Digital Commons Network^™

Ligand-Activated Egfr/Mapk Signaling But Not Pi3k, Are Key Resistance Mechanisms To Egfr-Therapy In Colorectal Cancer, Xueping Qu, Habib Hamidi, Radia M Johnson, Ethan S Sokol, Eva Lin, Cathy Eng, Tae Won Kim, Johanna Bendell, Smruthy Sivakumar, Benjamin Kaplan, Felipe De Sousa E Melo, Andrew Mancini, Matthew Wongchenko, Yi Shi, David Shames, Yibing Yan, Fortunato Ciardiello, Carlos Bais

Faculty, Staff and Student Publications

Understanding mechanisms of resistance to active therapies is crucial for developing more effective treatments. Here, we investigate resistance to anti-EGFR and anti-VEGF plus chemotherapy treatment in colorectal cancer (CRC) patients from the IMblaze370 trial (NCT02788279). While anti-VEGF does not select for secondary mutations, anti-EGFR leads to simultaneous mutations in EGFR and MAPK, but not PI3K pathway genes. Notably, we observe frequent acquired mutations in the EGFR extracellular but not intracellular domain and that patients with higher baseline expression of EGFR-ligands are prone to acquire resistant mutations. This data reveals a ligand-activated EGFR/MAPK-signaling dependency in CRC. We also observe enrichment for …

Sustained Growth-Promoting Effects Of Vosoritide In Children With Achondroplasia From An Ongoing Phase 3 Extension Study, Ravi Savarirayan, Melita Irving, William R Wilcox, Carlos A Bacino, Julie E Hoover-Fong, Paul Harmatz, Lynda E Polgreen, Katja Palm, Carlos E Prada, Takuo Kubota, Paul Arundel, Yumiko Kotani, Antonio Leiva-Gea, Michael B Bober, Jacqueline T Hecht, Janet M Legare, Sue Lawrinson, Andrea Low, Ian Sabir, Alice Huntsman-Labed, Jonathan R S Day

Faculty, Staff and Students Publications

Background: Vosoritide is a C-type natriuretic peptide analog that addresses an underlying pathway causing reduced bone growth in achondroplasia. Understanding the vosoritide treatment effect requires evaluation over an extended duration and comparison with outcomes in untreated children.

Methods: After completing ≥6 months of a baseline observational growth study and 52 weeks in a double-blind, placebo-controlled study (ClinicalTrials.gov: NCT03197766), participants were eligible to continue treatment in an open-label extension (ClinicalTrials.gov: NCT03424018) wherein all received 15 μg/kg vosoritide daily. Data from the CLARITY achondroplasia study provided an external untreated control population and reference data.

Findings: The population comprised 119 participants. …

High-Throughput Echocardiography-Guided Induction Of Myocardial Ischemia/Reperfusion In Mice, Florian Sicklinger, Niklas Hartmann, Attila Kovacs, Carla Weinheimer, Jess Nigro, Junedh M. Amrute, Kory J. Lavine, Et Al.

2020-Current year OA Pubs

BACKGROUND: Mouse models of myocardial ischemia with subsequent heart failure are common approaches to examine heart failure pathology and possible treatment strategies. We sought to establish a high-throughput approach for echocardiography-guided induction of myocardial ischemia/reperfusion (IR) in mice.

METHODS: After visualization of the left coronary artery with high-resolution ultrasound imaging and echocardiographic definition of the level of coronary occlusion, the left anterior descending artery was temporarily occluded with 2 micromanipulator-controlled needles. Functional and molecular changes were assessed and compared with commonly performed surgical techniques.

RESULTS: Echocardiography-guided induction of myocardial IR enabled standardized induction of myocardial IR injury with subsequent left …

Exploring The International Terminology Associated With Nurses Caring For Neonates, Infants, Children, Young People And Their Families., Matt Carey, Jane Coad, Imelda Coyne, Suja Somanadhan, Sarah Neill

School of Nursing and Midwifery

The terminology used for Registered Nurses specializing in caring for neonates, infants, children, young people (CYP), and their families varies globally. While many countries’ nursing students qualify as “Registered Nurses” upon completion of undergraduate education, specialist titles like “Children’s Nurses” in the United Kingdom or “Pediatric Nurses” in Italy denote expertise in CYP care. In countries like the United States and Canada, neonatal and pediatric nursing specialization typically requires postgraduate study. However, there is limited evidence on the range of international terms for nurses in this field. This expert opinion paper presents the results from a scoping survey designed to …

Sirt6 Deficiency Promotes Senescence And Age-Associated Intervertebral Disc Degeneration In Mice, Pranay Ramteke, Bahiyah Watson, Mallory Toci, Victoria Tran, Shira N Johnston, Maria Tsingas, Ruteja Barve, Ramkrishna Mitra, Richard Loeser, John Collins, Makarand Risbud

Department of Orthopaedic Surgery Faculty Papers

Intervertebral disc degeneration is a major risk factor contributing to chronic low back and neck pain. While the etiological factors for disc degeneration vary, age is still one of the most important risk factors. Recent studies have shown the promising role of SIRT6 in mammalian aging and skeletal tissue health, however its role in the intervertebral disc health remains unexplored. We investigated the contribution of SIRT6 to disc health by studying the age-dependent spinal phenotype of mice with conditional deletion of Sirt6 in the disc (Acan^CreERT2; Sirt6^fl/fl). Histological studies showed a degenerative phenotype in knockout mice …

Cpg Methylation Changes Associated With Hyperglycemia In Type 1 Diabetes Occur At Angiogenic Glomerular And Retinal Gene Loci., Xiaojian Shao, Sophie Le Fur, Warren A. Cheung, Marie-Pierre Belot, Kevin Perge, Natacha Bouhours-Nouet, Candace Bensignor, Lucie Levaillant, Bing Ge, Tony Kwan, Mark Lathrop, Tomi Pastinen, Pierre Bougnères

Manuscripts, Articles, Book Chapters and Other Papers

Chronic hyperglycemia is a major risk factor for glomerular or retinal microangiopathy and cardiovascular complications of type 1 diabetes (T1D). At the interface of genetics and environment, dynamic epigenetic changes associated with hyperglycemia may unravel some of the mechanisms contributing to these T1D complications. In this study, blood samples were collected from 112 young patients at T1D diagnosis and 3 years later in average. Whole genome-wide bisulfite sequencing was used to measure blood DNA methylation changes of about 28 million CpGs at single base resolution over this time. Chronic hyperglycemia was estimated every 3-4 months by HbA1c measurement. Linear regressions …

Investigating Social Network Peer Effects On Hiv Care Engagement Using A Fuzzy-Like Matching Approach: Cross-Sectional Secondary Analysis Of The N2 Cohort Study, Cho-Hee Shrader, Dustin T Duncan, Redd Driver, Juan G Arroyo-Flores, Makella S Coudray, Raymond Moody, Yen-Tyng Chen, Britt Skaathun, Lindsay Young, Natascha Del Vecchio, Kayo Fujimoto, Justin R Knox, Mariano Kanamori, John A Schneider

Faculty, Staff and Student Publications

BACKGROUND: Social network data are essential and informative for public health research and implementation as they provide details on individuals and their social context. For example, health information and behaviors, such as HIV-related prevention and care, may disseminate within a network or across society. By harmonizing egocentric and digital networks, researchers may construct a sociocentric-like "fuzzy" network based on a subgroup of the population.

OBJECTIVE: We aimed to generate a more complete sociocentric-like "fuzzy" network by harmonizing alternative sources of egocentric and digital network data to examine relationships between participants in the Neighborhoods and Networks (N2) cohort study. Further, we …

Overconfidence And Financial Risk Tolerance In Older Age, Colleen C Frank, Gary R Mottola, Meiru Chen, Lei Yu, Patricia A Boyle, Gregory R Samanez-Larkin, Kendra L Seaman

Faculty, Staff and Student Publications

Objectives: Excessive financial risk-taking in older age can have harmful consequences as opportunities to recover lost wealth are limited. Understanding financial risk-taking in older age is important for identifying vulnerabilities and developing interventions to empower aging investors to make wise financial choices. In this paper, we explore how overconfidence in financial knowledge affects financial risk-taking among older adults.

Methods: We examine this research question in older adults aged 58-101 (N = 1,242) using data from the Rush Memory and Aging Project (MAP).

Results: After controlling for demographics, overconfidence was associated with self-reported financial risk tolerance such that those who were …

Zanidatamab Monotherapy Or Combined With Chemotherapy In Her2-Expressing Gastroesophageal Adenocarcinoma: A Phase 1 Trial, Funda Meric-Bernstam, Sun Young Rha, Erika Hamilton, Yoon-Koo Kang, Diana L Hanna, Syma Iqbal, Keun-Wook Lee, Jeeyun Lee, Muralidhar Beeram, Do-Youn Oh, Jorge Chaves, Rachel A Goodwin, Jaffer A Ajani, Lin Yang, Rajen Oza, Elena Elimova

Faculty, Staff and Student Publications

There is a need for novel therapies for patients with previously treated HER2-positive gastroesophageal adenocarcinoma (GEA). This phase 1 (NCT02892123) dose-escalation and expansion trial evaluated zanidatamab (a dual HER2-targeted bispecific antibody) ± chemotherapy in previously treated patients with HER2-expressing, locally advanced/metastatic cancers. Here, we report the outcomes for GEA cohorts receiving zanidatamab monotherapy or with chemotherapy (paclitaxel or capecitabine). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rate (ORR), disease control rate, progression-free survival, pharmacokinetics, and immunogenicity. Seventy patients were enrolled (n = 29 monotherapy; n = 41 combination therapy); most received prior HER2-targeted agents (monotherapy, …

Hippocampal-Prefrontal Functional Neural Networks In A Rat Model Of Fragile X Syndrome Are Poorly Organized With Limited Resiliency, Mohamed Ouardouz, Patrick Jasinski, Mohamed Khalife, J. Matthew Mahoney, Amanda E. Hernan, Rod C. Scott

Department of Neurology Faculty Papers

Fragile X Syndrome (FXS) is a common cause of autism spectrum symptoms. The genetic mutation results in multiple molecular alterations that are hypothesized to negatively impact neural circuit development although the nature of any functional neural dynamic consequences remain unclear. Therefore, the characteristics of hippocampal-prefrontal (H-PFC) network dysfunction were investigated in a rat model of FXS. FMR-KO and control rats underwent behavioral tests assessing sociability, memory, and anxiety to validate and replicate previously recognized deficits. Single-unit electrophysiology in the H-PFC circuit during exploration was used to measure patterns of action potential firing that were then compared between groups using generalized …

Sirt6 Deficiency Promotes Senescence And Age-Associated Intervertebral Disc Degeneration In Mice, Pranay Ramteke, Bahiyah Watson, Mallory Toci, Victoria A Tran, Shira Johnston, Maria Tsingas, Ruteja A Barve, Ramkrishna Mitra, Richard F Loeser, John A Collins, Makarand V Risbud

2020-Current year OA Pubs

Intervertebral disc degeneration is a major risk factor contributing to chronic low back and neck pain. While the etiological factors for disc degeneration vary, age is still one of the most important risk factors. Recent studies have shown the promising role of SIRT6 in mammalian aging and skeletal tissue health, however its role in the intervertebral disc health remains unexplored. We investigated the contribution of SIRT6 to disc health by studying the age-dependent spinal phenotype of mice with conditional deletion of Sirt6 in the disc (Acan

Human Genetic Variation Determines 24-Hour Rhythmic Gene Expression And Disease Risk, Ying Chen, Panpan Liu, Aniko Sabo, Dongyin Guan

Faculty, Staff and Students Publications

24-hour biological rhythms are essential to maintain physiological homeostasis. Disruption of these rhythms increases the risks of multiple diseases. Biological rhythms are known to have a genetic basis formed by core clock genes, but how individual genetic variation shapes the oscillating transcriptome and contributes to human chronophysiology and disease risk is largely unknown. Here, we mapped interactions between temporal gene expression and genotype to identify quantitative trait loci (QTLs) contributing to rhythmic gene expression. These newly identified QTLs were termed as rhythmic QTLs (rhyQTLs), which determine previously unappreciated rhythmic genes in human subpopulations with specific genotypes. Functionally, rhyQTLs and their …

Development Of A Risk Score To Aid With The Diagnosis Of Infections After Spinal Cord Injury: Protocol For A Retrospective Cohort Study, Felicia Skelton, Larissa Grigoryan, Joann Pan, Ashley Collazo, Barbara Trautner

Faculty, Staff and Students Publications

Background: Patients with spinal cord injury (SCI) who develop urinary tract infection (UTI) present differently than the non-SCI population. UTIs can cause loss of quality of life and even lead to life-threatening complications including urosepsis. Challenges in SCI management include distinguishing symptomatic UTI from asymptomatic bacteriuria (ASB), which occurs often in patients with SCI, and the lack of standardization in UTI diagnosis in SCI.

Objective: This study aims to set the foundation for the development of a risk score to improve diagnostic accuracy of UTI after SCI.

Methods: This study will use data from the Veterans Health Administration Corporate Data …

The Association Of Resistin With Metabolic Health And Obesity In A Mexican-American Population, Reem Al-Dallal, Keziah Thomas, Minjae Lee, Aysha Chaudhri, Eleanor Davis, Priyanka Vaidya, Miryoung Lee, Joseph B Mccormick, Susan P Fisher-Hoch, Absalon D Gutierrez

Faculty, Staff and Student Publications

Research on the relationship between resistin levels, metabolic health, and obesity has produced inconsistent findings across different ethnic groups, making it unclear whether lower resistin levels are associated with these conditions in Mexican-Americans. This cross-sectional study investigated the relationship between resistin, metabolic health, and obesity in an adult Mexican-American cohort (n = 1511) using multivariable linear regression analysis. Related adipokines (leptin and adiponectin) were measured simultaneously. Participants were categorized into four groups by metabolic health (healthy/unhealthy) and obesity (obese/non-obese) status. “Metabolically unhealthy” was defined as ≥2 cardiometabolic abnormalities. Obesity was defined as a BMI ≥ 30 kg/m2. We also …

Residential Proximity, Duration, And Health-Related Quality Of Life: Insights From The Fernald Cohort, Sara Burcham, Wei-Wen Hsu, Sharon L. Larson, Phd, Jack Rubinstein, Susan M. Pinney

College of Population Health Faculty Papers

The impact of living near environmental contamination on the health-related quality of life (HRQoL) is not well understood. This study examined the impacts of the residential proximity (RP) and time spent near a former Department of Energy uranium processing facility (located in Fernald, Ohio) on the surrounding community’s HRQoL outcomes. A cross-sectional analysis was conducted using the data collected from participants using the Short Form-36 survey at the time of the enrollment in the Fernald Medical Monitoring Program (n = 7957). Mental and physical component summary scores (MCS and PCS, respectively) were computed for each participant. The scores were compared …

Characterising Acute And Chronic Care Needs: Insights From The Global Burden Of Disease Study 2019, A. A. Asadi-Pooya

Department of Neurology Faculty Papers

Chronic care manages long-term, progressive conditions, while acute care addresses short-term conditions. Chronic conditions increasingly strain health systems, which are often unprepared for these demands. This study examines the burden of conditions requiring acute versus chronic care, including sequelae. Conditions and sequelae from the Global Burden of Diseases Study 2019 were classified into acute or chronic care categories. Data were analysed by age, sex, and socio-demographic index, presenting total numbers and contributions to burden metrics such as Disability-Adjusted Life Years (DALYs), Years Lived with Disability (YLD), and Years of Life Lost (YLL). Approximately 68% of DALYs were attributed to chronic …

A Honduran Prevalence Study On Soil-Transmitted Helminths Highlights Serological Antibodies To Tm-Wap49 As A Diagnostic Marker For Exposure To Human Trichuriasis, Neima Briggs, Leroy Versteeg, Rojelio Mejia, Jeroen Pollet, Maria Jose Villar, Bin Zhan, Graeme Segal, Stephanie Novak, Patricia Lenihan, Paul Musgrave, Viviana Ellis, Carol Florencia Coello, K Jagannadha Sastry, Joe Craft, Peter J Hotez, Maria Elena Bottazzi

Faculty, Staff and Student Publications

Soil-transmitted helminth (STH) infections rank among the most prevalent communicable diseases of humans, yet detection of these parasites is mostly restricted to identifying active infection through fecal examinations. Currently, there are no commercial diagnostic tools to identify a prior whipworm or hookworm exposure, and the few serological assays for roundworm infection have not been well validated for crossreactivity or infections in humans. Such diagnostic restrictions limit the range of scientific and clinical questions that surround STH exposures and their implicated relationship to chronic diseases, such as autoimmunity, allergy, and cancer. The goal of this investigation was to evaluate the diagnostic …

Genomic Landscape Of Diffuse Glioma Revealed By Whole Genome Sequencing., B Kinnersley, J Jung, Cornish Aj, D Chubb, R Laxton, A Frangou, Gruber Aj, A Sud, G Caravagna, A Sottoriva, Wedge Dc, T Booth, S Al-Sarraj, K Ashkan, Ellie Edlmann

Peninsula Medical School

Diffuse gliomas are the commonest malignant primary brain tumour in adults. Herein, we present analysis of the genomic landscape of adult glioma, by whole genome sequencing of 403 tumours (256 glioblastoma, 89 astrocytoma, 58 oligodendroglioma; 338 primary, 65 recurrence). We identify an extended catalogue of recurrent coding and non-coding genetic mutations that represents a source for future studies and provides a high-resolution map of structural variants, copy number changes and global genome features including telomere length, mutational signatures and extrachromosomal DNA. Finally, we relate these to clinical outcome. As well as identifying drug targets for treatment of glioma our findings …

The Seroprevalence And Risk Factors For Spotted Fever Group And Typhus Group Rickettsia Along The Texas-Mexico Border, Frederick M Cramer, Lauren M Leining, Timothy A Erickson, Josephine Tolan, Craig L Hanis, Eric L Brown, Sarah M Gunter

Faculty, Staff and Students Publications

Rickettsial pathogens are an endemic and emergent source of disease in Texas, with a historically high rate of transmission along the United States-Mexico border. To better understand the prevalence and risk factors for spotted fever group Rickettsia (SFGR) and typhus group Rickettsia (TGR) along the Texas-Mexico border, we conducted a seroprevalence study of adults residing in Starr County, Texas (N = 616). Plasma samples were screened for IgG reactivity to SFGR and TGR using commercially available ELISA. ELISA-positive samples were confirmed using a dual spot IgG indirect immunofluorescent assay. Seropositivity was defined as having a ≥1:128 titer. Analysis was conducted …

Estradiol Protects Against Pain-Facilitated Fentanyl Use Via Suppression Of Opioid-Evoked Dopamine Activity In Males, Jessica A Higginbotham, Julian G Abt, Rachel H Teich, Joanna J Dearman, Tania Lintz, Jose A Morón

2020-Current year OA Pubs

Pain relief is the most frequently reported motivation for opioid misuse, but it remains unclear how pain alters reward pathway function contributing to maladaptive opioid use and whether these neuroadaptations occur in a sex-specific manner. Here, we show that persistent inflammatory pain leads to augmented fentanyl self-administration in male, not female, rats. Wireless in vivo fiber photometry recordings and chemogenetic manipulations indicate that pain-facilitated fentanyl use is mediated by enhanced ventral tegmental area dopamine (VTA

Genomic, Transcriptomic, And Immunogenomic Landscape Of Over 1300 Sarcomas Of Diverse Histology Subtypes., Alex Soupir, Oscar E. Ospina, Oliver Hampton, Michelle Churchman, Michael Radmacher, Dale Hedges, David Mckean, Phaedra Agius, Saman Zeeshan, Nathan D. Seligson, Raphael Pollock, David Liebner, James L. Chen, Gabriel Tinoco, Bodour Salhia, Martin Mccarter, Breelyn A. Wilky, Benjamin J. Miller, Michael J. Cavnar, John S. Groundland, Bryan P. Schneider, Gregory Riedlinger, Stephen B. Edge, Christopher A. Moskaluk, Kenneth Cardona, Abdul Rafeh Naqash, Ricardo J. Gonzalez, John E. Mullinax, David M. Joyce, Odion Binitie, G Douglas Letson, Arash O. Naghavi, Mihaela Druta, Damon R. Reed, Erin M. Siegel, Jamie K. Teer, Brooke L. Fridley, Andrew S. Brohl

Manuscripts, Articles, Book Chapters and Other Papers

Given their rarity and diversity, a fundamental understanding of the genomic underpinnings for many sarcoma subtypes is still lacking. To better define the molecular landscape of this group of diseases, we perform matched whole exome sequencing and RNA sequencing on a cohort of 1340 sarcoma tumor specimens. We identify recurrent somatic mutations and observe an increased mutational burden in metastatic vs. primary samples (p <  0.001). We observe frequent copy number alterations including whole genome doubling, with this feature being more common in metastatic tumors (p = 0.026). Estimation of immune cell abundances followed by hierarchical clustering identifies five immune subtypes ranging from low to high and we observe inferior overall survival in immune deplete clusters compared to immune enriched (p <  0.01). Interestingly, GIST predominantly form a distinct "immune intermediate" cluster that is marked by a specific enrichment for NK cells (FDR <  0.01).

Spectrum Of Coronary Artery Involvement With Multisystem Inflammatory Syndrome In Children Versus Kawasaki Disease., Simon Lee, Ashraf S. Harahsheh, Geetha Raghuveer, Michael A. Portman, Arash A. Sabati, Michael Khoury, Nagib Dahdah, Marianna Fabi, Supriya S. Jain, Audrey Dionne, Kyle Runeckles, Frederic Dallaire, Nadine F. Choueiter, Tyler H. Harris, Matthew D. Elias, Anji T. Yetman, Balasubramanian Sundaram, Luis M. Garrido-Garcia, Nilanjana Misra, Cedric Manlhiot, Pedrom Farid, Brian W. Mccrindle

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: There is significant overlap in clinical features between multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD). We sought to compare the prevalence, severity, and associated factors for coronary artery (CA) involvement.

METHODS AND RESULTS: From January 1, 2020 through January 31, 2023, 1191 patients with MIS-C and 554 patients contemporaneously diagnosed with KD were enrolled into the International Kawasaki Disease Registry. Demographic and clinical features, laboratory values, maximum Z score in any CA branch +2.5 or greater) were determined separately for each diagnosis using multivariable logistic regression analyses. The prevalence of CA aneurysms was lower for MIS-C …

Lifespan Reference Curves For Harmonizing Multi-Site Regional Brain White Matter Metrics From Diffusion Mri, Alyssa H Zhu, Talia M Nir, Shayan Javid, Julio E Villalón-Reina, Amanda L Rodrigue, Lachlan T Strike, Greig I De Zubicaray, Katie L Mcmahon, Margaret J Wright, Sarah E Medland, John Blangero, David C Glahn, Peter Kochunov, Douglas E Williamson, Asta K Håberg, Paul M Thompson, Neda Jahanshad

Faculty, Staff and Student Publications

Age-related white matter (WM) microstructure maturation and decline occur throughout the human lifespan, complementing the process of gray matter development and degeneration. Here, we create normative lifespan reference curves for global and regional WM microstructure by harmonizing diffusion MRI (dMRI)-derived data from ten public datasets (N = 40,898 subjects; age: 3-95 years; 47.6% male). We tested three harmonization methods on regional diffusion tensor imaging (DTI) based fractional anisotropy (FA), a metric of WM microstructure, extracted using the ENIGMA-DTI pipeline. ComBat-GAM harmonization provided multi-study trajectories most consistent with known WM maturation peaks. Lifespan FA reference curves were validated with test-retest data …

Examining Demographic, Geographic, And Temporal Patterns Of Melanoma Incidence In Texas From 2000 To 2018: Retrospective Study, Kehe Zhang, Madison M Taylor, Jocelyn Hunyadi, Hung Q Doan, Adewole S Adamson, Paige Miller, Kelly C Nelson, Cici Bauer

Faculty, Staff and Student Publications

Background: Melanoma currently ranks as the fifth leading cancer diagnosis and is projected to become the second most common cancer in the United States by 2040. Melanoma detected at earlier stages may be treated with less-risky and less-costly therapeutic options.

Objective: This study aims to analyze temporal and spatial trends in melanoma incidence by stage at diagnosis (overall, early, and late) in Texas from 2000 to 2018, focusing on demographic and geographic variations to identify high-risk populations and regions for targeted prevention efforts.

Methods: We used melanoma incidence data from all 254 Texas counties from the Texas Cancer Registry (TCR) …

Longitudinal Profiling Of Circulating Tumor Dna Reveals The Evolutionary Dynamics Of Metastatic Prostate Cancer During Serial Therapy, Yuehui Zhao, Naveen Ramesh, Ping Xu, Emi Sei, Min Hu, Shanshan Bai, Patricia Troncoso, Ana M Aparicio, Christopher J Logothetis, Paul G Corn, Nicholas E Navin, Amado J Zurita

Faculty, Staff and Student Publications

Treatment decisions in metastatic castration-resistant prostate cancer are mostly guided by clinical variables, but efforts to molecularly monitor the disease remain hampered by challenges in acquiring tumor tissue repeatedly. In this study, we simultaneously profiled the genome copy number and exome in longitudinal plasma circulating tumor DNA (ctDNA) acquired before, during, and upon progression to serial treatments with androgen signaling inhibitors and taxane chemotherapy from 60 patients with metastatic castration-resistant prostate cancer (2-10 samples per patient). The genomic data were used to delineate the clonal substructure and evolutionary dynamics of each patient, and an evolutionary dynamic index was developed to …

Efficacy And Safety Of Larotrectinib In Patients With Trk Fusion Gastrointestinal Cancer, Changsong Qi, Lin Shen, Thierry Andre, Hyun Cheol Chung, Timothy L Cannon, Elena Garralda, Antoine Italiano, Damian T Rieke, Tianshu Liu, Domnita-Ileana Burcoveanu, Natascha Neu, Chiara E Mussi, Rui-Hua Xu, David S Hong, Alexander Drilon, Jordan Berlin

Faculty, Staff and Student Publications

Background: Larotrectinib is the first-in-class, highly selective TRK inhibitor with demonstrated efficacy in various TRK fusion solid tumours. We report the efficacy and safety of larotrectinib in patients with TRK fusion gastrointestinal (GI) cancer.

Methods: Patients with TRK fusion GI cancer from NAVIGATE (NCT02576431) were included. Response was independent review committee (IRC)-assessed per RECIST v1.1.

Results: As of July 2023, 44 patients were enrolled. Tumour types included colorectal (CRC; n = 26), pancreatic (n = 7), cholangiocarcinoma (n = 4), gastric (n = 3), and one each of appendiceal, duodenal, oesophageal and hepatic cancers. Of the 26 patients …

Artificial Intelligence-Based Virtual Staining Platform For Identifying Tumor-Associated Macrophages From Hematoxylin And Eosin-Stained Images, Arpit Aggarwal, Mayukhmala Jana, Amritpal Singh, Tanmoy Dam, Himanshu Maurya, Tilak Pathak, Sandra Orsulic, Kailin Yang, Deborah Chute, Justin A Bishop, Farhoud Faraji, Wade M Thorstad, Shlomo Koyfman, Scott Steward, Qiuying Shi, Vlad Sandulache, Nabil F Saba, James S Lewis, Germán Corredor, Anant Madabhushi

Faculty, Staff and Students Publications

Background: Virtual staining is an artificial intelligence-based approach that transforms pathology images between stain types, such as hematoxylin and eosin (H&E) to immunohistochemistry (IHC), providing a tissue-preserving and efficient alternative to traditional IHC staining. However, existing methods for translating H&E to virtual IHC often fail to generate images of sufficient quality for accurately delineating cell nuclei and IHC+ regions. To address these limitations, we introduce VISTA, an artificial intelligence-based virtual staining platform designed to translate H&E into virtual IHC.

Methods: We applied VISTA to identify M2-subtype tumor-associated macrophages (M2-TAMs) in H&E images from 968 patients with HPV+ oropharyngeal squamous cell …

The Association Of Discrimination, Inflammation, And Coping Style On Self-Rated Health Among South Asian Individuals In The Masala Study, Raji Pillai, Sahiti Myneni, Constance M Johnson, Nilay S Shah, Alka M Kanaya, Jennifer E S Beauchamp

Faculty, Staff and Student Publications

Objectives: South Asian individuals (SAs) may have heightened levels of inflammatory markers, such as C reactive protein (CRP), Tumor Necrosis Factor-α (TNF-α), leptin, and resistin, and decreased levels of anti-inflammatory adiponectin, contributing to higher cardiovascular disease (CVD) incidence. Social determinants of health, like discrimination, are also associated with risks for CVD in SAs. This study examined the associations between discrimination and inflammation and whether coping styles moderated the association between discrimination and self-rated health (SRH) among SAs in the United States.

Design: Secondary analysis of data obtained from 1164 SAs (mean age = 57 years, SD = 9.4, 48% women) …

Deciphering The Longitudinal Trajectories Of Glioblastoma Ecosystems By Integrative Single-Cell Genomics., Avishay Spitzer, Kevin C Johnson, Masashi Nomura, Luciano Garofano, Djamel Nehar-Belaid, Noam Galili Darnell, Alissa C Greenwald, Lillian Bussema, Young Taek Oh, Frederick S Varn, Fulvio D'Angelo, Simon Gritsch, Kevin J Anderson, Simona Migliozzi, L Nicolas Gonzalez Castro, Tamrin Chowdhury, Nicolas Robine, Catherine Reeves, Jong Bae Park, Anuja Lipsa, Frank Hertel, Anna Golebiewska, Simone P Niclou, Labeeba Nusrat, Sorcha Kellet, Sunit Das, Hyo-Eun Moon, Sun Ha Paek, Franck Bielle, Alice Laurenge, Anna Luisa Di Stefano, Bertrand Mathon, Alberto Picca, Marc Sanson, Shota Tanaka, Nobuhito Saito, David M Ashley, Stephen T Keir, Keith L Ligon, Jason T Huse, W K Alfred Yung, Anna Lasorella, Antonio Iavarone, Roel G W Verhaak, Itay Tirosh, Mario L Suvà

Faculty Research 2025

The evolution of isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) after standard-of-care therapy remains poorly understood. Here we analyzed matched primary and recurrent GBMs from 59 patients using single-nucleus RNA sequencing and bulk DNA sequencing, assessing the longitudinal evolution of the GBM ecosystem across layers of cellular and molecular heterogeneity. The most consistent change was a lower malignant cell fraction at recurrence and a reciprocal increase in glial and neuronal cell types in the tumor microenvironment (TME). The predominant malignant cell state differed between most matched pairs, but no states were exclusive or highly enriched in either time point, nor was there …

Fentanyl Test Strip Use And Overdose Risk Reduction Behaviors Among People Who Use Drugs, Rachel A Vickers-Smith, Kitty H Gelberg, Janet E Childerhose, Denise C Babineau, Redonna Chandler, James L David, Lauren D'Costa, Megan Dzurec, Barry Eggleston, Amanda Fallin-Bennett, Laura C Fanucchi, Soledad Fernandez, Jace Gilbert, Louisa Gilbert, Megan E Hall, Brooke E Hiltz, Michael W Konstan, Kathryn E Lancaster, Beth Linas, Katherine R Marks, Nichole Michaels, Jennifer Miles, Fernando Montero, Haley J Ramsey Harden, Carter Roeber, Mary R Russo, Rachel Taylor, Melissa A Theis

Epidemiology and Environmental Health Faculty Publications

IMPORTANCE: Illegal fentanyl is driving overdose mortality, and fentanyl test strips (FTS) can be used to test drugs for fentanyl at the point of consumption. Evidence on whether FTS use is associated with overdose risk reduction behaviors is encouraging, but largely limited to smaller, single-site studies.

OBJECTIVE: To determine whether self-reported baseline FTS use among people who use drugs (PWUD) was associated with overdose risk reduction behaviors and nonfatal overdose over a 28-day follow-up.

DESIGN, SETTING, AND PARTICIPANTS: Multisite, observational cohort study of PWUD conducted from May to December 2023 as an ancillary study of the HEALing Communities Study, which …