimplifying A Complex Group Of Neoplasms?, Hong Fang, L Jeffery Medeiros, Wei Wang

Faculty, Staff and Student Publications

No abstract provided.

Development And Validation Of Age-Specific Risk Prediction Models For Primary Ovarian Insufficiency In Long-Term Survivors Of Childhood Cancer: A Report From The Childhood Cancer Survivor Study And St Jude Lifetime Cohort, Cindy Im, Zhe Lu, Sogol Mostoufi-Moab, Angela Delaney, Lin Yu, Jessica L Baedke, Yutong Han, Yadav Sapkota, Yutaka Yasui, Eric J Chow, Rebecca M Howell, Smita Bhatia, Melissa M Hudson, Kirsten K Ness, Gregory T Armstrong, Paul C Nathan, Yan Yuan

Faculty, Staff and Student Publications

BACKGROUND: Female survivors of childhood cancer are at risk for primary ovarian insufficiency (POI), defined as the cessation of gonadal function before the age of 40 years. We aimed to develop and validate models to predict age-specific POI risk among long-term survivors of childhood cancer.

METHODS: To develop models to predict age-specific POI risk for the ages of 21-40 years, we used data from the Childhood Cancer Survivor Study (CCSS). Female survivors aged 18 years or older at their latest follow-up, with self-reported menstrual history information and free of subsequent malignant neoplasms within 5 years of diagnosis, were included. We …

Enhanced Cd19 Activity In B Cells Contributes To Immunodeficiency In Mice Deficient In The Icf Syndrome Gene Zbtb24, Zhengzhou Ying, Swanand Hardikar, Joshua B Plummer, Tewfik Hamidi, Bin Liu, Yueping Chen, Jianjun Shen, Yunxiang Mu, Kevin M Mcbride, Taiping Chen

Faculty, Staff and Student Publications

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder characterized by DNA hypomethylation and antibody deficiency. It is caused by mutations in DNMT3B, ZBTB24, CDCA7, or HELLS. While progress has been made in elucidating the roles of these genes in regulating DNA methylation, little is known about the pathogenesis of the life-threatening hypogammaglobulinemia phenotype. Here, we show that mice deficient in Zbtb24 in the hematopoietic lineage recapitulate the major clinical features of patients with ICF syndrome. Specifically, Vav-Cre-mediated ablation of Zbtb24 does not affect lymphocyte development but results in reduced plasma cells and low levels …

Sam: Self-Adapting Mixture Prior To Dynamically Borrow Information From Historical Data In Clinical Trials, Peng Yang, Yuansong Zhao, Lei Nie, Jonathon Vallejo, Ying Yuan

Faculty, Staff and Student Publications

Mixture priors provide an intuitive way to incorporate historical data while accounting for potential prior-data conflict by combining an informative prior with a noninformative prior. However, prespecifying the mixing weight for each component remains a crucial challenge. Ideally, the mixing weight should reflect the degree of prior-data conflict, which is often unknown beforehand, posing a significant obstacle to the application and acceptance of mixture priors. To address this challenge, we introduce self-adapting mixture (SAM) priors that determine the mixing weight using likelihood ratio test statistics or Bayes factors. SAM priors are data-driven and self-adapting, favoring the informative (noninformative) prior component …

Editorial: Innovations, Advances, And Challenges In Precision Radiation Oncology Physics, Fada Guan, Lawrence Bronk, Jinbo Yue, Radhe Mohan, Zhe Chen

Faculty, Staff and Student Publications

No abstract provided.

Improving Radiotherapy In Immunosuppressive Microenvironments By Targeting Complement Receptor C5ar1, Callum Beach, David Maclean, Dominika Majorova, Stavros Melemenidis, Dhanya K Nambiar, Ryan K Kim, Gabriel N Valbuena, Silvia Guglietta, Carsten Krieg, Mahnaz Darvish-Damavandi, Tatsuya Suwa, Alistair Easton, Lily Vs Hillson, Ashley K Mcculloch, Ross K Mcmahon, Kathryn Pennel, Joanne Edwards, Sean M O'Cathail, Campbell S Roxburgh, Enric Domingo, Eui Jung Moon, Dadi Jiang, Yanyan Jiang, Qingyang Zhang, Albert C Koong, Trent M Woodruff, Edward E Graves, Tim Maughan, Simon Ja Buczacki, Manuel Stucki, Quynh-Thu Le, Simon J Leedham, Amato J Giaccia, Monica M Olcina

Faculty, Staff and Student Publications

An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell-specific functions. C5aR1 targeting resulted in increased …

Effect Of Epithelial-Specific Myd88 Signaling Pathway On Airway Inflammatory Response To Organic Dust Exposure, Amber N Johnson, John Dickinson, Amy Nelson, Rohit Gaurav, Katrina Kudrna, Scott E Evans, Katherine Janike, Todd A Wyatt, Jill A Poole

Faculty, Staff and Student Publications

The Toll-like receptor (TLR) adaptor protein MyD88 is integral to airway inflammatory response to microbial-enriched organic dust extract (ODE) exposures. ODE-induced airway neutrophil influx and release of pro-inflammatory cytokines was essentially abrogated in global MyD88-deficient mice, yet these mice demonstrate an increase in airway epithelial cell mucin expression. To further elucidate the role of MyD88-dependent responses specific to lung airway epithelial cells in response to ODE in vivo, the surfactant protein C protein (SPC) Cre+ embryologic expressing airway epithelial cells floxed for MyD88 to disrupt MyD88 signaling were utilized. The inducible club cell secretory protein (CCSP) Cre+, MyD88 floxed, …

Inhibition Of The Proline Metabolism Rate-Limiting Enzyme P5cs Allows Proliferation Of Glutamine-Restricted Cancer Cells, Samantha J Linder, Tiziano Bernasocchi, Bárbara Martínez-Pastor, Kelly D Sullivan, Matthew D Galbraith, Caroline A Lewis, Christina M Ferrer, Ruben Boon, Giorgia G Silveira, Hyo Min Cho, Charles Vidoudez, Stuti Shroff, Joao P Oliveira-Costa, Kenneth N Ross, Rami Massri, Yusuke Matoba, Eugene Kim, Bo R Rueda, Shannon L Stott, Eyal Gottlieb, Joaquin M Espinosa, Raul Mostoslavsky

Faculty, Staff and Student Publications

Glutamine is a critical metabolite for rapidly proliferating cells as it is used for the synthesis of key metabolites necessary for cell growth and proliferation. Glutamine metabolism has been proposed as a therapeutic target in cancer and several chemical inhibitors are in development or in clinical trials. How cells subsist when glutamine is limiting is poorly understood. Here, using an unbiased screen, we identify ALDH18A1, which encodes P5CS, the rate-limiting enzyme in the proline biosynthetic pathway, as a gene that cells can downregulate in response to glutamine starvation. Notably, P5CS downregulation promotes de novo glutamine synthesis, highlighting a previously unrecognized …

Clinico-Genomic Profiling Of Conventional And Dedifferentiated Chondrosarcomas Reveals Tp53 Mutation To Be Associated With Worse Outcomes, Ryan A Denu, Richard K Yang, Alexander J Lazar, Shalin S Patel, Valerae O Lewis, Jason Roszik, J Andrew Livingston, Wei-Lien Wang, Kenna R Shaw, Ravin Ratan, Maria A Zarzour, Justin Bird, Shaan Raza, Kadir C Akdemir, Jordi Rodon Ahnert, Vivek Subbiah, Shreyaskumar Patel, Anthony P Conley

Faculty, Staff and Student Publications

PURPOSE: Chondrosarcomas are the most common primary bone tumor in adults. Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations are prevalent. We aimed to assess the clinico-genomic properties of IDH mutant versus IDH wild-type (WT) chondrosarcomas as well as alterations in other genes.

EXPERIMENTAL DESIGN: We included 93 patients with conventional and dedifferentiated chondrosarcoma for which there were available clinical next-generation sequencing data. Clinical and genomic data were extracted and compared between IDH mutant and IDH WT chondrosarcomas and between TP53 mutant and TP53 WT chondrosarcomas.

RESULTS: IDH1 and IDH2 mutations are prevalent in chondrosarcoma (50.5%), more common in chondrosarcomas arising …

Obesity And Outcomes Of Kawasaki Disease And Covid-19-Related Multisystem Inflammatory Syndrome In Children., Michael Khoury, Ashraf S. Harahsheh, Geetha Raghuveer, Nagib Dahdah, Simon Lee, Marianna Fabi, Elif Seda Selamet Tierney, Michael A. Portman, Nadine F. Choueiter, Matthew Elias, Deepika Thacker, Frédéric Dallaire, William B. Orr, Tyler H. Harris, Kambiz Norozi, Dongngan T. Truong, Manaswitha Khare, Jacqueline R. Szmuszkovicz, Joseph J. Pagano, Cedric Manlhiot, Pedrom Farid, Brian W. Mccrindle, International Kawasaki Disease Registry

Manuscripts, Articles, Book Chapters and Other Papers

IMPORTANCE: Obesity may affect the clinical course of Kawasaki disease (KD) in children and multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19.

OBJECTIVE: To compare the prevalence of obesity and associations with clinical outcomes in patients with KD or MIS-C.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, analysis of International Kawasaki Disease Registry (IKDR) data on contemporaneous patients was conducted between January 1, 2020, and July 31, 2022 (42 sites, 8 countries). Patients with MIS-C (defined by Centers for Disease Control and Prevention criteria) and patients with KD (defined by American Heart Association criteria) were included. Patients with …

Epigenetic Age Acceleration, Neonatal Morbidities, And Neurobehavioral Profiles In Infants Born Very Preterm., Uriel Paniagua, Barry M. Lester, Carmen J Marsit, Marie Camerota, Brian S. Carter, Jennifer F. Check, Jennifer Helderman, Julie A. Hofheimer, Elisabeth C. Mcgowan, Charles R. Neal, Steven L. Pastyrnak, Lynne M. Smith, Sheri A. Dellagrotta, Lynne M. Dansereau, T Michael O'Shea, Todd M. Everson

Manuscripts, Articles, Book Chapters and Other Papers

Epigenetic age acceleration is a risk factor for chronic diseases of ageing and may reflect aspects of biological ageing. However, few studies have examined epigenetic ageing during the early neonatal period in preterm infants, who are at heightened risk of developmental problems. We examined relationships between neonatal age acceleration, neonatal morbidities, and neurobehavioral domains among very preterm (gestation) infants to characterize whether infants with early morbidities or different neurobehavioral characteristics had accelerated or decelerated epigenetic ageing. This study uses data from the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) study, restricted to infants with data on variables assessed …

Stereotactic Body Radiotherapy With Or Without Selective Dismutase Mimetic In Pancreatic Adenocarcinoma: An Adaptive, Randomised, Double-Blind, Placebo-Controlled, Phase 1b/2 Trial, Cullen M Taniguchi, Jessica M Frakes, Todd A Aguilera, Manisha Palta, Brian Czito, Manoop S Bhutani, Lauren E Colbert, Joseph Abi Jaoude, Vincent Bernard, Shubham Pant, Ching-Wei D Tzeng, Dae Won Kim, Mokenge Malafa, James Costello, Geena Mathew, Neal Rebueno, Eugene J Koay, Prajnan Das, Ethan B Ludmir, Matthew H G Katz, Robert A Wolff, Sam Beddar, Gabriel O Sawakuchi, Shalini Moningi, Rebecca S Slack Tidwell, Ying Yuan, Peter F Thall, Robert A Beardsley, Jon Holmlund, Joseph M Herman, Sarah E Hoffe

Faculty, Staff and Student Publications

BACKGROUND: Stereotactic body radiotherapy (SBRT) has the potential to ablate localised pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitise tumours while reducing normal tissue toxicity. This trial was designed to establish the efficacy and toxicity afforded by the selective dismutase mimetic avasopasem manganese when combined with ablative SBRT for localised pancreatic ductal adenocarcinoma.

METHODS: In this adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial, patients aged 18 years or older with borderline resectable or locally advanced pancreatic cancer who had received at least 3 months of chemotherapy and had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at six …

Larotrectinib Efficacy And Safety In Adult Patients With Tropomyosin Receptor Kinase Fusion Sarcomas, Shivaani Kummar, Lin Shen, David S Hong, Ray Mcdermott, Vicki L Keedy, Michela Casanova, George D Demetri, Afshin Dowlati, Soledad Gallego Melcón, Ulrik N Lassen, Serge Leyvraz, Tianshu Liu, Victor Moreno, Jyoti Patel, Tejas Patil, Atrayee Basu Mallick, Nuno Sousa, Makoto Tahara, David S Ziegler, Ricarda Norenberg, Pierre Arvis, Nicoletta Brega, Alexander Drilon, Daniel S W Tan

Faculty, Staff and Student Publications

Background: Larotrectinib, a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor, has demonstrated efficacy in adult and pediatric patients with various solid tumors harboring NTRK gene fusions. This subset analysis focuses on the efficacy and safety of larotrectinib in an expanded cohort of adult patients with TRK fusion sarcomas.

Methods: Patients (≥18 years old) with sarcomas harboring NTRK gene fusions were identified from three clinical trials. Patients received larotrectinib 100 mg orally twice daily. Response was investigator-assessed per RECIST v1.1. Data cutoff was July 20, 2021.

Results: At the data cutoff, 36 adult patients with TRK fusion sarcomas had initiated …

Kinome Profiling Identifies Mark3 And Stk10 As Potential Therapeutic Targets In Uveal Melanoma, Usman Baqai, Alison M Kurimchak, Isabella V Trachtenberg, Timothy J Purwin, Jelan I Haj, Anna Han, Kristine Luo, Nikole Fandino Pachon, Angela Jeon, Vivian Chua, Michael A Davies, J Silvio Gutkind, Jeffrey L Benovic, James S Duncan, Andrew E Aplin

Faculty, Staff and Student Publications

Most uveal melanoma cases harbor activating mutations in either GNAQ or GNA11. Despite activation of the mitogen-activated protein kinase (MAPK) signaling pathway downstream of Gαq/11, there are no effective targeted kinase therapies for metastatic uveal melanoma. The human genome encodes numerous understudied kinases, also called the "dark kinome". Identifying additional kinases regulated by Gαq/11 may uncover novel therapeutic targets for uveal melanoma. In this study, we treated GNAQ-mutant uveal melanoma cell lines with a Gαq/11 inhibitor, YM-254890, and conducted a kinase signaling proteomic screen using multiplexed-kinase inhibitors followed by mass spectrometry. We observed downregulated expression and/or activity of 22 kinases. …

Localization, Tissue Biology, And T Cell State — Implications For Cancer Immunotherapy, Jason M Schenkel, Kristen E Pauken

Faculty, Staff and Student Publications

Tissue localization is a critical determinant of T cell immunity. CD8+ T cells are contact-dependent killers, which requires them to physically be within the tissue of interest to kill peptide-MHC class I-bearing target cells. Following their migration and extravasation into tissues, T cells receive many extrinsic cues from the local microenvironment, and these signals shape T cell differentiation, fate and function. Because major organ systems are variable in their functions and compositions, they apply disparate pressures on T cells to adapt to the local microenvironment. Additional complexity arises in the context of malignant lesions (either primary or metastatic), and this …

Huntington Study Group's Neuropsychology Working Group: Implementing Non-Motor Diagnostic Criteria, Ciaran M Considine, M Agustina Rossetti, Victor A Del Bene, Kendra Anderson, Sharlet A Anderson, Andrea S Celka, Mary C Edmondson, Amelia L Nelson-Sheese, Adam Piccolino, Antonio L Teixeira, Julie C Stout

Faculty, Staff and Student Publications

Background: The clinical diagnosis of manifest Huntington's disease (HD) relies on a high level of clinical confidence (99% confidence) of HD-consistent motor signs. Longitudinal data have reliably identified cognitive and behavioral dysfunction predating clinical motor diagnosis by up to 15 years. Reliance on motor signs to establish a diagnosis of HD increases risk of early misdiagnosis or delayed diagnosis. Clinical neuropsychologists are uniquely positioned to advise on the clinical application of the Movement Disorder Society Task Force's recently proposed non-motor diagnostic criteria for HD.

Objectives: To provide (1) a recommended clinical approach toward non-motor diagnostic criteria in persons with HD …

Relapse Recovery In Relapsing-Remitting Multiple Sclerosis: An Analysis Of The Combirx Dataset, Marcus W Koch, Ester Moral, Luis Brieva, Jop Mostert, Eva Mm Strijbis, Jacynthe Comtois, Pavle Repovic, James D Bowen, Jerry S Wolinsky, Fred D Lublin, Gary Cutter

Faculty, Staff and Student Publications

BACKGROUND: Clinical relapses are the defining feature of relapsing forms of multiple sclerosis (MS), but relatively little is known about the time course of relapse recovery.

OBJECTIVE: The aim of this study was to investigate the time course of and patient factors associated with the speed and success of relapse recovery in people with relapsing-remitting MS (RRMS).

METHODS: Using data from CombiRx, a large RRMS trial (clinicaltrials.gov identifier NCT00211887), we measured the time to recovery from the first on-trial relapse. We used Kaplan-Meier survival analyses and Cox regression models to investigate the association of patient factors with the time to …

Randomized Phase Ii Trial Of Dendritic Cell/Myeloma Fusion Vaccine With Lenalidomide Maintenance After Upfront Autologous Hematopoietic Cell Transplantation For Multiple Myeloma: Bmt Ctn 1401., David J Chung, Nina Shah, Juan Wu, Brent Logan, Lina Bisharat, Natalie Callander, Giulia Cheloni, Kenneth Anderson, Thinle Chodon, Binod Dhakal, Steve Devine, Poorvi Somaiya Dutt, Yvonne Efebera, Nancy Geller, Haider Ghiasuddin, Peiman Hematti, Leona Holmberg, Alan Howard, Bryon Johnson, Dimitra Karagkouni, Hillard M Lazarus, Ehsan Malek, Philip Mccarthy, David Mckenna, Adam Mendizabal, Ajay Nooka, Nikhil Munshi, Lynn O'Donnell, Aaron P Rapoport, Jane Reese, Jacalyn Rosenblatt, Robert Soiffer, Dina Stroopinsky, Lynne Uhl, Ioannis S Vlachos, Edmund K Waller, James W Young, Marcelo C Pasquini, David Avigan

Oncology Articles

PURPOSE: Vaccination with dendritic cell (DC)/multiple myeloma (MM) fusions has been shown to induce the expansion of circulating multiple myeloma-reactive lymphocytes and consolidation of clinical response following autologous hematopoietic cell transplant (auto-HCT).

PATIENTS AND METHODS: In this randomized phase II trial (NCT02728102), we assessed the effect of DC/MM fusion vaccination, GM-CSF, and lenalidomide maintenance as compared with control arms of GM-CSF and lenalidomide or lenalidomide maintenance alone on clinical response rates and induction of multiple myeloma-specific immunity at 1-year posttransplant.

RESULTS: The study enrolled 203 patients, with 140 randomized posttransplantation. Vaccine production was successful in 63 of 68 patients. At …

The Application Of Simultaneous Mainstem Bronchus Dilation With Pulmonary Artery Stenting In The Context Of Hypoplastic Left Heart Syndrome, Sylwia Hasterok, Thomas G Scott, Devin G Roller, Adam Spencer, Arun B Dutta, Kizhakke M Sathyan, Daniel E Frigo, Michael J Guertin, Daniel Gioeli

Faculty, Staff and Student Publications

The clinical success of combined androgen deprivation therapy (ADT) and radiotherapy (RT) in prostate cancer created interest in understanding the mechanistic links between androgen receptor (AR) signaling and the DNA damage response (DDR). Convergent data have led to a model where AR both regulates, and is regulated by, the DDR. Integral to this model is that the AR regulates the transcription of DDR genes both at a steady state and in response to ionizing radiation (IR). In this study, we sought to determine which immediate transcriptional changes are induced by IR in an AR-dependent manner. Using PRO-seq to quantify changes …

Genome-Wide Significant Risk Loci For Mood Disorders In The Old Order Amish Founder Population, Elizabeth M Humphries, Kwangmi Ahn, Rachel L Kember, Fabiana L Lopes, Evelina Mocci, Juan M Peralta, John Blangero, David C Glahn, Fernando S Goes, Peter P Zandi, Peter Kochunov, Cristopher Van Hout, Alan R Shuldiner, Toni I Pollin, Braxton D Mitchell, Maja Bucan, L Elliot Hong, Francis J Mcmahon, Seth A Ament

Faculty, Staff and Student Publications

Genome-wide association studies (GWAS) of mood disorders in large case-control cohorts have identified numerous risk loci, yet pathophysiological mechanisms remain elusive, primarily due to the very small effects of common variants. We sought to discover risk variants with larger effects by conducting a genome-wide association study of mood disorders in a founder population, the Old Order Amish (OOA, n = 1,672). Our analysis revealed four genome-wide significant risk loci, all of which were associated with >2-fold relative risk. Quantitative behavioral and neurocognitive assessments (n = 314) revealed effects of risk variants on sub-clinical depressive symptoms and information processing speed. Network …