Medicine and Health Sciences Commons^™

Stimulating Tam-Mediated Anti-Tumor Immunity With Mannose-Decorated Nanoparticles In Ovarian Cancer, Evan B Glass, Alyssa A Hoover, Kennady K Bullock, Matthew Z Madden, Bradley I Reinfeld, Whitney Harris, Dominique Parker, Demetra H Hufnagel, Marta A Crispens, Dineo Khabele, W Kimryn Rathmell, Jeffrey C Rathmell, Andrew J Wilson, Todd D Giorgio, Fiona E Yull

2020-Current year OA Pubs

BACKGROUND: Current cancer immunotherapies have made tremendous impacts but generally lack high response rates, especially in ovarian cancer. New therapies are needed to provide increased benefits. One understudied approach is to target the large population of immunosuppressive tumor-associated macrophages (TAMs). Using inducible transgenic mice, we recently reported that upregulating nuclear factor-kappaB (NF-κB) signaling in TAMs promotes the M1, anti-tumor phenotype and limits ovarian cancer progression. We also developed a mannose-decorated polymeric nanoparticle system (MnNPs) to preferentially deliver siRNA payloads to M2, pro-tumor macrophages in vitro. In this study, we tested a translational strategy to repolarize ovarian TAMs via MnNPs loaded …

Burden Of Cardiovascular Risk Factors And Disease In Five Asian Groups In Catalonia: A Disaggregated, Population-Based Analysis Of 121 000 First-Generation Asian Immigrants, Priyanka Satish, Emili Vela, Usama Bilal, Montse Cleries, Alka M Kanaya, Namratha Kandula, Salim S Virani, Nadia Islam, Javier Valero-Elizondo, Tamer Yahya, Josep Comin-Colet, Khurram Nasir, Josepa Mauri, Miguel Cainzos-Achirica

Faculty, Staff and Students Publications

AIMS: To evaluate the burden of cardiovascular risk factors and disease (CVD) among five Asian groups living in Catalonia (Spain): Indian, Pakistani, Bangladeshi, Filipino, and Chinese.

METHODS AND RESULTS: Retrospective cohort study using the Catalan Health Surveillance System database including 42 488 Pakistanis, 40 745 Chinese, 21 705 Indians, 9544 Filipinos, and 6907 Bangladeshis; and 5.3 million native individuals ('locals'). We estimated the age-adjusted prevalence (as of 31 December 2019) and incidence (during 2019) of diabetes, hypertension, hyperlipidaemia, obesity, tobacco use, coronary heart disease (CHD), cerebrovascular disease, atrial fibrillation, and heart failure (HF). Bangladeshis had the highest prevalence of diabetes …

The Ep300/Tp53 Pathway, A Suppressor Of The Hippo And Canonical Wnt Pathways, Is Activated In Human Hearts With Arrhythmogenic Cardiomyopathy In The Absence Of Overt Heart Failure, Leila Rouhi, Siyang Fan, Sirisha M Cheedipudi, Aitana Braza-Boïls, Maria Sabater Molina, Yan Yao, Matthew J Robertson, Cristian Coarfa, Juan R Gimeno, Pilar Molina, Priyatansh Gurha, Esther Zorio, Ali J Marian

Faculty, Staff and Students Publications

AIMS: Arrhythmogenic cardiomyopathy (ACM) is a primary myocardial disease that typically manifests with cardiac arrhythmias, progressive heart failure, and sudden cardiac death (SCD). ACM is mainly caused by mutations in genes encoding desmosome proteins. Desmosomes are cell-cell adhesion structures and hubs for mechanosensing and mechanotransduction. The objective was to identify the dysregulated molecular and biological pathways in human ACM in the absence of overt heart failure.

METHODS AND RESULTS: Transcriptomes in the right ventricular endomyocardial biopsy samples from three independent individuals carrying truncating mutations in the DSP gene and five control samples were analysed by RNA-Seq (discovery group). These cases …

Polygenic Transcriptome Risk Scores For Copd And Lung Function Improve Cross-Ethnic Portability Of Prediction In The Nhlbi Topmed Program, Xiaowei Hu, Dandi Qiao, Wonji Kim, Matthew Moll, Pallavi P Balte, Leslie A Lange, Traci M Bartz, Rajesh Kumar, Xingnan Li, Bing Yu, Brian E Cade, Cecelia A Laurie, Tamar Sofer, Ingo Ruczinski, Deborah A Nickerson, Donna M Muzny, Ginger A Metcalf, Harshavardhan Doddapaneni, Stacy Gabriel, Namrata Gupta, Shannon Dugan-Perez, L Adrienne Cupples, Laura R Loehr, Deepti Jain, Jerome I Rotter, James G Wilson, Bruce M Psaty, Myriam Fornage, Alanna C Morrison, Ramachandran S Vasan, George Washko, Stephen S Rich, George T O'Connor, Eugene Bleecker, Robert C Kaplan, Ravi Kalhan, Susan Redline, Sina A Gharib, Deborah Meyers, Victor Ortega, Josée Dupuis, Stephanie J London, Tuuli Lappalainen, Elizabeth C Oelsner, Edwin K Silverman, R Graham Barr, Timothy A Thornton, Heather E Wheeler, Topmed Lung Working Group, Michael H Cho, Hae Kyung Im, Ani Manichaikul

Faculty, Staff and Student Publications

While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV1] and its ratio to forced vital capacity [FEV1/FVC]) in the UK Biobank. We examined prediction performance and …

Evidence Supporting A Role For The Immune Checkpoint Protein B7-H3 In Nk Cell-Mediated Cytotoxicity Against Aml, Anudishi Tyagi, Stanley Ly, Fouad El-Dana, Bin Yuan, Appalaraju Jaggupilli, Sabrina Grimm, Marina Konopleva, Hans-Jörg Bühring, V Lokesh Battula

Faculty, Staff and Student Publications

We observed that the immune checkpoint protein B7-H3 is overexpressed in acute myeloid leukemia (AML) patients with poor treatment outcomes. Inhibition of B7-H3 expression or blocking of its activity using a novel monoclonal antibody (T-1A5) in AML cells significantly enhanced natural killer (NK) cell-mediated cytotoxicity in AML cells in vitro and in vivo. Moreover, a human-mouse chimera of this antibody (ChT-1A5) induced antibody-dependent cell-mediated cytotoxicity (ADCC) in B7-H3+ primary AML cells, but not in normal hematopoietic cells, suggesting the specify of this antibody for AML cells. Epitope mapping studies identified that both T-1A5 and ChT-1A5 antibodies bind to the FG-loop …

Novel Fold Of Rotavirus Glycan-Binding Domain Predicted By Alphafold2 And Determined By X-Ray Crystallography, Liya Hu, Wilhelm Salmen, Banumathi Sankaran, Yi Lasanajak, David F Smith, Sue E Crawford, Mary K Estes, B V Venkataram Prasad

Faculty, Staff and Students Publications

The VP8* domain of spike protein VP4 in group A and C rotaviruses, which cause epidemic gastroenteritis in children, exhibits a conserved galectin-like fold for recognizing glycans during cell entry. In group B rotavirus, which causes significant diarrheal outbreaks in adults, the VP8* domain (VP8*B) surprisingly lacks sequence similarity with VP8* of group A or group C rotavirus. Here, by using the recently developed AlphaFold2 for ab initio structure prediction and validating the predicted model by determining a 1.3-Å crystal structure, we show that VP8*B exhibits a novel fold distinct from the galectin fold. This fold with a β-sheet clasping …

Assessing The Coverage Of Us Cancer Center Primary Catchment Areas., Amy E Leader, Christopher Mcnair, Christina Yurick, Matthew Huesser, Elizabeth Schade, Emily E Stimmel, Caryn Lerman, Karen E Knudsen

Kimmel Cancer Center Faculty Papers

Background: Cancer centers are expected to engage communities and reduce the burden of cancer in their catchment areas. However, the extent to which cancer centers adequately reach the entire US population is unknown. Methods: We surveyed all members of the Association of American Cancer Institutes (N ¼ 102 cancer centers) to document and map each cancer center’s primary catchment area. Catchment area descriptions were aggregated to the county level. Catchment area coverage scores were calculated for each county and choropleths generated representing coverage across the US. Similar analyses were used to overlay US population density, cancer incidence, and cancer-related mortality …

A State-Wide Education Program On Opioid Use Disorder: Influential Community Members' Knowledge, Beliefs, And Opportunities For Coalition Development, Lindsey Hohmann, Haley Phillippe, Karen Marlowe, Ruth Jeminiwa, Natalie Hohmann, Salisa Westrick, Amanda Fowler, Brent Fox

College of Pharmacy Faculty Papers

Background: Deep South states, particularly Alabama, experience disproportionately higher opioid prescribing rates versus national rates. Considering limited opioid use disorder (OUD) providers in this region, collaborative efforts between non-healthcare professionals is critical in mitigating overdose mortality. The Alabama Opioid Training Institute (OTI) was created in 2019 to empower community members to take action in combatting OUD in local regions. The OTI included: 1) eight full-day in-person conferences; and 2) an interactive mobile-enabled website ( https://alabamaoti.org ). This study assessed the impact of the OTI on influential community members' knowledge, abilities, concerns, readiness, and intended actions regarding OUD and opioid overdose …

Elucidating Human Milk Oligosaccharide Biosynthetic Genes Through Network-Based Multi-Omics Integration, Benjamin P Kellman, Anne Richelle, Jeong-Yeh Yang, Digantkumar Chapla, Austin W T Chiang, Julia A Najera, Chenguang Liang, Annalee Fürst, Bokan Bao, Natalia Koga, Mahmoud A Mohammad, Anders Bech Bruntse, Morey W Haymond, Kelley W Moremen, Lars Bode, Nathan E Lewis

Children’s Nutrition Research Center Staff Publications

Human Milk Oligosaccharides (HMOs) are abundant carbohydrates fundamental to infant health and development. Although these oligosaccharides were discovered more than half a century ago, their biosynthesis in the mammary gland remains largely uncharacterized. Here, we use a systems biology framework that integrates glycan and RNA expression data to construct an HMO biosynthetic network and predict glycosyltransferases involved. To accomplish this, we construct models describing the most likely pathways for the synthesis of the oligosaccharides accounting for >95% of the HMO content in human milk. Through our models, we propose candidate genes for elongation, branching, fucosylation, and sialylation of HMOs. Our …

A Bayesian Group Sequential Design For Randomized Biosimilar Clinical Trials With Adaptive Information Borrowing From Historical Data, Wen Zhang, Zhiying Pan, Ying Yuan

Faculty, Staff and Student Publications

At the time of developing a biosimilar, the reference product has been on market for years and thus ample data are available on its efficacy and characteristics. We develop a Bayesian adaptive design for randomized biosimilar clinical trials to leverage the rich historical data on the reference product. This design takes a group sequential approach. At each interim, we employ the elastic meta-analytic-predictive (EMAP) prior methodology to adaptively borrow information from the historical data of the reference product to make go/no-go decision based on Bayesian posterior probabilities. In addition, the randomization ratio between the test and reference arms is adaptively …

Iv Sotalol Use In Pediatric And Congenital Heart Patients: A Multicenter Registry Study., Lindsey Malloy-Walton, Nicholas H. Von Bergen, Seshadri Balaji, Peter S. Fischbach, Jason M. Garnreiter, S Yukiko Asaki, Jeffrey P. Moak, Luis A. Ochoa, Philip M. Chang, Hoang H. Nguyen, Akash R. Patel, Christa Kirk, Ashley K. Sherman, Jennifer N. Avari Silva, J Philip Saul

Manuscripts, Articles, Book Chapters and Other Papers

Background There is limited information regarding the clinical use and effectiveness of IV sotalol in pediatric patients and patients with congenital heart disease, including those with severe myocardial dysfunction. A multicenter registry study was designed to evaluate the safety, efficacy, and dosing of IV sotalol. Methods and Results A total of 85 patients (age 1 day-36 years) received IV sotalol, of whom 45 (53%) had additional congenital cardiac diagnoses and 4 (5%) were greater than 18 years of age. In 79 patients (93%), IV sotalol was used to treat supraventricular tachycardia and 4 (5%) received it to treat ventricular arrhythmias. …

Heart Failure And Patient-Reported Outcomes In Adults With Congenital Heart Disease From 15 Countries, Chun-Wei Lu, Kamila White, Et Al

2020-Current year OA Pubs

Background Heart failure (HF) is the leading cause of mortality and associated with significant morbidity in adults with congenital heart disease. We sought to assess the association between HF and patient-report outcomes in adults with congenital heart disease. Methods and Results As part of the APPROACH-IS (Assessment of Patterns of Patient-Reported Outcomes in Adults with Congenital Heart disease-International Study), we collected data on HF status and patient-reported outcomes in 3959 patients from 15 countries across 5 continents. Patient-report outcomes were: perceived health status (12-item Short Form Health Survey), quality of life (Linear Analogue Scale and Satisfaction with Life Scale), sense …

Bacille Calmette-Guérin Vaccine Reprograms Human Neonatal Lipid Metabolism In Vivo And In Vitro, Joann Diray-Arce, Asimenia Angelidou, Kristoffer Jarlov Jensen, Maria Giulia Conti, Rachel S Kelly, Matthew Pettengill, Mark Liu, Simon D Van Haren, Scott D Mcculloch, Greg Michelloti, Olubukola Idoko, Tobias R Kollmann, Beate Kampmann, Hanno Steen, Al Ozonoff, Jessica Lasky-Su, Christine S Benn, Ofer Levy

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Vaccines have generally been developed with limited insight into their molecular impact. While systems vaccinology enables characterization of mechanisms of action, these tools have yet to be applied to infants, who are at high risk of infection and receive the most vaccines. Bacille Calmette-Guérin (BCG) protects infants against disseminated tuberculosis (TB) and TB-unrelated infections via incompletely understood mechanisms. We employ mass-spectrometry-based metabolomics of blood plasma to profile BCG-induced infant responses in Guinea-Bissau in vivo and the US in vitro. BCG-induced lysophosphatidylcholines (LPCs) correlate with both TLR-agonist- and purified protein derivative (PPD, mycobacterial antigen)-induced blood cytokine production in vitro, raising the …

Mortality In Pulmonary Arterial Hypertension In The Modern Era: Early Insights From The Pulmonary Hypertension Association Registry, Kevin Y Chang, Sue Duval, David B Badesch, Todd M Bull, Murali M Chakinala, Teresa De Marco, Robert P Frantz, Anna Hemnes, Stephen C Mathai, Erika Berman Rosenzweig, John J Ryan, Thenappan Thenappan, Phar Investigators

2020-Current year OA Pubs

Background Current mortality data for pulmonary arterial hypertension (PAH) in the United States are based on registries that enrolled patients prior to 2010. We sought to determine mortality in PAH in the modern era using the PHAR (Pulmonary Hypertension Association Registry). Methods and Results We identified all adult patients with PAH enrolled in the PHAR between September 2015 and September 2020 (N=935). We used Kaplan-Meier survival analysis and Cox proportional hazards models to assess mortality at 1, 2, and 3 years. Patients were stratified based on disease severity by 3 validated risk scores. In treatment-naïve patients, we compared survival based …

Iv Sotalol Use In Pediatric And Congenital Heart Patients: A Multicenter Registry Study, Lindsey E Malloy-Walton, Nicholas H Von Bergen, Seshadri Balaji, Peter S Fischbach, Jason M Garnreiter, S Yukiko Asaki, Jeffrey P Moak, Luis A Ochoa, Philip M Chang, Hoang H Nguyen, Akash R Patel, Christa Kirk, Ashley K Sherman, Jennifer N Avari Silva, J Philip Saul

2020-Current year OA Pubs

Background There is limited information regarding the clinical use and effectiveness of IV sotalol in pediatric patients and patients with congenital heart disease, including those with severe myocardial dysfunction. A multicenter registry study was designed to evaluate the safety, efficacy, and dosing of IV sotalol. Methods and Results A total of 85 patients (age 1 day-36 years) received IV sotalol, of whom 45 (53%) had additional congenital cardiac diagnoses and 4 (5%) were greater than 18 years of age. In 79 patients (93%), IV sotalol was used to treat supraventricular tachycardia and 4 (5%) received it to treat ventricular arrhythmias. …

Pacing Therapy For Atrioventricular Dromotropathy: A Combined Computational-Experimental-Clinical Study, Floor C W M Salden, Peter R Huntjens, Et Al.

2020-Current year OA Pubs

AIMS: Investigate haemodynamic effects, and their mechanisms, of restoring atrioventricular (AV)-coupling using pacemaker therapy in normal and failing hearts in a combined computational-experimental-clinical study.

METHODS AND RESULTS: Computer simulations were performed in the CircAdapt model of the normal and failing human heart and circulation. Experiments were performed in a porcine model of AV dromotropathy. In a proof-of-principle clinical study, left ventricular (LV) pressure and volume were measured in 22 heart failure (HF) patients (LV ejection fraction <35%) with prolonged PR interval (>230 ms) and narrow or non-left bundle branch block QRS complex. Computer simulations and animal studies in normal hearts showed that restoring of AV-coupling …

Bhlhe40 Regulates The T-Cell Effector Function Required For Tumor Microenvironment Remodeling And Immune Checkpoint Therapy Efficacy, Avery J Salmon, Alexander S Shavkunov, Qi Miao, Nicholas N Jarjour, Sunita Keshari, Ekaterina Esaulova, Charmelle D Williams, Jeffrey P Ward, Anna M Highsmith, Josué E Pineda, Reshma Taneja, Ken Chen, Brian T Edelson, Matthew M Gubin

Faculty, Staff and Student Publications

Immune checkpoint therapy (ICT) using antibody blockade of programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can provoke T cell-dependent antitumor activity that generates durable clinical responses in some patients. The epigenetic and transcriptional features that T cells require for efficacious ICT remain to be fully elucidated. Herein, we report that anti-PD-1 and anti-CTLA-4 ICT induce upregulation of the transcription factor BHLHE40 in tumor antigen-specific CD8+ and CD4+ T cells and that T cells require BHLHE40 for effective ICT in mice bearing immune-edited tumors. Single-cell RNA sequencing of intratumoral immune cells in BHLHE40-deficient mice revealed differential …

Vikela Ekhaya: A Novel, Community-Based, Tuberculosis Contact Management Program In A High Burden Setting, Alexander W Kay, Micaela Sandoval, Godwin Mtetwa, Musa Mkhabela, Banele Ndlovu, Tara Devezin, Welile Sikhondze, Debrah Vambe, Joyce Sibanda, Gloria S Dube, Robert H Stevens, Bhekumusa Lukhele, Anna M Mandalakas

Faculty, Staff and Student Publications

BACKGROUND: The prevention of tuberculosis (TB) in child contacts of TB cases and people living with human immunodeficiency virus (HIV) is a public health priority, but global access to TB preventive therapy (TPT) remains low. In 2019, we implemented Vikela Ekhaya, a novel community-based TB contact management program in Eswatini designed to reduce barriers to accessing TPT.

METHODS: Vikela Ekhaya offered differentiated TB and HIV testing for household contacts of TB cases by using mobile contact management teams to screen contacts, assess their TPT eligibility, and initiate and monitor TPT adherence in participants' homes.

RESULTS: In total, 945 contacts from …

Systems Biology Approach To Functionally Assess The Clostridioides Difficile Pangenome Reveals Genetic Diversity With Discriminatory Power, Charles J Norsigian, Heather A Danhof, Colleen K Brand, Firas S Midani, Jared T Broddrick, Tor C Savidge, Robert A Britton, Bernhard O Palsson, Jennifer K Spinler, Jonathan M Monk

Faculty, Staff and Students Publications

Combatting Clostridioides difficile infections, a dominant cause of hospital-associated infections with incidence and resulting deaths increasing worldwide, is complicated by the frequent emergence of new virulent strains. Here, we employ whole-genome sequencing, high-throughput phenotypic screenings, and genome-scale models of metabolism to evaluate the genetic diversity of 451 strains of C. difficile. Constructing the C. difficile pangenome based on this set revealed 9,924 distinct gene clusters, of which 2,899 (29%) are defined as core, 2,968 (30%) are defined as unique, and the remaining 4,057 (41%) are defined as accessory. We develop a strain typing method, sequence typing by accessory genome (STAG), …

Iv Sotalol Use In Pediatric And Congenital Heart Patients: A Multicenter Registry Study, Lindsey E Malloy-Walton, Nicholas H Von Bergen, Seshadri Balaji, Peter S Fischbach, Jason M Garnreiter, S Yukiko Asaki, Jeffrey P Moak, Luis A Ochoa, Philip M Chang, Hoang H Nguyen, Akash R Patel, Christa Kirk, Ashley K Sherman, Jennifer N Avari Silva, J Philip Saul

Faculty, Staff and Student Publications

Background There is limited information regarding the clinical use and effectiveness of IV sotalol in pediatric patients and patients with congenital heart disease, including those with severe myocardial dysfunction. A multicenter registry study was designed to evaluate the safety, efficacy, and dosing of IV sotalol. Methods and Results A total of 85 patients (age 1 day-36 years) received IV sotalol, of whom 45 (53%) had additional congenital cardiac diagnoses and 4 (5%) were greater than 18 years of age. In 79 patients (93%), IV sotalol was used to treat supraventricular tachycardia and 4 (5%) received it to treat ventricular arrhythmias. …

Timing Of Medicaid Enrollment, Late-Stage Breast Cancer Diagnosis, Treatment Delays, And Mortality, Evaline Xie, Graham A Colditz, Min Lian, Tracy Greever-Rice, Chester Schmaltz, Jill Lucht, Ying Liu

2020-Current year OA Pubs

BACKGROUND: Disrupted and delayed Medicaid coverage has been consistently associated with lower rates of cancer screening and early-stage cancer diagnosis compared with continuous coverage. However, the relationships between Medicaid coverage timing, breast cancer treatment delays, and survival are less clear.

METHODS: Using the linked Missouri Cancer Registry-Medicaid claims data, we identified 4583 women diagnosed with breast cancer between 2007 and 2016. We used logistic regression to estimate odds ratios (ORs) of late-stage diagnosis and treatment delays for prediagnosis (>30 days, >90 days, and >1 year before diagnosis) vs peridiagnosis enrollment. Cox proportional hazards models were used to estimate the …

Demographic And Clinical Characteristics Associated With The Failure Of Nonoperative Management Of Uncomplicated Appendicitis In Children: Secondary Analysis Of A Nonrandomized Clinical Trial, Peter C Minneci, Jacqueline M Saito, Et Al.

2020-Current year OA Pubs

Importance: The factors associated with the failure of nonoperative management of appendicitis and the differences in patient-reported outcomes between successful and unsuccessful nonoperative management remain unknown.

Objectives: To investigate factors associated with the failure of nonoperative management of appendicitis and compare patient-reported outcomes between patients whose treatment succeeded and those whose treatment failed.

Design, Setting, and Participants: This study was a planned subgroup secondary analysis conducted in 10 children's hospitals that included 370 children aged 7 to 17 years with uncomplicated appendicitis enrolled in a prospective, nonrandomized clinical trial between May 1, 2015, and October 31, 2018, with 1-year follow-up …

Racial And Ethnic Differences In Rural-Urban Trends In 5-Year Survival Of Patients With Lung, Prostate, Breast, And Colorectal Cancers: 1975-2011 Surveillance, Epidemiology, And End Results (Seer), Marquita W Lewis-Thames, Marvin E Langston, Saira Khan, Yunan Han, Lindsay Fuzzell, Shuai Xu, Justin Xavier Moore

2020-Current year OA Pubs

Importance: Considering reported rural-urban cancer incidence and mortality trends, rural-urban cancer survival trends are important for providing a comprehensive description of cancer burden. Furthermore, little is known about rural-urban differences in survival trends by racial and ethnic groups.

Objective: To examine national rural-urban trends in 5-year cancer-specific survival probabilities for lung, prostate, breast, and colorectal cancers in a diverse sample of racial and ethnic groups.

Design, Setting, and Participants: This cross-sectional study used an epidemiologic assessment with 1975 to 2016 Surveillance, Epidemiology, and End Results (SEER) data to analyze patients diagnosed no later than 2011. Patients were classified as living …

A Community-Led Mobile Health Clinic To Improve Structural And Social Determinants Of Health Among (Im)Migrant Workers, Shannon Guillot-Wright, N Miles Farr, Ellie Cherryhomes

Faculty, Staff and Student Publications

BACKGROUND: Community-led interventions that address structural and social determinants of health are lacking among (im)migrant workers, especially seafood workers. This lack of medical attention is especially alarming given their high rate of injury and death.

METHODS: Community-based participatory research (CBPR), a relational model that values the participants as equal partners in research, dissemination, and implementation, guided the interviews and mobile clinic. Seafood workers were engaged throughout data collection, analysis, and interpretation and played a significant role in moving the findings from research into actionable change.

RESULTS: to address the lack of healthcare options for (im)migrants, and at the request of …

Diminished Immune Surveillance During Histologic Progression Of Intraductal Papillary Mucinous Neoplasms Offers A Therapeutic Opportunity For Cancer Interception, Sharia Hernandez, Edwin Roger Parra, Naohiro Uraoka, Ximing Tang, Yu Shen, Wei Qiao, Mei Jiang, Shanyu Zhang, Barbara Mino, Wei Lu, Renganayaki Pandurengan, Cara Haymaker, Kajsa Affolter, Courtney L Scaife, Michele Yip-Schneider, C Max Schmidt, Matthew A Firpo, Sean J Mulvihill, Eugene J Koay, Huamin Wang, Ignacio I Wistuba, Anirban Maitra, Luisa M Solis, Subrata Sen

Faculty, Staff and Student Publications

Purpose: Intraductal papillary mucinous neoplasms (IPMN) are bona fide precursors to pancreatic ductal adenocarcinoma (PDAC). While genomic alterations during multistep IPMN progression have been well cataloged, the accompanying changes within the tumor immune microenvironment (TIME) have not been comprehensively studied. Herein, we investigated TIME-related alterations during IPMN progression, using multiplex immunofluorescence (mIF) coupled with high-resolution image analyses.

Experimental design: Two sets of formalin-fixed, paraffin-embedded tissue samples from surgically resected IPMNs were analyzed. The training set of 30 samples consisted of 11 low-grade IPMN (LG-IPMN), 17 high-grade IPMN (HG-IPMN), and 2 IPMN with PDAC, while a validation set of 93 samples …

Overall Survival In Phase 3 Clinical Trials And The Surveillance, Epidemiology, And End Results Database In Patients With Metastatic Colorectal Cancer, 1986-2016: A Systematic Review, Chan Shen, Daniel Tannenbaum, Robert Horn, Jane Rogers, Cathy Eng, Shouhao Zhou, Benny Johnson, Scott Kopetz, Van Morris, Michael Overman, Christine Parseghian, George J Chang, Maria A Lopez-Olivo, Raghav Kanwal, Lee M Ellis, Arvind Dasari

Faculty, Staff and Student Publications

Importance: Phase 3 trials for patients with metastatic colorectal cancer (mCRC) have been conducted with varying designs and often with surrogate end points for overall survival (OS).

Objectives: To critically examine the factors associated with clinically relevant improvement in OS (defined as ≥2 months) in these trials and to evaluate their association with outcomes reflected in Surveillance, Epidemiology, and End Results (SEER) registry data.

Evidence review: Medline, EMBASE, Cochrane, Web of Science, ClinicalTrials.gov, EU Clinical Trials Register, and the International Clinical Trials Registry Platform were searched for phase 3 trials of systemic therapy for patients with mCRC by decade (1986-1996, …

Tumor Immune Microenvironment Of Brain Metastases: Toward Unlocking Antitumor Immunity, Matthew R Strickland, Christopher Alvarez-Breckenridge, Justin F Gainor, Priscilla K Brastianos

Faculty, Staff and Student Publications

UNLABELLED: Brain metastasis (BrM) is a devastating complication of solid tumors associated with poor outcomes. Immune-checkpoint inhibitors (ICI) have revolutionized the treatment of cancer, but determinants of response are incompletely understood. Given the rising incidence of BrM, improved understanding of immunobiologic principles unique to the central nervous system (CNS) and dissection of those that govern the activity of ICIs are paramount toward unlocking BrM-specific antitumor immunity. In this review, we seek to discuss the current clinical landscape of ICI activity in the CNS and CNS immunobiology, and we focus, in particular, on the role of glial cells in the CNS …

Hypomethylating Agent And Venetoclax With Flt3 Inhibitor “Triplet” Therapy In Older/Unfit Patients With Flt3 Mutated Aml, Musa Yilmaz, Hagop Kantarjian, Nicholas J Short, Patrick Reville, Marina Konopleva, Tapan Kadia, Courtney Dinardo, Gautam Borthakur, Naveen Pemmaraju, Abhishek Maiti, Elias Jabbour, Nitin Jain, Ghayas Issa, Koichi Takahashi, Koji Sasaki, Maro Ohanian, Sherry Pierce, Guillin Tang, Sanam Loghavi, Keyur Patel, Sa A Wang, Guillermo Garcia-Manero, Michael Andreeff, Farhad Ravandi, Naval Daver

Faculty, Staff and Student Publications

In older/unfit newly diagnosed patients with FLT3 mutated acute myeloid leukemia (AML), lower intensity chemotherapy (LIC) in combination with either a FLT3 inhibitor or with venetoclax results in poor overall survival (median 8 to 12.5 months). We performed a retrospective analysis of 87 newly diagnosed FLT3 mutated AML patients treated on triplet (LIC + FLT3 inhibitor + Venetoclax, [N = 27]) and doublet (LIC + FLT3 inhibitor, [N = 60]) regimens at our institution. Data were collected from prospective clinical trials in 75% (N = 65) and 25% (N = 22) who received the same treatment regimens outside of a …

Genomic Correlates Of Outcome In Tumor-Infiltrating Lymphocyte Therapy For Metastatic Melanoma, Caitlin A Creasy, Yuzhong Jeff Meng, Marie-Andrée Forget, Tatiana Karpinets, Katarzyna Tomczak, Chip Stewart, Carlos A Torres-Cabala, Shari Pilon-Thomas, Amod A Sarnaik, James J Mulé, Levi Garraway, Matias Bustos, Jianhua Zhang, Sapna P Patel, Adi Diab, Isabella C Glitza, Cassian Yee, Hussein Tawbi, Michael K Wong, Jennifer Mcquade, Dave S B Hoon, Michael A Davies, Patrick Hwu, Rodabe N Amaria, Cara Haymaker, Rameen Beroukhim, Chantale Bernatchez

Faculty, Staff and Student Publications

Purpose: Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL) historically yields a 40%-50% response rate in metastatic melanoma. However, the determinants of outcome are largely unknown.

Experimental design: We investigated tumor-based genomic correlates of overall survival (OS), progression-free survival (PFS), and response to therapy by interrogating tumor samples initially collected to generate TIL infusion products.

Results: Whole-exome sequencing (WES) data from 64 samples indicated a positive correlation between neoantigen load and OS, but not PFS or response to therapy. RNA sequencing analysis of 34 samples showed that expression of PDE1C, RTKN2, and NGFR was enriched in responders who had improved …

Comparison Of Collaborative Goal Setting With Enhanced Education For Managing Diabetes-Associated Distress And Hemoglobin A1c Levels: A Randomized Clinical Trial, Lechauncy Woodard, Amber B Amspoker, Natalie E Hundt, Howard S Gordon, Brian Hertz, Edward Odom, Anne Utech, Javad Razjouyan, Suja S Rajan, Nipa Kamdar, Jasmin Lindo, Lea Kiefer, Praveen Mehta, Aanand D Naik

Faculty, Staff and Student Publications

IMPORTANCE: Type 2 diabetes is a prevalent and morbid condition. Poor engagement with self-management can contribute to diabetes-associated distress and hinder diabetes control.

OBJECTIVE: To evaluate the implementation and effectiveness of Empowering Patients in Chronic Care (EPICC), an evidence-based intervention to improve diabetes-associated distress and hemoglobin A1c (HbA1c) levels after the intervention and after 6-month maintenance.

DESIGN, SETTING, AND PARTICIPANTS: This hybrid (implementation-effectiveness) randomized clinical trial was performed in Veterans Affairs clinics across Illinois, Indiana, and Texas from July 1, 2015, to June 30, 2017. Participants included adults with uncontrolled type 2 diabetes (HbA1c level >8.0%) who received primary care …