Digital Commons Network^™

Music As A Strategy To Improve Hypertension And Stroke Management: Evidence From A Crowdsourcing Open Call And Designathon In Nigeria, Chidi Okafor, Shravya Allena, Olufunto A Olusanya, Titilola Gbaja-Biamila, Temitope Ojo, Juliet Iwelunmor, Et Al.

2020-Current year OA Pubs

BACKGROUND: In Nigeria, cardiovascular diseases, especially hypertension, are on the rise. This increase in hypertension correlates with more strokes, significantly impacting mortality. Since hypertension often persists into adulthood, early interventions are crucial to prevent its complications. Non-invasive methods, such as music and creative activities, can effectively improve blood pressure and reduce stroke risk. This study aims to improve intergenerational awareness of hypertension and promote sustainable preventive practices by involving youth and caregivers within families and communities.

METHODS: We employed a participatory, observational design, incorporating a five-month crowdsourcing open call followed by a designathon event. Participatory social and health innovations were …

National Alliance Of Sickle Cell Centers Consensus Recommendations On Sickle Cell Disease Health Maintenance: A Consensus Statement, Seethal A Jacob, Sana Saif-Ur-Rehman, Et Al.

2020-Current year OA Pubs

IMPORTANCE: The most common inherited blood disorder in the world, sickle cell disease (SCD) is a known global health concern. While survival of children into adulthood has improved significantly over the last few decades in high-resource countries, substantial gaps in care standards and limited practice harmonization persist.

OBJECTIVE: To provide up-to-date recommendations for preventive care and treatment of all people living with SCD and its related comorbidities.

EVIDENCE REVIEW: As part of the National Alliance of Sickle Cell Centers (NASCC), 41 pediatric and adult sickle cell disease experts developed consensus standards and recommendations based on available evidence and expert consensus …

Availability Of Multidisciplinary Treatment Modalities And Outcomes Among Patients With Resected Early-Stage Non-Small Cell Lung Cancer, Brendan T Heiden, Su-Hsin Chang, Yan Yan, Ana A Baumann, Theodore S Thomas, Steven Tohmasi, Nikki Rossetti, Daniel Kreisel, Ruben G Nava, Bryan F Meyers, Benjamin D Kozower, Varun Puri, Et Al.

2020-Current year OA Pubs

BACKGROUND: Comprehensive, multidisciplinary care is crucial for managing early-stage non-small cell lung cancer (NSCLC), typically treated via lung resection or stereotactic body radiation therapy (SBRT). We evaluated how variable access to on-site SBRT may be associated with clinical outcomes for patients with stage I NSCLC receiving surgical resection within an integrated health-care system.

METHODS: We performed a retrospective cohort study of patients with stage I NSCLC treated with lung resection at Veterans Health Administration (VHA) facilities between 2006 and 2016. The VHA provides thoracic surgery at approximately 100 facilities, whereas lung SBRT is currently available at approximately 20 facilities. We …

A Clinical Practice Guideline For The Management Of Pregnancy Alloimmunized To Red Blood Cell Antigens, Kenneth J Moise, Jay Malone, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Red blood cell alloimmunization is typically associated with the transplacental transfer of incompatible fetal red blood cells into maternal circulation. Subsequent pregnancies can be affected by fetal anemia, hydrops fetalis, and perinatal death. Most cases of Rhesus D (RhD) alloimmunization due to pregnancy can be prevented by the proper administration of Rhesus immune globulin. However, an emerging practice of using low-titer, O, RhD-positive whole blood (LTOWB) in cases of life-threatening hemorrhage has the potential to increase the exposure of the female population to a new source of incompatible red blood cells.

OBJECTIVE: To establish recommendations for the management of …

Pip2-Driven Cytoplasmic Domain Motions Are Coupled To Kir2 Channel Gating, Eva-Maria Zangerl-Plessl, Anna Stary-Weinzinger, Colin G Nichols, Sun-Joo Lee

2020-Current year OA Pubs

Inwardly rectifying potassium (Kir) channel activity is important in the control of membrane potentials in both excitable and non-excitable cells and is regulated through various ligands, including specific membrane lipids. Phosphatidyl-4,5-bisphosphate (PIP2) is required for activity of all Kir channels, binding to the cytoplasmic domain in a compact conformation tightly tethered to the transmembrane domain. Most Kir2 channel structures determined in complex with PIP2 molecules are nevertheless in a closed state, requiring additional conformational changes for channel opening. We have carried out full atomistic MD simulations, which indicate PIP2-dependent conformational changes that are coupled to opening and closing of the …

Overexpression Of The Signaling Coordinator Gab2 Can Play An Important Role In Acute Myeloid Leukemia Progression, Michael H. Kramer, Stephanie N. Richardson, Yang Li, Tiankai Yin, Nichole M. Helton, Daniel R. George, Michelle Cai, Sai Mukund Ramakrishnan, Casey Ds Katerndahl, Christopher A. Miller, Timothy J. Ley

2020-Current year OA Pubs

Mutations that initiate acute myeloid leukemia (AML) can cause clonal expansion without transformation (clonal hematopoiesis). Cooperating mutations, usually in signaling genes, are needed to cause overt disease, but these may require a specific fitness state to be tolerated. Here, we show that nearly all AMLs arising in a mouse model expressing 2 common AML-initiating mutations (Dnmt3aR878H and Npm1cA) acquired a single copy amplification of chromosome 7 (chr7), followed by activating mutations in signaling genes. We show that overexpression of a single gene on chr7 (Gab2, which coordinates signaling pathways) was tolerated in the presence of the Npm1cA mutation, could accelerate …

Physical Activity And Molecular Subtypes Of Colorectal Cancer: A Pooled Observational Analysis And Mendelian Randomization Study, Christos V Chalitsios, Yin Cao, Et Al.

2020-Current year OA Pubs

BACKGROUND: Physical activity is associated with lower colorectal cancer (CRC) risk, but its association with molecular subtypes defined by genetic and epigenetic alterations of the disease is unclear. Such information may enhance the understanding of the mechanisms related to the benefits of physical activity.

METHODS: Pooled observational (cases: n = 5386; controls: n = 6798; studies n = 5) and genome-wide association data (cases: n = 8178; controls: n = 10 472; studies n = 5) were used. We used multivariable logistic regression models and Mendelian randomization to assess the association between physical activity and the risk of CRC subtypes …

Evaluation Of Integrative Oncology Modalities For Symptom Management: A Mascc/Sio Global Survey, Alexandre Chan, Reem Nasr, Daniela Arcos, Dalia Kagramanov, Chioma Asuzu, Ting Bao, Yin Ting Cheung, Jung Hye Kwon, Judith Lacey, Richard T. Lee, Maryam Lustberg, Beatrice M. Ohaeri, Santosh Rao, Enrique Soto-Perez-De-Celis, Claudia M. Witt, Ana M. Lopez

Kimmel Cancer Center Faculty Papers

BACKGROUND: With growing evidence pointing towards the potential of integrative oncology modalities (IOM) in addressing cancer and cancer-treatment related symptoms, research on IOM utilization and implementation is warranted. This study examines global stakeholder perspectives on integrative oncology (IO) utilization for supportive cancer care.

METHODS: Members of the Multinational Association of Supportive Care in Cancer (MASCC) and the Society for Integrative Oncology (SIO) completed a survey on the utilization of IOM for supportive cancer care. Descriptive statistics were used to assess demographic data, IOM usage patterns, IOM education, and financial considerations for utilizing IOM.

RESULTS: Among 344 participants representing eight geographical …

Risk Of Late-Onset Depression In Long-Term Survivors Of Breast, Prostate, And Colorectal Cancer, Melissa Taylor, Sarah Westvold, Jessica Long, Terry Hyslop, Andrea Silber, Rebecca Forman, Faiza Yasin, Tendai Kwaramba, Shi-Yi Wang, Michael Leapman, Michael Cecchini, Ira Leeds, Lisa Spees, Stephanie Wheeler, Cary Gross, Kevin Oeffinger, Michaela Dinan

Kimmel Cancer Center Faculty Papers

IMPORTANCE: The prevalence of depression is higher in cancer survivors than in the general population. As the long-term cancer survivor population increases, it is increasingly important to understand risk factors for late-onset depression.

OBJECTIVE: To identify risk factors associated with late-onset depression in long-term (5-year) survivors of breast, prostate, or colorectal cancer.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used 2022 linkage of Surveillance, Epidemiology, and End Results (SEER) and Medicare data to identify 5-year survivors of breast, prostate, or colorectal cancer 66 years or older who were enrolled in fee-for-service Medicare and had no previous depression diagnosis. Long-term …

Human Kallikrein 2: A Novel Lineage-Specific Surface Target In Prostate Cancer, Fei Shen, Ryan Smith, Theresa Mcdevitt, Krista Menard, Shaozhou Tian, Gerald Chu, Ruchi Chaudhary, Jennifer Mccann, Halley Oyer, Sherry C. Wang, Steven Max, Peter Francis, William K. Kelly, Charles G. Drake

Kimmel Cancer Center Faculty Papers

PURPOSE: Targeted therapies for metastatic prostate cancer are limited, highlighting the need for novel drug targets and mechanisms of action (MoA). Human kallikrein 2 (KLK2) is a prostate-specific antigen expressed across the prostate cancer disease continuum. However, it was not recognized as a therapeutic target for prostate cancer in the past due to limited evidence of its cell surface expression. In this study, we systematically characterized KLK2 expression in prostate cancer, confirmed its cell surface expression, and demonstrated the preclinical efficacy of three KLK2-targeting therapeutics with distinct MoA.

EXPERIMENTAL DESIGN: The KLK2 expression profile in different stages of prostate cancer …

National Alliance Of Sickle Cell Centers Consensus Recommendations On Sickle Cell Disease Health Maintenance: A Consensus Statement, Seethal A. Jacob, Melissa Frei-Jones, Sana Saif-Ur-Rehman, Monica L. Hulbert, Andrew R. W. O'Brien, Crawford Strunk, Anthony Villella, Ravi Talati, Amma Owusu-Ansah, Francis Coyne, Patrick T. Mcgann, Parul Rai, Robin Miller, Angeli Rampersad, Vishwas Sakhalkar, Neha Bhasin, Deepa Manwani, Sophie Lanzkron, Julie Kanter

Cardeza Foundation for Hematologic Research

IMPORTANCE: The most common inherited blood disorder in the world, sickle cell disease (SCD) is a known global health concern. While survival of children into adulthood has improved significantly over the last few decades in high-resource countries, substantial gaps in care standards and limited practice harmonization persist.

OBJECTIVE: To provide up-to-date recommendations for preventive care and treatment of all people living with SCD and its related comorbidities.

EVIDENCE REVIEW: As part of the National Alliance of Sickle Cell Centers (NASCC), 41 pediatric and adult sickle cell disease experts developed consensus standards and recommendations based on available evidence and expert consensus …

A Clinical Practice Guideline For The Management Of Pregnancy Alloimmunized To Red Blood Cell Antigens\, Kenneth J Moise, Kara B Markham, Philip C Spinella, Molly R Sherwood, Karen A Robinson, Lisa M Wilson, Jay Malone, Jimmy Espinoza, Donna Dizon-Townson, Laura Mercer, Russell Miller, Leonardo Pereira, Anthony Sciscione, Alireza A Shamshirsaz, Kathryn Shanahan, Saul Snowise, Thomas Trevett, Juan M González Vélez, Bethany Weathersby

Faculty, Staff and Student Publications

Importance: Red blood cell alloimmunization is typically associated with the transplacental transfer of incompatible fetal red blood cells into maternal circulation. Subsequent pregnancies can be affected by fetal anemia, hydrops fetalis, and perinatal death. Most cases of Rhesus D (RhD) alloimmunization due to pregnancy can be prevented by the proper administration of Rhesus immune globulin. However, an emerging practice of using low-titer, O, RhD-positive whole blood (LTOWB) in cases of life-threatening hemorrhage has the potential to increase the exposure of the female population to a new source of incompatible red blood cells.

Objective: To establish recommendations for the management of …

A Multi-National Cross-Sectional Exploration Of Rehabilitation Services For Children And Young People Following Brain Injury In Low And Middle Income Countries, Mark A Linden, Leigh Schrieff-Brown, Linda Ewing-Cobbs, R A Leonard, Rajendra Prasad, Juan Carlos Arango-Lasprilla, Sandra Strazzer, Lucia Braga, Consuelo Reyes Payeras, Kim C Davis, Lisa Kalungwana-Mambwe, Flavia Dorrego, Mathilde Chevignard

Faculty, Staff and Student Publications

Background: Brain injury (BI) is the largest cause of mortality and morbidity among children and can lead to significant cognitive, social, emotional and behavioural deficits. There has been an absence of research examining the availability of rehabilitation services for affected children and young people in low and middle income countries (LMICs). This study therefore investigated current rehabilitation provision in LMICs for children and young people with BI.

Methods: An online survey was developed which collected data on funding support for rehabilitation, causes of BI and access to services. The survey was distributed to healthcare professionals known to members of the …

Genetic Contribution To Treatment-Related Dyslipidemia In Adult Survivors Of Childhood Cancer: Findings From The Ccss, Sjlife, And Dccss-Later Cohorts, Melissa Bolier, Vincent G Pluimakers, Linda Broer, Sebastian J C M M Neggers, Demi T C De Winter, Fan Wang, Jessica L Baedke, André G Uitterlinden, Kateryna Petrykey, Leontien C M Kremer, Jacqueline J Loonen, Marloes Louwerens, Heleen J Van Der Pal, E Lieke A M Feijen, Kevin C Oeffinger, Rebecca M Howell, Eric J Chow, Wendy M Leisenring, Maria Monica M Gramatges, Lindsay M Morton, Leslie L Robison, Melissa M Hudson, Kirsten K Ness, Yadav Sapkota, Gregory T Armstrong, Smita Bhatia, Yutaka Yasui, Marry M Van Den Heuvel-Eibrink

Faculty, Staff and Student Publications

Background: Dyslipidemia can occur as a long-term side effect of childhood cancer treatment. The difference in prevalence among children receiving comparable treatment suggests a role for genetic variation. We conducted the first genome-wide association study on dyslipidemia in a large childhood cancer survivor cohort, using three additional cohorts for replication.

Methods: Discovery analysis was performed in the original Childhood Cancer Survivor Study (CCSS) cohort (N = 4,332). Replication analyses were carried out in the CCSS expansion (N = 2,212), St. Jude Lifetime (N = 2,829), and Dutch Childhood Cancer Survivor Study (DCCSS-LATER) (N = 1,814) cohorts. In the CCSS cohorts, …

Preclinical Fluorescence-Guided Imaging Leveraging Surrounding Sentinel Tumor Microenvironment Identifies High-Risk Premalignant Pancreatic Lesions, Shilpa Sharma, Xiaoxia Wen, Jianbo Wang, Beibei Huang, Denise A Hernandez, Cong-Dat Pham, Zhiwen Liu, Susanne Je-Han Lin, Aiko Yamaguchi, Dimitra K Georgiou, Ryan P Coll, H Charles Manning

Faculty, Staff and Student Publications

Purpose: Because surgery is the only potential cure for pancreatic cancer, high-risk premalignant pancreatic lesions often evade detection by palpation or white-light visualization, increasing the risk of recurrence. We asked whether near-infrared fluorescence imaging of tumor-associated inflammation could identify high-risk premalignant lesions, leveraging the tumor microenvironment as a sentinel of local disease and, thus, enhance surgery outcomes.

Experimental design: Fluorescence-guided surgery was performed on genetically engineered mice [Ptf1a-Cre; LSL-KrasG12D/+; Smad4flox/flox (KSC)] at discrete stages of disease progression, histologically confirmed high-risk, premalignant lesions in postnatal mice to locally advanced pancreatic tumors in adults, using the imaging agent V-1520, a translocator protein …

Early Ctdna Dynamics Inform First-Line Therapy In Patients With Extensive-Stage Small Cell Lung Cancer, Carmela Ciardullo, Luis Tobalina, T Hedley Carr, Philip Szekeres, Silvija Kraljevic, Lauren Averett Byers, Giulia Fabbri

Faculty, Staff and Student Publications

Purpose: Small cell lung cancer (SCLC) is an aggressive malignancy with a poor prognosis despite initial treatment responses. This study evaluates ctDNA for monitoring disease and assessing the efficacy of first-line therapy in patients with extensive-stage SCLC (1L ES-SCLC).

Experimental design: In the TAZMAN trial, 31 patients with 1L ES-SCLC received standard treatment with durvalumab and etoposide plus carboplatin or cisplatin. We analyzed 228 plasma samples from 27 of 31 patients using a liquid biopsy approach to detect somatic mutations and copy-number aberrations, while also accounting for clonal hematopoiesis mutations.

Results: Baseline ctDNA analysis detected somatic alterations in 96.3% of …

Condition-Specific Growth Charts For Children With Alagille Syndrome., Koen Huysentruyt, Shannon M. Vandriel, Mathieu Roelants, David A. Piccoli, Kathleen M. Loomes, Elizabeth B. Rand, Noelle H. Ebel, Jeffrey A. Feinstein, Irena Jankowska, Piotr Czubkowski, Dorota Gliwicz-Miedzinska, Emmanuel M. Gonzales, Emmanuel Jacquemin, Jérôme Bouligand, Saul J. Karpen, Rene Romero, Henry C. Lin, Björn Fischler, Henrik Arnell, Li-Ting Li, Jian-She Wang, Rima Fawaz, Silvia Nastasio, Kyung Mo Kim, Seak Hee Oh, Lorenzo D'Antiga, Emanuele Nicastro, Ryan T. Fischer, Susan M. Siew, Michael Stormon, Chatmanee Lertudomphonwanit, Winita Hardikar, Sahana Shankar, James E. Squires, Shikha S. Sundaram, Catherine Larson-Nath, Deirdre A. Kelly, Jane Hartley, Pinar Bulut, M Kyle Jensen, Catalina Jaramillo, Amin J. Roberts, Helen M. Evans, Étienne M. Sokal, Tanguy Demaret, Henkjan J. Verkade, Richard J. Thompson, Bettina E. Hansen, Tim J. Cole, Binita M. Kamath, Dominique Debray, Florence Lacaille, Jernej Brecelj, Nehal M. El-Koofy, Mohamed A. Elmonem, Way Seah Lee, Maria Camila Sanchez, Maria Lorena Cavalieri, Christina Hajinicolaou, Kathleen B. Schwarz, Elisa Carvalho, Nathalie Rock, Wikrom Karnsakul, Ruben E. Quiros-Tejeira, Seema Alam, Gabriella Nebbia, Yael Mozer-Glassberg, Pamela L. Valentino, Ermelinda Santos-Silva, Zerrin Önal, Antal Dezsofi-Gottl, Melina Melere, María Legarda Tamara, John Eshun, Aglaia Zellos, Giuseppe Indolfi, Maria Rogalidou, Niviann Blondet, Pier Luigi Calvo, Marisa Beretta, Andréanne N. Zizzo, Cigdem Arikan, Mureo Kasahara, Nanda Kerkar, Amal A. Aqul, Victorien M. Wolters, Raquel Borges Pinto, Jesus Quintero Bernabeu, Jennifer Garcia, Sabina Wiecek, Christos Tzivinikos, Quais Mujawar, Carolina Jimenez-Rivera, Cristina Molera Busoms, Cristina Gonçalves, Luis Bujanda, Global Alagille Alliance (Gala) Study Group

Manuscripts, Articles, Book Chapters and Other Papers

IMPORTANCE: Different degrees of growth delay have been reported in children with Alagille syndrome (ALGS), yet these patients are routinely evaluated using standard growth charts.

OBJECTIVE: To develop condition-specific growth charts for ALGS using modern statistical approaches.

DESIGN, SETTING, AND PARTICIPANTS: This case series used data from the international, multicenter Global Alagille Alliance (GALA) study accrued between May 14, 2018, and March 20, 2023. Children born at full term between January 1, 1997, and August 31, 2019, with a clinically and/or genetically confirmed ALGS diagnosis and their native liver were included. Data from children with a known history of prematurity …

Therapeutic Radiation Drives Leptomeningeal Dissemination Of Medulloblastoma Through An Innate Immune Process, Carolina Nör, Kaitlin Kharas, Alex Rasnitsyn, Maria C Vladoiu, Nam Woo Cho, Jacob S Young, Felipe Nör, Ncedile Mankahla, Joonas Haapasalo, Kristiina Nordfors, Sara Rapic, Patryk Skowron, Raúl A Suárez, Alexander T Bahcheli, Oliver Ocsenas, Xin Chen, Shahrzad Bahrampour, Ali Momin, Lakshmikirupa Sundaresan, Winnie Ong, Liam D Hendrikse, Namal Abeysundara, Kyle Juraschka, Michelle Ly, Jonelle G Pallota, Tajana Douglas, Ning Huang, Hao Wang, Esta Mak, Lei Qin, Jessica Liu, Lily Shen, Betty Luu, Alex Manno, Sachin A Kumar, Laura K Donovan, Vernon Fong, Cory Richman, Craig Daniels, Livia Garzia, Jeremy N Rich, Cynthia Hawkins, Xiaochong Wu, Ralph Dacosta, Jüri Reimand, Xi Huang, Vijay Ramaswamy, David R Raleigh, Michael D Taylor

Faculty, Staff and Students Publications

Leptomeningeal metastases are the most important source of morbidity and mortality for medulloblastoma patients. Radiation of the entire brain is highly effective in the treatment and/or prevention of medulloblastoma leptomeningeal metastases. Infants treated on clinical trials with focal tumor radiation recur metastatically, whereas infants treated with only chemotherapy relapse locally. In murine medulloblastoma model systems, provision of a single dose of radiation to the tumor drives leptomeningeal dissemination. An inflammatory response after radiation-induced tumor cell death recruits a variety of immune cells. Inflammation opens the local blood-brain barrier, allowing intravasation of medulloblastoma cells. Experimental induction of inflammation with lipopolysaccharide drives …

A Multiomics Recovery Factor Predicts Long Covid In The Impacc Study, Gisela Gabernet, Jessica Maciuch, Jeremy P Gygi, John F Moore, Annmarie Hoch, Caitlin Syphurs, Tianyi Chu, Naresh Doni Jayavelu, David B Corry, Farrah Kheradmand, Lindsey R Baden, Rafick-Pierre Sekaly, Grace A Mccomsey, Elias K Haddad, Charles B Cairns, Nadine Rouphael, Ana Fernandez-Sesma, Viviana Simon, Jordan P Metcalf, Nelson I Agudelo Higuita, Catherine L Hough, William B Messer, Mark M Davis, Kari C Nadeau, Bali Pulendran, Monica Kraft, Chris Bime, Elaine F Reed, Joanna Schaenman, David J Erle, Carolyn S Calfee, Mark A Atkinson, Scott C Brakenridge, Esther Melamed, Albert C Shaw, David A Hafler, Alison D Augustine, Patrice M Becker, Al Ozonoff, Steven E Bosinger, Walter Eckalbar, Holden T Maecker, Seunghee Kim-Schulze, Hanno Steen, Florian Krammer, Kerstin Westendorf, Bjoern Peters, Slim Fourati, Matthew C Altman, Ofer Levy, Kinga K Smolen, Ruth R Montgomery, Joann Diray-Arce, Steven H Kleinstein, Leying Guan, Lauren Ir Ehrlich

Faculty, Staff and Students Publications

Background: Following SARS-CoV-2 infection, approximately 10%–35% of patients with COVID-19 experience long COVID (LC), in which debilitating symptoms persist for at least 3 months. Elucidating the biologic underpinnings of LC could identify therapeutic opportunities.

Methods: We utilized machine learning methods on biologic analytes provided over 12 months after hospital discharge from more than 500 patients with COVID-19 in the IMPACC cohort to identify a multiomics “recovery factor,” trained on patient-reported physical function survey scores. Immune profiling data included PBMC transcriptomics, serum O-link and plasma proteomics, plasma metabolomics, and blood mass cytometry by time of flight (CyTOF) protein levels. Recovery factor …

Integrative Proteogenomics And Forward Genetics Reveal A Novel Mitotic Vulnerability In Triple-Negative Breast Cancer, Nicholas J Neill, Shankha Satpathy, Karsten Krug, Jitendra K Meena, Nivetha Ramesh Babu, Cheyenne Calderon, Desmon Reed, Marcus J Weber, Lacey E Dobrolecki, Alaina Lewis, Christina Sallas, Meenakshi Anurag, Kimberly R Holloway, Chen Huang, Suhas Vasaikar, Maria F Cardenas, Beom-Jun Kim, Doug W Chan, Shayan C Avanessian, Siddhartha Tyagi, Mayra Orellana, Sufeng Mao, Heyuan Li, Fade Gong, Sarah J Kurley, Kristen L Meerbrey, Calla M Olson, Amritha Nair, Tingting Sun, Hsiang-Ching Chung, Elizabeth A Bowling, Jarey H Wang, Pengju Zhang, Peng Xiao, Duxiao Yang, Fabio Stossi, Mei-Yin C Polley, Alexander B Saltzman, Filip Mundt, D R Mani, Michael A Gillette, Susan G Hilsenbeck, George Miles, Carolina Gutierrez, C Kent Osborne, Charles Y Lin, Nathanael S Gray, Jinpeng Sun, David A Wheeler, Charles M Perou, Anna Malovannaya, Michael T Lewis, Bing Zhang, Matthew J Ellis, Steven A Carr, Thomas F Westbrook

Faculty, Staff and Students Publications

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with few effective targeted therapies. Taxanes and other microtubule-targeting agents (MTAs) are frontline chemotherapies for TNBC; however, the molecular pathways that cause TNBC taxane sensitivity are largely unknown, preventing selection of taxane-responsive patients and development of more selective therapeutic strategies. In this study, we identified tumor-selective vulnerabilities in TNBC harboring inactivation of the tumor suppressor PTPN12 by integrating proteogenomic characterization and synthetic lethality screening. We discovered that PTPN12 inactivation drives mitotic defects through aberrant hyperactivation of the ubiquitin ligase complex APCFZR1, a critical regulator of the cell cycle. Consistent …

Proteomic Perspectives On Kras-Driven Cancers And Emerging Therapeutic Approaches, Ramesh Karki, Ru Chen, Sheng Pan

Faculty, Staff and Student Publications

KRAS mutations are implicated in approximately 23% of all human malignancies, with particularly high prevalence in pancreatic ductal adenocarcinoma (PDAC) (~92%), colorectal cancer (CRC) (~49%), and non-small cell lung cancer (NSCLC) (~35%). The recent approval of the KRASG12C-specific inhibitors for NSCLC represents a pivotal advancement in KRAS-targeted therapy. Nevertheless, the emergence of intrinsic and acquired resistance to KRAS-targeted therapies poses a significant clinical obstacle to targeting KRAS, which necessitates a deeper understanding of the resistance mechanisms. Recent progress in proteomic studies has enabled comprehensive profiling of the proteomic alterations driven by KRAS mutations, offering valuable insights into the disrupted KRAS …

Scaling Up Biomedical Vision-Language Models: Fine-Tuning, Instruction Tuning, And Multi-Modal Learning, Cheng Peng, Kai Zhang, Mengxian Lyu, Hongfang Liu, Lichao Sun, Yonghui Wu

Faculty, Staff and Student Publications

Objective: To advance biomedical vision language model capabilities through scaling up, fine-tuning, and instruction tuning, develop vision-language models with improved performance in handling long text, explore strategies to efficiently adopt vision language models for diverse multi-modal biomedical tasks, and examine the zero-shot learning performance.

Methods: We developed two biomedical vision language models, BiomedGPT-Large and BiomedGPT-XLarge, based on an encoder-decoder-based transformer architecture. We fine-tuned the two models on 23 benchmark datasets from 6 multi-modal biomedical tasks, including one image-only task (image classification), three language-only tasks (text understanding, text summarization, and question answering), and two vision-language tasks (visual question answering and image …

From Human To Mouse And Back Again: Genetic And Genomic Ta(I)Les Of Islet Dysfunction In Type 2 Diabetes., Romy Kursawe, Khushdeep Bandesh, Sai Nivedita Krishnan, Kevin S Liu, Redwan M Bhuiyan, Michael L. Stitzel

Faculty Research 2025

Type 2 diabetes (T2D) is a complex genetic disease with substantial environmental inputs leading to glucose homeostasis defects. Insulin production is central to proper glucose control, and islet cell dysfunction and death lie at the nexus of T2D genetics and pathophysiology. Comprehensive identification of genes and pathways contributing to these processes is essential for mechanistic understanding and therapeutic targeting. Here, we summarize the latest human and mouse T2D genetic and genomic studies and assess how these parallel variant-to-function efforts and associated data contribute convergent or complementary insights and new opportunities to dissect T2D islet (dys)function. We distill mechanistic and phenotypic …

Neurometabolic And Vascular Dysfunction As An Early Diagnostic For Alzheimer's Disease And Related Dementias., Juan Antonio K Chong Chie, Scott A Persohn, Ravi S Pandey, Gregory W. Carter, Olivia R Simcox, Paul Salama, Paul R Territo, The Alzheimer’S Disease Neuroimaging Initiative

Faculty Research 2025

INTRODUCTION: Recent studies suggest that the brain undergoes anatomical and functional restructuring, resulting in neurometabolic and vascular dysregulation (MVD) prior to amyloid beta accumulation, which begins at an early age and leads to the onset of Alzheimer's disease (AD).

METHODS: Using a retrospective clinical population (n = 403) from the Alzheimer's Disease Neuroimaging Initiative, cerebral perfusion and metabolism changes across 59 brain regions were evaluated from clinical studies. Results were verified by transcriptomic signatures and clinical cognitive assessments.

RESULTS: Our findings suggest that disease progression follows a stage-dependent MVD pattern that can identify at-risk regions. Although each region progresses at …

The Ecological Genome Project And The Promises Of Ecogenomics For Society: Realising A Shared Vision As One Health., Benjamin Capps, Ruth Chadwick, Yann Joly, Claire Lajaunie, Iva Hauptmannova, Susannah Mackenzie, John J Mulvihill, Elizabeth Mumford, Sonja A Rasmussen, Kunal Sanghavi, Donrich W Thaldar, James Yeates, Maud C Quinzin, Zohar Lederman

Faculty Research 2025

This paper develops a vision for The Ecological Genome Project: an aspirational, global endeavour to connect human genomic sciences with the ethos of ecological sciences. The Project's goal is to strengthen interdisciplinary networks that relate to diverse initiatives using genomic technologies, with respect to shared ethical frameworks and governance structures. To this end, this paper proposes a practical definition of ecogenomics to align various methodologies and values in a single environmental field using principles used to safeguard all forms of life in their habitats. We achieve this by using a One Health approach as a pretext for disparate disciplines to …

Single-Cell Transcriptomics Of The Myeloid Milieu Reveals An Angiogenic Niche In Triple-Negative Breast Cancer., Yechan Choi, Minkyu Shim, Suhn Hyung Kim, Duk Ki Kim, Juhee Jeong, Jinyoung Byeon, Giyong Jang, Ji-Yeon Kim, Paul Robson, Charles Lee, Han-Byoel Lee, Keehoon Jung

Faculty Research 2025

Intratumoral myeloid cells are highly heterogeneous in terms of development and function and are pivotal for forming and regulating the tumor microenvironment. However, the myeloid milieu in triple-negative breast cancer (TNBC) remains poorly understood. Here, to elucidate this myeloid milieu, we integrated in-house and public single-cell RNA sequencing data. We detected diverse neutrophil and mononuclear-phagocyte subtypes and delineated their developmental trajectories and functions. Of particular interest were the VEGFA

The Ecological Genome Project And The Promises Of Ecogenomics For Society: Realising A Shared Vision As One Health., Benjamin Capps, Ruth Chadwick, Yann Joly, Claire Lajaunie, Iva Hauptmannova, Susannah Mackenzie, John J Mulvihill, Elizabeth Mumford, Sonja A Rasmussen, Kunal Sanghavi, Donrich W Thaldar, James Yeates, Maud C Quinzin, Zohar Lederman

Faculty Research 2025

This paper develops a vision for The Ecological Genome Project: an aspirational, global endeavour to connect human genomic sciences with the ethos of ecological sciences. The Project's goal is to strengthen interdisciplinary networks that relate to diverse initiatives using genomic technologies, with respect to shared ethical frameworks and governance structures. To this end, this paper proposes a practical definition of ecogenomics to align various methodologies and values in a single environmental field using principles used to safeguard all forms of life in their habitats. We achieve this by using a One Health approach as a pretext for disparate disciplines to …

Risk Score Roulette: A Cautionary Tale Of Polygenic Risk Score Reliability, Diane Xue, Elizabeth E Blue, Alexis C Wood, Jerome I Rotter, Alison E Fohner

Children’s Nutrition Research Center Staff Publications

Genetic risk prediction for Alzheimer's disease (AD) has high potential impact, yet few studies have assessed the reliability of various polygenic risk score (PRS) methods at the individual level. Here, we evaluated the reliability of AD PRS estimates among 6338 participants from the Multi-Ethnic Study of Atherosclerosis. We compared four PRS models that have been previously associated with dementia risk. Despite similar population-level performance metrics, inter-model reliability of individual-level risk assessment was low, even among individuals classified in the top and bottom deciles. These findings raise serious concerns about the downstream application of PRS for guiding interventions for AD.

J. Robert Gladden Orthopaedic Society Research Grants: What Is The Return On Invesments, Lancelot Benn, Susan Stephens, Mark Ehioghae, Rishi Balkissoon, Brendan A. Williams, Shaina Lipa, David N. Bernstein, Gbolabo Sokunbi, Barrett I. Woods, Wakenda Tyler, Jaysson Brooks, Randall C. Morgan, Kwadwo Owusu-Akyaw, Wayne Johnson, Eric Carson, George V. Russell, Addisu Mesfin

Rothman Institute Papers

INTRODUCTION: The J. Robert Gladden Orthopaedic Society (JRGOS) aims to increase diversity in orthopaedic surgery and promote high-quality musculoskeletal care for all. Through targeted research funding, JRGOS supports projects aligned with its mission. Despite awarding over $300,000 in research grants since 2011, the return on investment (ROI) of this program has not been analyzed. This study evaluates the ROI of JRGOS research grants from 2011 to 2023.

METHODS: We conducted a retrospective review of all JRGOS research grants awarded between 2011 and 2023. Data included recipient demographics, grant titles, award year, institution, and amount. PubMed and Google Scholar were used …

A Historical Cohort Comparison After Inpatient Admission For Adolescents With Anorexia Nervosa: Feasibility Of Virtual Group Therapy, Elizabeth V Franklin, Margaret Mathias, Rachel Wolfe, Duc T Nguyen, Drusilla M Rosales, Sofia Pedroza, Albert C Hergenroeder, Constance M Wiemann

Center for Medical Ethics and Health Policy Staff Publications

Objective: Access to follow-up care after a medical admission for adolescents with anorexia nervosa (AN) is important; yet access can be delayed or unavailable. This study assessed the feasibility and acceptability of a supplemental virtual 8-week outpatient group therapy program following inpatient care. A secondary aim explored the outpatient program's impact on self-reported anxiety, disordered eating, and depression symptoms, and readmission rates.

Method: A retrospective chart review study compared 68 adolescents (aged 11-18) with AN enrolled in an 8-week group therapy program (Recovery and Prevention Program [RAPP]) to 64 adolescents who were not enrolled in RAPP (historical cohort). "RAPP completers" …