Digital Commons Network^™

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 …

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. …

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 …

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 …

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, …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

Clonal Dynamics And Somatic Evolution Of Haematopoiesis In Mouse., Chiraag D Kapadia, Nicholas Williams, Kevin J Dawson, Caroline Watson, Matthew J Yousefzadeh, Duy Le, Kudzai Nyamondo, Sreeya Kodavali, Alex Cagan, Sarah Waldvogel, Xiaoyan Zhang, Josephine De La Fuente, Daniel Leongamornlert, Emily Mitchell, Marcus A Florez, Krzysztof Sosnowski, Rogelio Aguilar, Alejandra Martell, Anna Guzman, David E Harrison, Laura J Niedernhofer, Katherine Y King, Peter J Campbell, Jamie Blundell, Margaret A Goodell, Jyoti Nangalia

Faculty Research 2025

Haematopoietic stem cells maintain blood production throughout life1 . Although extensively characterized using the laboratory mouse, little is known about clonal selection and population dynamics of the haematopoietic stem cell pool during murine ageing. We isolated stem cells and progenitors from young and old mice, identifying 221,890 somatic mutations genome-wide in 1,845 single-cell-derived colonies. Mouse stem cells and progenitors accrue approximately 45 somatic mutations per year, a rate only approximately threefold greater than human progenitors despite the vastly different organismal sizes and lifespans. Phylogenetic patterns show that stem and multipotent progenitor cell pools are established during embryogenesis, after which they …

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 …

Men In Family Science Courses: Perspectives Of Family Science Faculty And Administrators, Michael Langlais, J. Mitchell Vaterlaus, Sophia Rotella

Journal of Human Sciences and Extension

The goal of this qualitative study is to describe the perspectives of higher education family science faculty and administrators regarding men’s enrollment in family science courses. University family science courses educate students on how to promote developmental potential for individuals, couples, and families. Information from these classes can assist students’ personal and professional development regardless of gender, yet there are far fewer men enrolled in these courses compared to women. Data come from 78 faculty members and 12 administrators from randomly selected universities using the National Council on Family Relations’ Degree Programs in Family Science directory. Using coding reliability thematic …

Normative Variability In Retinal Nerve Fiber Layer Thickness: Does It Matter Where The Peaks Are?, Sowjanya Gowrisankaran, Ashkan Abbasi, Xubo Song, Joel Schuman, Gadi Wollstein, Bhavna Antony, Hiroshi Ishikawa

Wills Eye Hospital Papers

PURPOSE: Retinal nerve fiber layer thickness (RNFLT), a glaucoma biomarker, has a wide normative range affecting its sensitivity and specificity for abnormality detection. The interindividual RNFLT peak location variability contribution to this wide normative range has not been directly evaluated. The purpose of this study is to assess the effect of RNFLT peak normalization (PN) on normative variability.

METHODS: Circumpapillary RNFLT profiles at 1.7 mm radius from the optic nerve head (ONH) were re-sampled from optical coherence tomography (OCT) volumes (Cirrus HD-OCT, 200 × 200) obtained from one eye of 83 healthy individuals. Fovea-ONH axis (FOA) was calculated from corresponding …

Clonal Dynamics And Somatic Evolution Of Haematopoiesis In Mouse, Chiraag D Kapadia, Nicholas Williams, Kevin J Dawson, Caroline Watson, Matthew J Yousefzadeh, Duy Le, Kudzai Nyamondo, Sreeya Kodavali, Alex Cagan, Sarah Waldvogel, Xiaoyan Zhang, Josephine De La Fuente, Daniel Leongamornlert, Emily Mitchell, Marcus A Florez, Krzysztof Sosnowski, Rogelio Aguilar, Alejandra Martell, Anna Guzman, David Harrison, Laura J Niedernhofer, Katherine Y King, Peter J Campbell, Jamie Blundell, Margaret A Goodell, Jyoti Nangalia

Center on Aging Staff Publications

Haematopoietic stem cells maintain blood production throughout life1. Although extensively characterized using the laboratory mouse, little is known about clonal selection and population dynamics of the haematopoietic stem cell pool during murine ageing. We isolated stem cells and progenitors from young and old mice, identifying 221,890 somatic mutations genome-wide in 1,845 single-cell-derived colonies. Mouse stem cells and progenitors accrue approximately 45 somatic mutations per year, a rate only approximately threefold greater than human progenitors despite the vastly different organismal sizes and lifespans. Phylogenetic patterns show that stem and multipotent progenitor cell pools are established during embryogenesis, after which …

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) …

Survival In Patients With Rheumatoid Arthritis And Recently Diagnosed Early-Stage Colorectal, Lung, Or Prostate Cancer Receiving Tumour Necrosis Factor Inhibitors: A Retrospective Cohort Study, Juan I Ruiz, Xiudong Lei, Sharon H Giordano, Hui Zhao, Suja S Rajan, Heather Lin, Maria E Suarez-Almazor

Faculty, Staff and Student Publications

Background: Tumor necrosis factor (TNF) inhibitors could impair tumoural immunity in patients with rheumatoid arthritis and cancer. We aimed to investigate the association between survival and TNF inhibitor treatment during the first 3 years after a diagnosis of colorectal, lung, or prostate cancer in patients with rheumatoid arthritis.

Methods: In this cohort study, we conducted a secondary data analysis of the Surveillance, Epidemiology, and End Results Medicare-linked dataset. We included patients aged 66 years and older with rheumatoid arthritis diagnosed with colorectal, lung, or prostate cancer between Jan 1, 2008, and Dec 31, 2019, using ICD-O-3 site and histology codes. …

Trajectories Of Attention Problems In Preschoolers Born Very Preterm., Marie Camerota, Francisco Xavier Castellanos, Brian S. Carter, Jennifer Check, Jennifer Helderman, Julie A. Hofheimer, Elisabeth C. Mcgowan, Charles R. Neal, Steven L. Pastyrnak, Lynne M. Smith, Thomas Michael O'Shea, Carmen J. Marsit, Barry M. Lester

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Children born preterm are at heightened risk for neurodevelopmental impairment, including specific deficits in attention. Few studies have investigated change over time in attention problems prior to school entry. The current study aims to describe trajectories of attention problems from age 2 through 5 years in a cohort of children born(GA), identify sociodemographic, medical, and neurobehavioral characteristics associated with attention trajectories, and test whether attention problem trajectories predict the risk of a reported attention-deficit/hyperactivity disorder (ADHD) diagnosis.

METHODS: We studied 608 infants from the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study, a prospective, multisite study of …

Phase Ii Trial Of Atezolizumab And Bevacizumab For Treatment Of Hpv-Positive Unresectable Or Metastatic Squamous Cell Carcinoma Of The Anal Canal, Van K Morris, Suyu Liu, Kangyu Lin, Haifeng Zhu, Seema Prasad, Armeen Mahvash, Priya Bhosale, Baohua Sun, Edwin R Parra, Ignacio Wistuba, Arjun Peddireddy, James Yao, Julia Mendoza-Perez, Mark Knafl, Scott E Woodman, Cathy Eng, Daniel Halperin

Faculty, Staff and Student Publications

Purpose: Anti-PD-L1 antibodies are associated with responses in < 25% of patients with metastatic human papillomavirus-associated malignancies. VEGF signaling causes immune evasion and immune suppression within the tumor. We evaluated the anti-PD-L1 antibody atezolizumab and anti-VEGF antibody bevacizumab for patients with unresectable, advanced anal cancer.

Patients and methods: For this phase II study, participants with previously treated, immunotherapy-naïve anal cancer received atezolizumab (1,200 mg) and bevacizumab (15 mg/kg) intravenously every 21 days. Responses were evaluated every 9 weeks (RECIST version 1.1). The primary endpoint was the best radiographic response. Median survival was estimated by Kaplan-Meier and compared for selected biomarkers (including paired pre- and on-treatment biopsies) using a log-rank test.

Results: Among 20 participants, the overall response rate was 11% [95% confidence interval (CI): 1.2-32]. Median progression-free survival and overall survival were 4.1 months (95% CI, 2.6-not …

Maternal Cardiometabolic Risk Factors In Pregnancy And Offspring Blood Pressure At Age 2 To 18 Years., Zhongzheng Niu, Ako Adams Ako, Sarah Dee Geiger, Caitlin G. Howe, Wei Perng, Rachana Singh, Margaret R. Karagas, Amy J. Elliott, Andrea Cassidy-Bushrow, Carlos A. Camargo, Keia Sanderson, Cynthia T. Mcevoy, Emily Oken, Dana Dabelea, Tina V. Hartert, Brian S. Carter, Annemarie Stroustrup, Andrea Lampland, Thomas G. O'Connor, Semsa Gogcu, Mark L. Hudak, Lyndsey E. Shorey-Kendrick, Qi Zhao, Yu Ni, Jeffrey Vanwormer, Assiamira Ferrara, Monique Hedderson, Yeyi Zhu, Akram Alshawabkeh, Jose Cordero, Daphne Koinis-Mitchell, Susan Carnell, Carrie V. Breton, Theresa M. Bastain, Shohreh F. Farzan, Echo Cohort Consortium

Manuscripts, Articles, Book Chapters and Other Papers

IMPORTANCE: Higher blood pressure in early life may signal cardiovascular disease over the life course, but determinants of blood pressure in early life are poorly understood.

OBJECTIVE: To examine the association of maternal cardiometabolic risk factors during pregnancy with offspring blood pressure from age 2 to 18 years and explore whether the association is modified by offspring sex and race and ethnicity.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed data from the Environmental Influences on Child Health Outcomes program between January 1, 1994, and March 31, 2023. Three common maternal cardiometabolic risk factors during pregnancy were examined: prepregnancy obesity, …

Tumour Size Is Associated With Growth Rates Of >0.5 Cm/Year And Delayed Intervention In Small Renal Masses In Patients On Active Surveillance, Maximilian Pallauf, Michael Rezaee, Roy Elias, Tina Wlajnitz, Sean A Fletcher, Joseph Cheaib, Khalid Alkhatib, Peter Chang, Andrew A Wagner, James M Mckiernan, Mohamad E Allaf, Phillip M Pierorazio, Nirmish Singla

Faculty, Staff and Student Publications

Objective: To evaluate the association between tumour size and the growth rate (GR) of small renal masses (SRMs) in patients managed by active surveillance (AS).

Materials and methods: We queried the prospective, multi-institutional Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry for patients on AS with an imaging interval of ≥6 months, identifying 456 patients. We tracked tumour size over time; a GR >0.5 cm/year was defined as a GR event. We used multivariable recurrent events and time-to-event Cox regression modelling to evaluate the association between tumour size and GR events (primary outcome) and tumour size and delayed …

Bmal1-Hif2a Heterodimer Modulates Circadian Variations Of Myocardial Injury, Wei Ruan, Tao Li, In Hyuk Bang, Jaewoong Lee, Wankun Deng, Xinxin Ma, Cong Luo, Fang Du, Seung-Hee Yoo, Boyun Kim, Jiwen Li, Xiaoyi Yuan, Katherine Figarella, Yu A An, Yin-Ying Wang, Yafen Liang, Matthew Deberge, Dongze Zhang, Zhen Zhou, Yanyu Wang, Joshua M Gorham, Jonathan G Seidman, Christine E Seidman, Sary F Aranki, Ragini Nair, Lei Li, Jagat Narula, Zhongming Zhao, Alemayehu A Gorfe, Jochen D Muehlschlegel, Kuang-Lei Tsai, Holger K Eltzschig

Faculty, Staff and Student Publications

Acute myocardial infarction is a leading cause of morbidity and mortality worldwide1. Clinical studies have shown that the severity of cardiac injury after myocardial infarction exhibits a circadian pattern, with larger infarcts and poorer outcomes in patients experiencing morning-onset events2–7. However, the molecular mechanisms underlying these diurnal variations remain unclear. Here we show that the core circadian transcription factor BMAL17–11 regulates circadian-dependent myocardial injury by forming a transcriptionally active heterodimer with a non-canonical partner—hypoxia-inducible factor 2 alpha (HIF2A)12–16—in a diurnal manner. To substantiate this finding, we determined …

Longevity Humans Have Youthful Erythrocyte Function And Metabolic Signatures, Fang Yu, Changhan Chen, Wuping Liu, Zhixiang Zhao, Yuhua Fan, Zhenjiang Li, Weilun Huang, Tingting Xie, Cheng Luo, Zhouzhou Yao, Qi Guo, Zhiyu Yang, Juan Liu, Yujin Zhang, Rodney E Kellems, Jian Xia, Ji Li, Yang Xia

Faculty, Staff and Student Publications

Longevity individuals have lower susceptibility to chronic hypoxia, inflammation, oxidative stress, and aging-related diseases. It has long been speculated that "rejuvenation molecules" exist in their blood to promote extended lifespan. We unexpectedly discovered that longevity individuals exhibit erythrocyte oxygen release function similar to young individuals, whereas most elderly show reduced oxygen release capacity. Untargeted erythrocyte metabolomics profiling revealed that longevity individuals are characterized by youth-like metabolic reprogramming and these metabolites effectively differentiate the longevity from the elderly. Quantification analyses led us to identify multiple novel longevity-related metabolites within erythrocytes including adenosine, sphingosine-1-phosphate (S1P), and glutathione (GSH) related amino acids. Mechanistically, …