Medicine and Health Sciences Commons^™

Stabilizing Histamine Release In Gut Mast Cells Mitigates Peripheral And Central Inflammation After Stroke, Tyler J Lefevre, Wenyuan Wei, Elizaveta Mukhaleva, Sai Pranathi Meda Venkata, Naincy R Chandan, Saji Abraham, Yong Li, Carmen W Dessauer, Nagarajan Vaidehi, Alan V Smrcka

Faculty, Staff and Student Publications

Highly homologous members of the Gαi family, Gαi1-3, have distinct tissue distributions and physiological functions, yet their biochemical and functional properties are very similar. We recently identified PDZ-RhoGEF (PRG) as a novel Gαi1 effector that is poorly activated by Gαi2. In a proteomic proximity labeling screen we observed a strong preference for Gαi1 relative to Gαi2 with respect to engagement of a broad range of potential targets. We investigated the mechanistic basis for this selectivity using PRG as a representative target. Substitution of either the helical domain (HD) from Gαi1 into Gαi2 or substitution of a single amino acid, A230 …

Coronary Stenosis And Cardiogenic Shock Secondary To Aortitis Following Aortic Root Support Procedure, Alexander Carpenter, Stephanie Connaire, Nitin Chandra Mohan, Stephanie L Curtis, Serban C Stoica, Massimo Caputo, Julian W Strange

Faculty, Staff and Student Publications

A woman with recent personalized external aortic root support implant presented in cardiogenic shock with bilateral coronary ostial occlusion and aortic inflammation requiring emergency coronary angioplasty. Subsequent computed tomography with positron emission tomography scanning demonstrated aortitis with extensive inflammation adjacent to the personalized external aortic root support mesh, the first report of this important complication.

When Intervention Becomes Imperative: A Case Report Of Spontaneous Vulvar Edema During Pregnancy, Vo Anh Vinh Trang, Thao-Ngan Nguyen Pham, Bao Huy Le, Thien Tan Tri Tai Truyen, Hoang Kim Tu Trinh, Kieu-Minh Le, Huu Doan Pham, Ngoc Minh Tam Nguyen, Quoc Kha Tran, Phuc Cam Hoang Nguyen, Vinh Hung Tran

Faculty, Staff and Student Publications

Spontaneous idiopathic vulvar edema during the second trimester is a rare condition. The approach to managing this condition involves relieving symptoms, identifying underlying causes, and implementing appropriate treatment. Managing such cases during pregnancy is challenging because of concerns for potential adverse fetal outcomes. Conservative management expects the condition to be relieved spontaneously postpartum, whereas invasive treatment offers a more rapid resolution. Treatment choices are controversial because each method has its pros and cons and influences the delivery process to a certain extent. Surgical drainage becomes a viable option when patients are not responsive to medications. We report a case of …

Safety And Tolerability Of Online Adaptive High-Field Magnetic Resonance-Guided Radiotherapy, Jasmijn M Westerhoff, Lois A Daamen, John P Christodouleas, Erwin L A Blezer, Ananya Choudhury, Rosalyne L Westley, Beth A Erickson, Clifton D Fuller, Shaista Hafeez, Uulke A Van Der Heide, Martijn P W Intven, Anna M Kirby, Susan Lalondrelle, Bruce D Minsky, Stella Mook, Marlies E Nowee, Corrie A M Marijnen, Kristina M Orrling, Arjun Sahgal, Christopher J Schultz, Corinne Faivre-Finn, Robbert J H A Tersteeg, Alison C Tree, Chia-Lin Tseng, Tine Schytte, Dustin M Silk, Dave Eggert, Marco Luzzara, Jochem R N Van Der Voort Van Zyp, Helena M Verkooijen, William A Hall

Faculty, Staff and Student Publications

Importance: In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy.

Objective: To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach).

Design, setting, and participants: This cohort study included adults with solid tumors treated with a …

Pet Imaging Of Metabolism, Perfusion, And Hypoxia: Fdg And Beyond, Austin R Pantel, Seong-Woo Bae, Elizabeth J Li, Sophia R O'Brien, H Charles Manning

Faculty, Staff and Student Publications

Imaging glucose metabolism with [18F]fluorodeoxyglucose positron emission tomography has transformed the diagnostic and treatment algorithms of numerous malignancies in clinical practice. The cancer phenotype, though, extends beyond dysregulation of this single pathway. Reprogramming of other pathways of metabolism, as well as altered perfusion and hypoxia, also typifies malignancy. These features provide other opportunities for imaging that have been developed and advanced into humans. In this review, we discuss imaging metabolism, perfusion, and hypoxia in cancer, focusing on the underlying biology to provide context. We conclude by highlighting the ability to image multiple facets of biology to better characterize cancer and …

Dynamics Of Karyotype Evolution, Elena Kuzmin, Toby M Baker, Peter Van Loo, Leon Glass

Faculty, Staff and Student Publications

In the evolution of species, the karyotype changes with a timescale of tens to hundreds of thousand years. In the development of cancer, the karyotype often is modified in cancerous cells over the lifetime of an individual. Characterizing these changes and understanding the mechanisms leading to them has been of interest in a broad range of disciplines including evolution, cytogenetics, and cancer genetics. A central issue relates to the relative roles of random vs deterministic mechanisms in shaping the changes. Although it is possible that all changes result from random events followed by selection, many results point to other non-random …

The Prognostic Value Of Mek Pathway-Associated Estrogen Receptor Signaling Activity For Female Cancers, Chun Wai Ng, Yvonne T M Tsang, David M Gershenson, Kwong-Kwok Wong

Faculty, Staff and Student Publications

Background: Other than for breast cancer, endocrine therapy has not been highly effective for gynecologic cancers. Endocrine therapy resistance in estrogen receptor positive gynecologic cancers is still poorly understood. In this retrospective study, we examined the estrogen receptor (ER) signaling pathway activities of breast, ovarian, endometrial, and cervical cancers to identify those that may predict endocrine therapy responsiveness.

Methods: Clinical and genomic data of women with breast and gynecological cancers were downloaded from cBioPortal for Cancer Genomics. Estrogen receptor alpha (ESR1) expression level and sample-level pathway enrichment scores (EERES) were calculated to classify patients into four groups (low/high ESR1 and …

First-Line Ibrutinib Treatment In Patients With Chronic Lymphocytic Leukemia Is Associated With Overall Survival Rates Similar To Those Of An Age-Matched General Population: A Pooled Post Hoc Analysis, Paolo Ghia, Carolyn Owen, John N Allan, Jacqueline C Barrientos, Paul M Barr, Chunxue Shi, Anita Szoke, Christopher Abbazio, Gabriel S Krigsfeld, Jan A Burger

Faculty, Staff and Student Publications

No abstract provided.

An Interpretable Framework To Identify Responsive Subgroups From Clinical Trials Regarding Treatment Effects: Application To Treatment Of Intracerebral Hemorrhage, Yaobin Ling, Muhammad Bilal Tariq, Kaichen Tang, Jaroslaw Aronowski, Yang Fann, Sean I Savitz, Xiaoqian Jiang, Yejin Kim

Faculty, Staff and Student Publications

Randomized Clinical trials (RCT) suffer from a high failure rate which could be caused by heterogeneous responses to treatment. Despite many models being developed to estimate heterogeneous treatment effects (HTE), there remains a lack of interpretable methods to identify responsive subgroups. This work aims to develop a framework to identify subgroups based on treatment effects that prioritize model interpretability. The proposed framework leverages an ensemble uplift tree method to generate descriptive decision rules that separate samples given estimated responses to the treatment. Subsequently, we select a complementary set of these decision rules and rank them using a sparse linear model. …

On The Optimal Diagnosis And The Evolving Role Of Pimavanserin In Parkinson's Disease Psychosis, Fernando L Pagan, Paul E Schulz, Yasar Torres-Yaghi, Gregory M Pontone

Faculty, Staff and Student Publications

Parkinson's disease (PD) is associated with the development of psychosis (PDP), including hallucinations and delusions, in more than half of the patient population. Optimal PD management must therefore involve considerations about both motor and non-motor symptoms. Often, clinicians fail to diagnosis psychosis in patients with PD and, when it is recognized, treat it suboptimally, despite the availability of multiple interventions. In this paper, we provide a summary of the current guidelines and clinical evidence for treating PDP with antipsychotics. We also provide recommendations for diagnosis and follow-up. Finally, an updated treatment algorithm for PDP that incorporates the use of pimavanserin, …

Impact Of Pretransplant Minimal Residual Disease In Patients With Multiple Myeloma And A Very Good Partial Response Or Better Receiving Autologous Hematopoietic Stem Cell Transplantation, Oren Pasvolsky, Sarah Pasyar, Roland L Bassett, Hina N Khan, Mark R Tanner, Qaiser Bashir, Samer Srour, Neeraj Saini, Paul Lin, Jeremy Ramdial, Yago Nieto, Hans C Lee, Krina K Patel, Partow Kebriaei, Sheeba K Thomas, Donna M Weber, Robert Z Orlowski, Elizabeth J Shpall, Richard E Champlin, Muzaffar H Qazilbash

Faculty, Staff and Student Publications

Background: The prognostic significance of minimal residual disease (MRD) status before autologous hematopoietic stem cell transplantation (autoHCT) in patients with multiple myeloma (MM) has not been clearly elucidated.

Methods: Retrospective single-center study of adult MM patients who achieved ≥very good partial response (VGPR) after induction therapy from 2015 to 2021 received upfront autoHCT and had available pretransplant MRD status by next-generation flow cytometry. The cohort was divided into pretransplant MRD-negative (MRDneg) and MRD-positive (MRDpos) groups.

Results: A total of 733 patients were included in our analysis; 425 were MRDneg and 308 MRDpos at autoHCT. In the MRDpos group, more patients …

Benefit Of Axicabtagene Ciloleucel Versus Chemoimmunotherapy In Older Patients And/Or Patients With Poor Ecog Performance Status With Relapsed Or Refractory Large B-Cell Lymphoma After 2 Or More Lines Of Prior Therapy, Matthew A Lunning, Hai-Lin Wang, Zhen-Huan Hu, Frederick L Locke, Tanya Siddiqi, Caron A Jacobson, Sairah Ahmed, David B Miklos, Yi Lin, Brian T Hill, Armin Ghobadi, Sattva S Neelapu, Jason Westin, Chrisopher Dieyi, Polly Field, Harry Miao, Shilpa A Shahani, Anik Patel, Clare Spooner, Christine Fu, David Muramoto, Hairong Xu, Marcelo C Pasquini

Faculty, Staff and Student Publications

Axicabtagene ciloleucel (axi-cel) in trials has demonstrated favorable efficacy compared with historical controls after ≥2 lines of therapy for the treatment of relapsed or refractory (R/R) large B cell lymphoma (LBCL). Herein, we compared the real-world effectiveness of axi-cel with efficacy and effectiveness of chemoimmunotherapy (CIT) in patients aged ≥65 years and patients with Eastern Cooperative Oncology Group performance status (ECOG PS) of 2. A total of 1146 patients treated with commercial axi-cel for R/R LBCL with ≥2 lines of prior therapy were included from the Center for International Blood and Marrow Transplantation Research prospective observational study, and 469 patients …

Artificial Intelligence-Powered Assessment Of Pathologic Response To Neoadjuvant Atezolizumab In Patients With Nsclc: Results From The Lcmc3 Study, Sanja Dacic, William D Travis, Jennifer M Giltnane, Filip Kos, John Abel, Stephanie Hilz, Junya Fujimoto, Lynette Sholl, Jon Ritter, Farah Khalil, Yi Liu, Amaro Taylor-Weiner, Murray Resnick, Hui Yu, Fred R Hirsch, Paul A Bunn, David P Carbone, Valerie Rusch, David J Kwiatkowski, Bruce E Johnson, Jay M Lee, Stephanie R Hennek, Ilan Wapinski, Alan Nicholas, Ann Johnson, Katja Schulze, Mark G Kris, Ignacio I Wistuba

Faculty, Staff and Student Publications

Introduction: Pathologic response (PathR) by histopathologic assessment of resected specimens may be an early clinical end point associated with long-term outcomes with neoadjuvant therapy. Digital pathology may improve the efficiency and precision of PathR assessment. LCMC3 (NCT02927301) evaluated neoadjuvant atezolizumab in patients with resectable NSCLC and reported a 20% major PathR rate.

Methods: We determined PathR in primary tumor resection specimens using guidelines-based visual techniques and developed a convolutional neural network model using the same criteria to digitally measure the percent viable tumor on whole-slide images. Concordance was evaluated between visual determination of percent viable tumor (n = …

Discovering Genetic Biomarkers For Targeted Cancer Therapeutics With Explainable Artificial Intelligence, Debaditya Chakraborty, Elizabeth Gutierrez-Chakraborty, Cristian Rodriguez-Aguayo, Hakan Başağaoğlu, Gabriel Lopez-Berestein, Paola Amero

Faculty, Staff and Student Publications

No abstract provided.

Survival Outcomes Of Patients With Her2/Neu-Positive Breast Cancer With Germline Brca Mutations, Fatma Nihan Akkoc Mustafayev, Mihir Amitabh Shukla, Amanda Lanier, Denái R Milton, Angelica M Gutierrez, Stephen K Gruschkus, John E Lewis, Rashmi K Murthy, Banu K Arun

Faculty, Staff and Student Publications

Background: Breast cancer (BC) with germline BRCA1/2 mutations and their association with triple-negative BC has been thoroughly investigated. However, some carriers of BRCA1/2 mutations have human epidermal growth factor receptor 2 (HER2/neu)-positive BC, which has a different targeted therapy approach, and data are scarce for this patient population. The authors sought to characterize the clinical characteristics and outcomes of patients with HER2/neu-positive BC who had germline BRCA1/2 mutations.

Methods: This was a retrospective analysis of data from 1099 patients diagnosed with HER2/neu-positive BC who were screened for germline BRCA mutations between 1996 and 2022. Clinicopathologic features and survival rates were …

A Novel Sik2 Inhibitor Sic-19 Exhibits Synthetic Lethality With Parp Inhibitors In Ovarian Cancer, Fang Wang, Xuejiao Yu, Jun Qian, Yumin Cao, Shunli Dong, Shenghua Zhan, Zhen Lu, Robert C Bast, Qingxia Song, Youguo Chen, Yi Zhang, Jinhua Zhou

Faculty, Staff and Student Publications

Purpose: Ovarian cancer patients with HR proficiency (HRP) have had limited benefits from PARP inhibitor treatment, highlighting the need for improved therapeutic strategies. In this study, we developed a novel SIK2 inhibitor, SIC-19, and investigated its potential to enhance the sensitivity and expand the clinical utility of PARP inhibitors in ovarian cancer.

Methods: The SIK2 protein was modeled using a Molecular Operating Environment (MOE), and the most favorable model was selected based on a GBVI/WSA dG scoring function. The Chembridge Compound Library was screened, and the top 20 candidate compounds were tested for their interaction with SIK2 and downstream substrates, …

Frequency Of Clinically Significant Findings In The Surgical Pathology Specimen Following Laparoscopic Sleeve Gastrectomy And Concordance With Preoperative Endoscopy: Insights From A Large Single-Center Experience, Christopher K Owen, Melissa M Felinski, Kulvinder S Bajwa, Peter A Walker, Sheilendra S Mehta, Erik B Wilson, Stefanie Boodoo, Vishal Kudav, Shaan J Akhtar, Shinil K Shah, M Elaine Kling

Faculty, Staff and Student Publications

Background: The field of bariatric surgery has seen peaks and troughs in the types of metabolic procedures performed. Our primary aim was to evaluate bariatric case volumes among fellows enrolled in bariatric Fellowship Council (FC)-accredited programs. Our secondary aim was to assess trends in revisional case volumes.

Methods: We reviewed de-identified FC case logs for all bariatric surgery-accredited programs from 2010 through 2019. The number of primary sleeve gastrectomy, gastric band, gastric bypass, biliopancreatic diversion, and major revisional bariatric surgical procedures (defined as a revision with creation of a new anastomosis) were graphed for each academic year. Fellows were stratified …

Factors Associated With The Ability Of Us Nursing Homes To Accept Residents With Severe Obesity, Cynthia Mcmahan, Bianca Shieu, Alison Trinkoff, Nicholas Castle, David G Wolf, Steven Handler, John A Harris

Faculty, Staff and Student Publications

Objectives: Severe obesity in nursing home (NH) residents is associated with specialized care needs, limited mobility, and challenges in daily living. The COVID-19 pandemic strained NH resources and exacerbated staffing shortages. This study aimed to assess the ability of US NHs to accept and care for residents with severe obesity post-COVID, as well as associated NH factors.

Design: Cross-sectional nationwide survey of NH administrators (2021-2022).

Setting and participants: 290 NHs from a national sample (n = 224) and a targeted sample in Massachusetts and New Jersey (n = 66).

Methods: A survey designed to assess how NHs approach admitting and …

Igwas: Image-Based Genome-Wide Association Of Self-Supervised Deep Phenotyping Of Retina Fundus Images, Ziqian Xie, Tao Zhang, Sangbae Kim, Jiaxiong Lu, Wanheng Zhang, Cheng-Hui Lin, Man-Ru Wu, Alexander Davis, Roomasa Channa, Luca Giancardo, Han Chen, Sui Wang, Rui Chen, Degui Zhi

Faculty, Staff and Student Publications

Existing imaging genetics studies have been mostly limited in scope by using imaging-derived phenotypes defined by human experts. Here, leveraging new breakthroughs in self-supervised deep representation learning, we propose a new approach, image-based genome-wide association study (iGWAS), for identifying genetic factors associated with phenotypes discovered from medical images using contrastive learning. Using retinal fundus photos, our model extracts a 128-dimensional vector representing features of the retina as phenotypes. After training the model on 40,000 images from the EyePACS dataset, we generated phenotypes from 130,329 images of 65,629 British White participants in the UK Biobank. We conducted GWAS on these phenotypes …

Patient Priorities Care Increases Long-Term Service And Support Use: Propensity Match Cohort Study, Rafael Samper-Ternent, Javad Razjouyan, Lilian Dindo, Jaime Halaszynski, Jennifer Silva, Terri Fried, Aanand D Naik

Faculty, Staff and Student Publications

OBJECTIVES: Patient priorities care (PPC) is an evidence-based approach designed to help patients achieve what matters most to them by identifying their health priorities and working with clinicians to align the care they provide to the patient's priorities. This study examined the impact of the PPC approach on long-term service and support (LTSS) use among veterans.

DESIGN: Quasi-experimental study examining differences in LTSS use between veterans exposed to PPC and propensity-matched controls not exposed to PPC adjusting for covariates.

SETTING AND PARTICIPANTS: Fifty-six social workers in 5 Veterans Health Administration (VHA) sites trained in PPC in 2018, 143 veterans who …

Systemic Symptoms In Huntington's Disease: A Comprehensive Review, Raja Mehanna, Joseph Jankovic

Faculty, Staff and Student Publications

Background: Although Huntington's disease (HD) is usually thought of as a triad of motor, cognitive, and psychiatric symptoms, there is growing appreciation of HD as a systemic illness affecting the entire body.

Objectives: This review aims to draw attention to these systemic non-motor symptoms in HD.

Methods: We identified relevant studies published in English by searching MEDLINE (from 1966 to September 2023), using the following subject headings: Huntington disease, autonomic, systemic, cardiovascular, respiratory, gastrointestinal, urinary, sexual and cutaneous, and additional specific symptoms.

Results: Data from 123 articles were critically reviewed with focus on systemic features associated with HD, such as …

Voiding Phase Dysfunction In Multiple Sclerosis: Contemporary Review Of Terminology, Diagnosis, Management, And Future Directions, Catherine Frances Ingram, John A Lincoln, Rose Khavari

Faculty, Staff and Student Publications

Lower urinary tract symptoms (LUTS) are highly prevalent in individuals with multiple sclerosis (MS). However, assessment of these symptoms is often hindered by vague definitions or absence of screening in asymptomatic patients. It is crucial to exercise caution when applying the non-neurogenic definition of urinary retention in this population. For men with MS experiencing persistent and treatment-resistant LUTS, urodynamic studies should be used to identify the underlying causes of symptoms. Although numerous therapies are presently accessible for managing LUTS in MS, there is a need for further investigation into emerging treatments such as percutaneous tibial nerve, and noninvasive brain stimulation.

The Hepatokine Orosomucoid 2 Mediates Beneficial Metabolic Effects Of Bile Acids, Sung Ho Lee, Ji Ho Suh, Mi Jeong Heo, Jong Min Choi, Yang Yang, Hyun-Jung Jung, Zhanguo Gao, Yongmei Yu, Sung Yun Jung, Mikhail G Kolonin, Aaron R Cox, Sean M Hartig, Holger K Eltzschig, Cynthia Ju, David D Moore, Kang Ho Kim

Faculty, Staff and Student Publications

Bile acids (BAs) are pleiotropic regulators of metabolism. Elevated levels of hepatic and circulating BAs improve energy metabolism in peripheral organs, but the precise mechanisms underlying the metabolic benefits and harm still need to be fully understood. In the current study, we identified orosomucoid 2 (ORM2) as a liver-secreted hormone (i.e., hepatokine) induced by BAs and investigated its role in BA-induced metabolic improvements in mouse models of diet-induced obesity. Contrary to our expectation, under a high-fat diet (HFD), our Orm2 knockout (Orm2-KO) exhibited a lean phenotype compared with C57BL/6J control, partly due to the increased energy expenditure. However, when challenged …

Single-Nucleotide Variant Calling In Single-Cell Sequencing Data With Monopogen, Jinzhuang Dou, Yukun Tan, Kian Hong Kock, Jun Wang, Xuesen Cheng, Le Min Tan, Kyung Yeon Han, Chung-Chau Hon, Woong-Yang Park, Jay W Shin, Haijing Jin, Yujia Wang, Han Chen, Li Ding, Shyam Prabhakar, Nicholas Navin, Rui Chen, Ken Chen

Faculty, Staff and Student Publications

Single-cell omics technologies enable molecular characterization of diverse cell types and states, but how the resulting transcriptional and epigenetic profiles depend on the cell's genetic background remains understudied. We describe Monopogen, a computational tool to detect single-nucleotide variants (SNVs) from single-cell sequencing data. Monopogen leverages linkage disequilibrium from external reference panels to identify germline SNVs and detects putative somatic SNVs using allele cosegregating patterns at the cell population level. It can identify 100 K to 3 M germline SNVs achieving a genotyping accuracy of 95%, together with hundreds of putative somatic SNVs. Monopogen-derived genotypes enable global and local ancestry inference …

Proton Therapy Mediates Dose Reductions To Brain Structures Associated With Cognition In Children With Medulloblastoma, Julianna Sienna, Lisa S Kahalley, Donald Mabbott, David Grosshans, Anna Theresa Santiago, Arnold Dela Cruz Paulino, Thomas E Merchant, Gohar S Manzar, Hitesh Dama, David C Hodgson, Murali Chintagumpala, Mehmet Fatih Okcu, William E Whitehead, Normand Laperriere, Vijay Ramaswamy, Ute Bartels, Uri Tabori, Julie M Bennett, Anirban Das, Tim Craig, Derek S Tsang

Faculty, Staff and Student Publications

Purpose: Emerging evidence suggests proton radiation therapy may offer cognitive sparing advantages over photon radiation therapy, yet dosimetry has not been compared previously. The purpose of this study was to examine dosimetric correlates of cognitive outcomes in children with medulloblastoma treated with proton versus photon radiation therapy.

Methods and materials: In this retrospective, bi-institutional study, dosimetric and cognitive data from 75 patients (39 photon and 36 proton) were analyzed. Doses to brain structures were compared between treatment modalities. Linear mixed-effects models were used to create models of global IQ and cognitive domain scores.

Results: The mean dose and dose to …

Circulating Immune Signatures In Chronic Pancreatitis With And Without Preceding Acute Pancreatitis: A Pilot Study, Rasmus Hagn-Meincke, Dhiraj Yadav, Dana K Andersen, Santhi Swaroop Vege, Evan L Fogel, Jose Serrano, Melena D Bellin, Mark D Topazian, Darwin L Conwell, Liang Li, Stephen K Van Den Eeden, Asbjørn M Drewes, Stephen J Pandol, Chris E Forsmark, William E Fisher, Phil A Hart, Søren S Olesen, Walter G Park, Consortium For The Study Of Chronic Pancreatitis, Diabetes, And Pancreatic Cancer (Cpdpc)

Faculty, Staff and Student Publications

Objective: To investigate profiles of circulating immune signatures in healthy controls and chronic pancreatitis patients (CP) with and without a preceding history of acute pancreatitis (AP).

Methods: We performed a phase 1, cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies (PROCEED) study. All samples were collected during a clinically quiescent phase. CP subjects were categorized into two subgroups based on preceding episode(s) of AP. Healthy controls were included for comparison. Blinded samples were analyzed using an 80-plex Luminex assay of cytokines, chemokines, and adhesion molecules. Group and pairwise comparisons …

A West African Ancestry-Associated Snp On 8q24 Predicts A Positive Biopsy In African American Men With Suspected Prostate Cancer Following Psa Screening, Jian Gu, Lisly Chery, Graciela M Nogueras González, Chad Huff, Sara Strom, Jeffrey A Jones, Donald P Griffith, Steven E Canfield, Xuemei Wang, Xuelin Huang, Pamela Roberson, Qing H Meng, Patricia Troncoso, Michael Ittmann, Michael Covinsky, Michael Scheurer, Margarita Irizarry Ramirez, Curtis A Pettaway

Faculty, Staff and Student Publications

BACKGROUND: African American (AA) men have the highest incidence and mortality rates of prostate cancer (PCa) among all racial groups in the United States. While race is a social construct, for AA men, this overlaps with west African ancestry. Many of the PCa susceptibility variants exhibit distinct allele frequencies and risk estimates across different races and contribute substantially to the large disparities of PCa incidence among races. We previously reported that a single-nucleotide polymorphism (SNP) in 8q24, rs7824364, was strongly associated with west African ancestry and increased risks of PCa in both AA and Puerto Rican men. In this study, …

Genome-Wide Analysis In Over 1 Million Individuals Of European Ancestry Yields Improved Polygenic Risk Scores For Blood Pressure Traits, Jacob M Keaton, Zoha Kamali, Tian Xie, Ahmad Vaez, Ariel Williams, Slavina B Goleva, Alireza Ani, Evangelos Evangelou, Jacklyn N Hellwege, Loic Yengo, William J Young, Matthew Traylor, Ayush Giri, Zhili Zheng, Jian Zeng, Daniel I Chasman, Andrew P Morris, Mark J Caulfield, Shih-Jen Hwang, Jaspal S Kooner, David Conen, John R Attia, Alanna C Morrison, Ruth J F Loos, Kati Kristiansson, Reinhold Schmidt, Andrew A Hicks, Peter P Pramstaller, Christopher P Nelson, Nilesh J Samani, Lorenz Risch, Ulf Gyllensten, Olle Melander, Harriette Riese, James F Wilson, Harry Campbell, Stephen S Rich, Bruce M Psaty, Yingchang Lu, Jerome I Rotter, Xiuqing Guo, Kenneth M Rice, Peter Vollenweider, Johan Sundström, Claudia Langenberg, Martin D Tobin, Vilmantas Giedraitis, Jian'an Luan, Jaakko Tuomilehto, Zoltan Kutalik, Samuli Ripatti, Veikko Salomaa, Giorgia Girotto, Stella Trompet, J Wouter Jukema, Pim Van Der Harst, Paul M Ridker, Franco Giulianini, Veronique Vitart, Anuj Goel, Hugh Watkins, Sarah E Harris, Ian J Deary, Peter J Van Der Most, Albertine J Oldehinkel, Bernard D Keavney, Caroline Hayward, Archie Campbell, Michael Boehnke, Laura J Scott, Thibaud Boutin, Chrysovalanto Mamasoula, Marjo-Riitta Järvelin, Annette Peters, Christian Gieger, Edward G Lakatta, Francesco Cucca, Jennie Hui, Paul Knekt, Stefan Enroth, Martin H De Borst, Ozren Polašek, Maria Pina Concas, Eulalia Catamo, Massimiliano Cocca, Ruifang Li-Gao, Edith Hofer, Helena Schmidt, Beatrice Spedicati, Melanie Waldenberger, David P Strachan, Maris Laan, Alexander Teumer, Marcus Dörr, Vilmundur Gudnason, James P Cook, Daniela Ruggiero, Ivana Kolcic, Eric Boerwinkle, Michela Traglia, Terho Lehtimäki, Olli T Raitakari, Andrew D Johnson, Christopher Newton-Cheh, Morris J Brown, Anna F Dominiczak, Peter J Sever, Neil Poulter, John C Chambers, Roberto Elosua, David Siscovick, Tõnu Esko, Andres Metspalu, Rona J Strawbridge, Markku Laakso, Anders Hamsten, Jouke-Jan Hottenga, Eco De Geus, Andrew D Morris, Colin N A Palmer, Ilja M Nolte, Yuri Milaneschi, Jonathan Marten, Alan Wright, Eleftheria Zeggini, Joanna M M Howson, Christopher J O'Donnell, Tim Spector, Mike A Nalls, Eleanor M Simonsick, Yongmei Liu, Cornelia M Van Duijn, Adam S Butterworth, John N Danesh, Cristina Menni, Nicholas J Wareham, Kay-Tee Khaw, Yan V Sun, Peter W F Wilson, Kelly Cho, Peter M Visscher, Joshua C Denny, Million Veteran Program, Lifelines Cohort Study, Charge Consortium, Icbp Consortium, Daniel Levy, Todd L Edwards, Patricia B Munroe, Harold Snieder, Helen R Warren

Faculty, Staff and Student Publications

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

Bmp4 And Grem1 Are Targets Of Shh Signaling And Downstream Regulators Of Collagen In The Penis, Jiangping Deng, Timothy Searl, Samuel Ohlander, Danuta Dynda, Daniel A Harrington, Kevin T Mcvary, Carol A Podlasek

Faculty, Staff and Student Publications

Background: Cavernous nerve (CN) injury, caused by prostatectomy and diabetes, initiates a remodeling process (smooth muscle apoptosis and increased collagen) in the corpora cavernosa of the penis of patients and animal models that is an underlying cause of erectile dysfunction (ED), and the Sonic hedgehog (SHH) pathway plays an essential role in the response of the penis to denervation, as collagen increases with SHH inhibition and decreases with SHH treatment.

Aim: We examined if part of the mechanism of how SHH prevents penile remodeling and increased collagen with CN injury involves bone morphogenetic protein 4 (BMP4) and gremlin1 (GREM1) and …

Phase I Trial Of Single-Photon Emission Computed Tomography-Guided Liver-Directed Radiotherapy For Patients With Low Functional Liver Volume, Enoch Chang, Franklin C L Wong, Beth A Chasen, William D Erwin, Prajnan Das, Emma B Holliday, Albert C Koong, Ethan B Ludmir, Bruce D Minsky, Sonal S Noticewala, Grace L Smith, Cullen M Taniguchi, Maria J Rodriguez, Sam Beddar, Rachael M Martin-Paulpeter, Joshua S Niedzielski, Gabriel O Sawakuchi, Emil Schueler, Luis A Perles, Lianchun Xiao, Janio Szklaruk, Peter C Park, Arvind N Dasari, Ahmed O Kaseb, Bryan K Kee, Sunyoung S Lee, Michael J Overman, Jason A Willis, Robert A Wolff, Ching-Wei D Tzeng, Jean-Nicolas Vauthey, Eugene J Koay

Faculty, Staff and Student Publications

BACKGROUND: Traditional constraints specify that 700 cc of liver should be spared a hepatotoxic dose when delivering liver-directed radiotherapy to reduce the risk of inducing liver failure. We investigated the role of single-photon emission computed tomography (SPECT) to identify and preferentially avoid functional liver during liver-directed radiation treatment planning in patients with preserved liver function but limited functional liver volume after receiving prior hepatotoxic chemotherapy or surgical resection.

METHODS: This phase I trial with a 3 + 3 design evaluated the safety of liver-directed radiotherapy using escalating functional liver radiation dose constraints in patients with liver metastases. Dose-limiting toxicities were …