Digital Commons Network^™

Senescence Caused By Telomerase Inactivation In Myeloid, Mesenchymal, And Endothelial Cells Has Distinct Effects On Cancer Progression, Joseph Rupert, Zhanguo Gao, Yongmei Yu, Mikhail G Kolonin

Faculty, Staff and Student Publications

The effects of cell senescence in individual cell populations of the tumor microenvironment (TME) on cancer progression remain unclear. Here, we investigated the effects of cell senescence caused by inactivation of the catalytic subunit of telomerase (Tert) in distinct TME components. We generated genetic Tert knockout (KO) mice driven by the LysM promoter in myeloid cells, by the Pdgfra or Pdgfrb promoter in mesenchymal cells, and by the Tie2e promoter in endothelial cells. We compared the effect of the Tert KOs in syngeneic models of orthotopically grafted E0771 breast adenocarcinoma, RM1 prostate adenocarcinoma, and KPC pancreatic adenocarcinoma. Tumors in LysM-Tert …

Omitting Regional Nodal Irradiation After Response To Neoadjuvant Chemotherapy, Eleftherios P Mamounas, Hanna Bandos, Julia R White, Thomas B Julian, Atif J Khan, Simona F Shaitelman, Mylin A Torres, Frank A Vicini, Patricia A Ganz, Susan A Mccloskey, Peter C Lucas, Nilendu Gupta, X Allen Li, Beryl Mccormick, Benjamin Smith, Rahul D Tendulkar, Vivek S Kavadi, Koji Matsumoto, Samantha Andrews Seaward, William J Irvin, Jolinta Y Lin, Robert W Mutter, Thierry M Muanza, Jannifer Stromberg, Reshma Jagsi, Anna C Weiss, Walter J Curran, Norman Wolmark

Faculty, Staff and Student Publications

Background: The benefit of regional nodal irradiation in the treatment of breast cancer is well established for patients with pathologically positive axillary nodes, but whether it is also beneficial for patients whose nodes become pathologically tumor free (ypN0) after neoadjuvant chemotherapy remains unclear.

Methods: We evaluated whether regional nodal irradiation improves outcomes in patients with biopsy-proven, node-positive breast cancer who reach ypN0 status after neoadjuvant chemotherapy. Patients with breast cancer with a clinical stage of T1 to T3 (tumor size, ≤2 cm to >5 cm), N1, and M0 (indicating spread to one to three axillary lymph nodes but no distant …

Variants In Bsn, Encoding The Presynaptic Protein Bassoon, Result In A Distinct Neurodevelopmental Disorder With A Broad Phenotypic Range, Stacy G Guzman, Sarah M Ruggiero, Shiva Ganesan, Colin A Ellis, Alicia G Harrison, Katie R Sullivan, Zornitza Stark, Natasha J Brown, Sajel L Kana, Anabelle Tuttle, Jair Tenorio, Pablo Lapunzina, Julián Nevado, Marie T Mcdonald, Courtney Jensen, Patricia G Wheeler, Lila Stange, Jennifer Morrison, Boris Keren, Solveig Heide, Meg W Keating, Kameryn M Butler, Mike A Lyons, Shailly Jain, Mehdi Yeganeh, Michelle L Thompson, Molly Schroeder, Hoanh Nguyen, Jorge Granadillo, Kari M Johnston, Chaya N Murali, Katie Bosanko, T Andrew Burrow, Chop Birth Defects Biorepository, Penn Medicine Biobank, Syreeta Morgan, Deborah J Watson, Hakon Hakonarson, Ingo Helbig

Faculty, Staff and Students Publications

Disease-causing variants in synaptic function genes are a common cause of neurodevelopmental disorders (NDDs) and epilepsy. Here, we describe 14 individuals with de novo disruptive variants in BSN, which encodes the presynaptic protein Bassoon. To expand the phenotypic spectrum, we identified 15 additional individuals with protein-truncating variants (PTVs) from large biobanks. Clinical features were standardized using the Human Phenotype Ontology (HPO) across all 29 individuals, which revealed common clinical characteristics including epilepsy (13/29, 45%), febrile seizures (7/29, 25%), generalized tonic-clonic seizures (5/29, 17%), and focal-onset seizures (3/29, 10%). Behavioral phenotypes were present in almost half of all individuals (14/29, 48%), …

Loss Of Function Of The Zinc Finger Homeobox 4 Gene, Zfhx4, Underlies A Neurodevelopmental Disorder, María Del Rocío Pérez Baca, María Palomares-Bralo, Michiel Vanhooydonck, Lisa Hamerlinck, Eva D'Haene, Sebastian Leimbacher, Eva Z Jacobs, Laurenz De Cock, Erika D'Haenens, Annelies Dheedene, Zoë Malfait, Lies Vantomme, Ananilia Silva, Kathleen Rooney, Xiaonan Zhao, Amir Hossein Saeidian, Nichole Marie Owen, Fernando Santos-Simarro, Roser Lleuger-Pujol, Sixto García-Miñaúr, Itsaso Losantos-García, Björn Menten, Gaia Gestri, Nicola Ragge, Bekim Sadikovic, Elke Bogaert, Kris Vleminckx, Thomas Naert, Delfien Syx, Bert Callewaert, Sarah Vergult

Faculty, Staff and Students Publications

8q21.11 microdeletions involving ZFHX4 have previously been associated with a syndromic form of intellectual disability, hypotonia, unstable gait, and hearing loss. We report on 63 individuals-57 probands and 6 affected family members-with protein-truncating variants (n = 41), (micro)deletions (n = 21), or an inversion (n = 1) affecting ZFHX4. Probands display variable developmental delay and intellectual disability, distinctive facial characteristics, morphological abnormalities of the central nervous system, behavioral alterations, short stature, hypotonia, and occasionally cleft palate and anterior segment dysgenesis. The phenotypes associated with 8q21.11 microdeletions and ZFHX4 intragenic loss-of-function (LoF) variants largely overlap, although leukocyte-derived DNA shows a mild …

Cross-Sectional Analysis Of Wound-Associated Soluble Factors In Early, Established, And Chronic Wounds Of Recessive Dystrophic Epidermolysis Bullosa Patients, Vitali Alexeev, Leonie Huitema, Taylor Phillips, Paras Patel, Mauricio Garza, Franziska Ringpfeil, Julio Salas-Alanis, Olga Igoucheva

Department of Dermatology and Cutaneous Biology Faculty Papers

BACKGROUND: Poorly healing wounds represent the primary health-related burden for hereditary recessive dystrophic epidermolysis bullosa (RDEB) patients. Contribution of wound-associated soluble constituents to wound progression remains not well defined.

OBJECTIVE: To conduct cross-sectional analysis of cytokine, chemokine, and growth factor in exudates from RDEB wounds and define changes associated with wound progression.

METHODS: Concentrations of selected cytokines, chemokines, and growth factors were evaluated by multiplex ELISA in eight blister fluids and 66 exudates from early, established, and chronic RDEB and five chronic venous ulcers (VU). A cross-sectional analysis was performed.

RESULTS: Our data demonstrated that proinflammatory CXCL8 and IL-1β tend …

177lu-Labeled Antibody-Drug Conjugate: A Dual-Mechanistic Treatment Modality In Solid Tumors, Aiko Yamaguchi, Chisato M Yamazaki, Yasuaki Anami, Summer Y Y Ha, Wei Xiong, Robert T Ta, Ningyan Zhang, H Charles Manning, Zhiqiang An, Kyoji Tsuchikama

The Brown Foundation: Institute of Molecular Medicine

To explore the potential of site-selectively radiolabeled antibody-drug conjugates (ADC) against solid tumors, we constructed and evaluated radiolabeled ADCs equipped with lutetium-177 (177Lu) and a membrane-permeable antimitotic agent. Site-selective 177Lu-labeled ADCs [anti-trophoblast cell-surface antigen 2 (TROP2) 177Lu-DTPA ADCs or anti-HER2 177Lu-DO3A ADCs], a 177Lu-labeled homogeneous radioimmunoconjugate (homogeneous RIC), and 177Lu-labeled conventional RIC (heterogeneous RIC) were constructed. We confirmed that 177Lu-labeled ADCs and the homogeneous RIC were obtained with high homogeneity and defined chelator/payload-to-antibody ratios. Next, we performed biodistribution studies and treatment efficacy studies in xenograft mouse models bearing orthotopic breast tumors. Compared with the heterogeneous RIC, the 177Lu-DTPA TROP2 ADC …

Mesenchymal Stem Cells And Fibroblasts Contribute To Microvascular Proliferation In Glioblastoma And Are Correlated With Immunosuppression And Poor Outcome, Candice C Poon, Shelley M Herbrich, Yulong Chen, Anwar Hossain, Gregory N Fuller, Sonali Jindal, Sreyashi Basu, Daniel Ledbetter, Marc Macaluso, Lynnette M Phillips, Joy Gumin, Zhong He, Brittany C Parker Kerrigan, Sanjay K Singh, Pratishtha Singh, Mohammed Fayyad Zaman, Derek Ng Tang, Sangeeta Goswami, Frederick F Lang, Padmanee Sharma

Faculty, Staff and Student Publications

Microvascular proliferation (MVP) is a disease-defining hallmark of glioblastoma and other World Health Organization grade 4 gliomas. MVP also serves as a poor prognostic marker in various solid tumors. Despite its clinical significance, the mechanisms and biological consequences of MVP are controversial and remain unclear. In this study, we performed single-cell RNA sequencing on paired CD45-CD105+ vascular/perivascular stromal cells (PVSC) and CD45+CD105± immune cells from 16 primary glioma patient samples, both with and without MVP. This analysis revealed the presence of developmentally related mesenchymal stem cells alongside cancer-associated fibroblasts, pericytes, fibromyocytes, and smooth muscle cells within the CD45-CD105+ compartment. RNA …

Prediction Of Methotrexate Neurotoxicity Using Clinical, Sociodemographic, And Area-Based Information In Children With Acute Lymphoblastic Leukemia, Rachel D Harris, Olga A Taylor, Maria Monica Gramatges, Amy E Hughes, Mark Zobeck, Sandi Pruitt, M Brooke Bernhardt, Ashley Chavana, Van Huynh, Kathleen Ludwig, Laura Klesse, Kenneth Heym, Timothy Griffin, Rodrigo Erana, Juan Carlos Bernini, Ashley Choi, Yuu Ohno, Melissa A Richard, Alanna C Morrison, Han Chen, Bing Yu, Philip J Lupo, Karen R Rabin, Michael E Scheurer, Austin L Brown

Center for Medical Ethics and Health Policy Staff Publications

Background: Methotrexate is a critical component of pediatric acute lymphoblastic leukemia (ALL) therapy that can result in neurotoxicity which has been associated with an increased risk of relapse. We leveraged machine learning to develop a neurotoxicity risk prediction model in a diverse cohort of children with ALL.

Methods: We included children (age 2-20 years) diagnosed with ALL (2005-2019) and treated in Texas without pre-existing neurologic disease. Clinical information was obtained by medical record review. Neurotoxicity occurring post-induction and prior to maintenance therapy was defined as neurologic episodes occurring within 21 days of methotrexate. Suspected cases were independently confirmed by 2 …

Linking Dna Methylation In Brain Regions To Alzheimer’S Disease Risk: A Mendelian Randomization Study, Hua Zhong, Jingjing Zhu, Shuai Liu, Dan Zhou, Quan Long, Chong Wu, Bingxin Zhao, Chao Cheng, Yaohua Yang, Qing Wu, Yong Wu, Changwei Li, Zhaoming Wang, Jianyong Wu, Xingyi Guo, Degui Zhi, Youping Deng, Lang Wu

Faculty, Staff and Students Publications

Aim: DNA methylation in brain regions represents a potential mechanism linking genetic variation to Alzheimer's disease (ad) risk, yet most studies have focused on blood-derived methylation markers. In this study, we conducted a systematic Mendelian randomization (MR) study to evaluate associations between predicted brain region-specific DNA methylation levels and ad risk, using methylation quantitative trait loci (mQTL) as genetic instruments.

Methods: We analyzed mQTLs from five human brain regions: cerebellum (CRBLM), frontal cortex (FCTX), causal pons (PONS), and temporal cortex (TCTX) from 600 individuals in Gibbs et al's study, as well as mQTLs from dorsolateral prefrontal cortex (DLPFC) of 543 …

Comparison Of Open And Laparo-Endoscopic Repair Techniques For Patients With Bilateral Inguinal Hernias, Divyansh Agarwal, Tina Bharani, Nora Fullington, Lauren Ott, Kortney Hodgson, Daelyn Mcclain, Kaela Blake, Michael Reinhorn

Department of Surgery Faculty Papers

INTRODUCTION: For primary bilateral inguinal hernias, international guidelines favor a laparoscopic posterior mesh repair due to relatively lower risk of acute and chronic pain, faster recovery, and favorable biomechanical properties compared to open anterior approaches (Lichtenstein, plug and patch, etc.). However, studies comparing open mesh-based bilateral inguinal hernia repairs to bilateral laparoscopic and robotic mesh-based approaches are limited. The Abdominal Core Health Quality Collaborative (ACHQC) registry includes longitudinal data on bilateral inguinal hernia repairs performed via open as well as laparo-endoscopic approaches. We hypothesize that outcomes for bilateral inguinal hernia repair are similar between open and laparo-endoscopic approaches in the …

Lipoprotein(A) And Heart Failure Among Black And White Participants In Atherosclerosis Risk In Communities Study, Framingham Offspring Study, And Multi-Ethnic Study Of Atherosclerosis: The Pooling Project, Sarah Nomura, Weihua Guan, Yixin Zhang, Geoffrey H Tison, Hiroaki Ikezaki, Margaret R Diffenderfer, Ching-Ti Liu, Ron C Hoogeveen, Christie M Ballantyne, Ernst J Schaefer, Michael Y Tsai

Faculty, Staff and Students Publications

Background: This study investigated Lp(a) (lipoprotein(a)) levels with heart failure (HF) incidence overall and ejection fraction (EF) subtypes among Black and White participants in a pooled analysis of MESA (Multi-Ethnic Study of Atherosclerosis), FOS (Framingham Offspring Study), and ARIC (Atherosclerosis Risk in Communities Study).

Methods: This study was conducted among 16 771 White and Black participants in ARIC (N=10 347), MESA (N=4150), and FOS (N=2274). Baseline was time of Lp(a) measurement (ARIC Visit 4: 1996-1998; MESA Visit 1: 2000-2002; FOS Cycle 6: 1995-1998). HF with reduced EF (HFrEF) was defined as EF < 50% and ≥50% as HF with preserved EF (HFpEF). Cox proportional hazards regression was used to evaluate associations between Lp(a) (log-transformed continuous, dichotomized at ≥30 mg/dL and ≥50 mg/dL, and quartiles) and HF (overall, HFpEF, HFrEF) in the overall population and stratified by race. Analyses were replicated excluding prior history of myocardial infarction.

Results: There were 2759 HF cases (HFpEF N=859; …

Maternal Loss Of Mouse Nlrp2 Alters The Transcriptome And Dna Methylome In Gv Oocytes And Impairs Zygotic Genome Activation In Embryos, Zahra Anvar, Michael D Jochum, Imen Chakchouk, Momal Sharif, Hannah Demond, Alvin K To, Daniel C Kraushaar, Ying-Wooi Wan, Michael C Mari, Simon Andrews, Gavin Kelsey, Ignatia B Van Den Veyver

Center for Medical Ethics and Health Policy Staff Publications

Background: NLRP2 is a subcortical maternal complex (SCMC) protein of mammalian oocytes and preimplantation embryos. SCMC proteins are encoded by maternal effect genes and play a pivotal role in the maternal-to-zygotic transition (MZT), early embryogenesis, and epigenetic (re)programming. Maternal inactivation of genes encoding SCMC proteins has been linked to infertility and subfertility in mice and humans, but the underlying molecular mechanisms for the diverse functions of SCMC proteins, and specifically the role of NLRP2, are incompletely understood.

Results: We profiled the DNA methylome of pre-ovulatory germinal-vesicle (GV) oocytes from Nlrp2-null, heterozygous (Het), and wild-type (WT) female mice and assessed the …

A Novel Cardiomyopathy Phenotype Linked To A Chd7 Missense Variant, In Young Park, Chih-Wei Hsu, Karim Bouazoune, Christina E Espindola, Madeline Hannah Mclaughlin Armond, Cristian Coarfa, Sandra L Grimm, James F Martin, Donna M Martin, Cheryl Lyn Walker

Center for Medical Ethics and Health Policy Staff Publications

Loss of function in the chromatin remodeler CHD7 causes CHARGE syndrome, characterized by variable penetrance and diverse abnormalities. However, establishing genotype-phenotype correlations has been challenging, as most CHD7 inactivating mutations are null alleles. Through CHD7 missense variant analysis at potential phosphorylation sites, we identified T730 (T720 in mice) as a critical residue associated with pathogenesis. Using a CHD7 T730 missense variant (Chd7T720A) and a frameshift null allele (Chd7fs) in a mouse model, we found that Chd7fs/fs mice were non-viable, while Chd7fs/+ mice exhibited haploinsufficiency-related circling behavior. Notably, Chd7fs/T720A mice died before postnatal …

Correlations Within And Between Highly Multiplexed Proteomic Assays Of Human Plasma, Mary R Rooney, Jingsha Chen, Christie M Ballantyne, Ron C Hoogeveen, Eric Boerwinkle, Bing Yu, Keenan A Walker, Pascal Schlosser, Elizabeth Selvin, Nilanjan Chatterjee, David Couper, Morgan E Grams, Josef Coresh

Faculty, Staff and Students Publications

Introduction: The number of assays on proteomic platforms has grown rapidly. The leading platforms, SomaScan and Olink, have strengths and limitations. Comparisons of precision on the latest platforms-SomaScan 11k and Olink Explore HT-have not yet been established.

Methods: Among 102 participants in the Atherosclerosis Risk in Communities Study (mean age 74 years, 53% women, 47% Black), we used split plasma samples to measure platform precision. CV and Spearman correlations were calculated for each assay. Cross-platform agreement was assessed for overlapping proteins.

Results: SomaScan 11k demonstrated a median correlation of 0.85 for the 10 778 assays and a median CV of …

Three Dimensional Multiscalar Neurovascular Nephron Connectivity Map Of The Human Kidney Across The Lifespan, Liam Mclaughlin, Bo Zhang, Siddharth Sharma, Amanda L Knoten, Madhurima Kaushal, Jeffrey M Purkerson, Heidie L Huyck, Gloria S Pryhuber, Joseph P Gaut, Sanjay Jain

2020-Current year OA Pubs

The human kidney maintains homeostasis through a complex network of up to a million nephrons, its fundamental tissue units. Using innovative tissue processing and light sheet fluorescence microscopy, we mapped the 3D neurovascular connectivity of nephrons to understand how their structural organization enables coordinated functions like filtration, absorption, and blood pressure regulation. Our analysis revealed developmental changes in glomerular orientation, density, volume, and innervation from birth through aging. We discovered an extensive nerve network connecting different nephron segments and organizing glomeruli into distinct communities. These communities are linked through "mother glomeruli" that serve as control centers, creating a repeating pattern …

A Comprehensive, Multi-Center, Immunogenomic Analysis Of Melanoma Brain Metastases, Lucy Boyce Kennedy, Amanda E D Van Swearingen, Marissa R Lee, Layne W Rogers, Alexander B Sibley, Jeff Sheng, Dadong Zhang, Xiaodi Qin, Eric S Lipp, Swaminathan Kumar, Aron Joon, Pixu Shi, Michael A Davies, Kouros Owzar, Carey K Anders, April K S Salama

Faculty, Staff and Student Publications

Background: Melanoma brain metastases (MBM) have a unique molecular profile compared to extracranial metastases (ECM). Description of the biological features and clinical outcomes of MBM will facilitate the design of rational therapies.

Methods: We examined the mutational landscape and gene expression profiles of MBM (74 patients) and ECM (34 patients) in paired patient samples from a previously published dataset with whole-exome sequencing (WES) and RNA sequencing (RNAseq) data from MD Anderson Cancer Center (MDACC). We also present findings from MBM from a new cohort of 14 patients from Duke University to strengthen investigation of somatic mutations and gene expression profiles. …

Social, Microbial, And Immune Factors Linking Bacterial Vaginosis And Infectious Diseases, Nicole M. Gilbert, Luis A. Ramirez Hernandez, Daniela Berman, Sydney Morrill, Pascal Gagneux, Amanda L. Lewis

2020-Current year OA Pubs

Bacterial vaginosis (BV) is a polymicrobial condition of the vaginal microbiota associated with a variety of sexually transmitted infections, infections of maternal and fetal tissues during pregnancy, and even some infections outside of the reproductive tract, including the urinary tract and mouth. BV has also been associated with conditions in which the body generates prominent inflammatory reactions to microbes, including infections of the cervix and other upper genital tract tissues. For reasons still not understood, BV is a highly recurrent and often difficult-to-treat condition, complicating attempts to prevent these associated infections. An additional layer of complexity arises from the increasing …

Iron Deficiency Without Anemia And Reduced Basal Ganglia Iron Content In Youths, Dimitri Fiani, Joo-Won Kim, Mianzhi Hu, Ramiro Salas, Sarah Heilbronner, Jacquelyn Powers, Muhammad Haque, Stephanie Dinh, Xiaofan Huang, Darrell Worthy, Sridevi Devaraj, Junqian Xu, Chadi Calarge

Faculty, Staff and Students Publications

Importance: Although brain iron is necessary for neurogenesis, myelination, and neurotransmitter synthesis, iron deficiency (ID) is defined solely based on hematological outcomes.

Objective: To examine the association of ID without anemia with basal ganglia (BG) iron content and its structural and functional sequelae in adolescents.

Design, setting, and participants: This cross-sectional study enrolled participants using the electronic medical record system from a large network of pediatrics clinics between December 2020 and April 2024. Otherwise healthy, unmedicated participants aged 10 to 17 years with a depressive or anxiety disorder or with no psychopathology were consecutively enrolled. Anemia and acute inflammation led …

Intraosseous Vs Intravenous Access For Epinephrine In Pediatric Out-Of-Hospital Cardiac Arrest, Masashi Okubo, Sho Komukai, Junichi Izawa, Sunhee Chung, Cameron Dezfulian, Francis X Guyette, Joshua R Lupton, Christian Martin-Gill, Sylvia Owusu-Ansah, Sriram Ramgopal, Clifton W Callaway

Faculty, Staff and Students Publications

Importance: While epinephrine is commonly administered in children with out-of-hospital cardiac arrest (OHCA) via an intraosseous (IO) or intravenous (IV) route, the optimal route of epinephrine delivery is unclear.

Objective: To evaluate the association between the route of epinephrine administration (IO or IV) and patient outcomes after pediatric OHCA.

Design, setting, and participants: Retrospective cohort study of pediatric patients (aged < 18 years) with nontraumatic OHCA treated by emergency medical services who received prehospital epinephrine either via an IO or IV route. Patients were included in the Resuscitation Outcomes Consortium Epidemiologic Registry, a prospective OHCA registry at 10 sites in the US and Canada from April 2011 to June 2015. Data analysis was performed from May 2024 to April 2025.

Exposure: Epinephrine administration route: IO or IV route.

Main outcomes and measures: The primary outcome was survival to hospital discharge. The secondary outcome was return of spontaneous circulation (ROSC) before hospital arrival. Propensity scores were calculated and inverse probability of …

Identification Of A Seasonal Influenza Vaccine-Induced Broadly Protective Neuraminidase Antibody, Anders Madsen, Nisreen M A Okba, Tossapol Pholcharee, Hanover C Matz, Huibin Lv, Maria Ibanez Trullen, Julian Q Zhou, Jackson S Turner, Aaron J Schmitz, Fangjie Han, Stephen C Horvath, Sameer Kumar Malladi, Florian Krammer, Nicholas C Wu, Ali H Ellebedy

2020-Current year OA Pubs

Seasonal influenza viruses cause significant global illness and death annually, and the potential spillover of avian H5N1 poses a serious pandemic threat. Traditional influenza vaccines target the variable hemagglutinin (HA) protein, necessitating annual vaccine updates, while the slower-evolving neuraminidase (NA) presents a promising target for broader protection. We investigated the breadth of anti-NA B cell responses to seasonal influenza vaccination in humans. We screened plasmablast-derived monoclonal antibodies (mAbs) from three donors, identifying 11 clonally distinct NA mAbs from 268 vaccine-specific mAbs. Among these, mAb-297 showed exceptionally broad NA inhibition, effectively protecting mice against lethal doses of influenza A and B …

Phenotypes Of Atopic Dermatitis And Development Of Allergic Diseases, Alexandra R Sitarik, Katherine Rivera-Spoljaric, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Atopic dermatitis (AD) is the most common inflammatory disease in childhood, and children with AD are more likely to develop other allergic diseases, including food allergy, allergic rhinitis, and asthma.

OBJECTIVE: To determine the phenotypes of AD expression across 12 US birth cohorts and identify factors associated with phenotype and development of allergic diseases.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study compiled longitudinal data from 12 observational US birth cohorts across decades (children born from April 1980 to June 2019) in the Environmental Influences on Child Health Outcomes (ECHO) Children's Respiratory and Environmental Workgroup with follow-up to September 2022. …

Placental And Cord Blood Dna Methylation Changes Associated With Gestational Diabetes Mellitus In A Marginalized Population: The Untold Role Of Saturated Fats., Fatima Ahmad, Sidra Aftab Uzair, Arun P Lakshmanan, Shaikha Alabduljabbar, Salma H Ahmed, Basirudeen Syed Ahamed Kabeer, Alexandra Katharina Marr, Tomoshige Kino, Tobias Brummaier, Rose Mcgready, François Nosten, Damien Chaussabel, Souhaila Al Khodor, Annalisa Terranegra

Faculty Research 2025

The role of DNA methylation (DNAm) and its modulation by dietary factors in gestational diabetes mellitus (GDM) remains underexplored, particularly in marginalized populations. This study investigates DNAm alterations in GDM-exposed cord blood and placenta and their association with maternal dietary quality and single nutrient intake in a low-income population from the Myanmar-Thailand border. A matched case-control design (GDM: n = 38, controls: n = 34) was selected from a Myanmar-Thailand pregnancy cohort. Dietary intake was assessed via 24-h recalls and analyzed using Nutritionist Pro, with dietary quality evaluated by the healthy eating index (HEI). DNAm was profiled in 72 cord …

Colorectal Adenosquamous Carcinoma: Clinicopathologic Analysis Of Two Large Cohorts And Literature Review Confirm Poor Prognosis And Reveal Prognostic Aspects, Raul S Gonzalez, Rachel K Horton, Xuchen Zhang, Rondell P Graham, Teri A Longacre, Anupamjit Mehrotra, Daniela S Allende, Kelsey E Mchugh, Jinru Shia, Maria Westerhoff, Amitabh Srivastava, Wei Chen, Jennifer Vazzano, Paul E Swanson, Deyali Chatterjee, Hassam Cheema, Changqing Ma, Rifat Mannan, Runjan Chetty, Klaudia M Nowak, Stefano Serra, Diana Agostini-Vulaj, Rossana Kazemimood, Patrick Henn, Sanjay Kakar, Won-Tak Choi, Oyedele Adeyi, Sarah M Jenkins, Iris D Nagtegaal

Faculty, Staff and Student Publications

Aims: We compiled two cohorts of colorectal adenosquamous carcinoma (ASC) to describe its histologic and molecular aspects using modern parameters to compare them with literature reports using meta-analysis of cohorts and individual case series.

Methods and results: We identified 53 colorectal ASC from 19 North American academic medical centres, in addition to national database reports on 94 Dutch cases. We analysed available clinical, histologic, and immunohistochemical features and patient outcome. ASC comprised 0.02% of colorectal cancers in the Dutch database. The median cohort patient ages at resection were 65 and 69 years (North American and Dutch cohorts, respectively), with a …

Diabetes-Related Distress Over Time And Its Associations With Glucose Levels In School-Aged Children., Susana R. Patton, Nicole Kahhan, Amy Milkes, Ryan J. Mcdonough, Matthew Benson, Mark A. Clements, Jessica S. Pierce

Manuscripts, Articles, Book Chapters and Other Papers

INTRODUCTION: In a cohort of families of school-age children (8-12.99 years old) with type 1 diabetes, we examined the stability of parent and child diabetes-related distress (DRD) over 6 months and the associations between parent and child DRD and child glycated hemoglobin (HbA1c) over time.

RESEARCH DESIGN AND METHODS: We recruited families from two large pediatric hospital systems in the USA and used validated measures of parent (Parent Problem Areas in Diabetes-Child, PPAID-C) and child (Problem Areas in Diabetes-Child, PAID-C) DRD and children's HbA1c. We collected data at baseline and 6 months. We calculated minimal clinically important differences in PPAID-C …

Changes In The Fxr-Cistrome And Alterations In Bile Acid Physiology In Wilson Disease, Clavia Ruth Wooton-Kee, Hari K Yalamanchili, Islam Mohamed, Manal Hassan, Kenneth D R Setchell, Monica Narvaez Rivas, Ayse K Coskun, Vasanta Putluri, Nagireddy Putluri, Prasun Jalal, Michael L Schilsky, David D Moore

Children’s Nutrition Research Center Staff Publications

Background: Wilson disease (WD) is an autosomal recessive disorder that results in excessive hepatic copper, causing hepatic steatosis, inflammation, fibrosis, cirrhosis, and liver failure. Previous studies have revealed dysregulation of many farnesoid X receptor (FXR) metabolic target genes in WD, including the bile salt exporter pump, the major determinant of bile flow.

Methods: We tested the hypothesis that the FXR-cistrome is decreased in Atp7b-/- mice in accord with dysregulated bile acid homeostasis.

Results: FXR binding within Atp7b-/- mouse livers displayed surprising complexity: FXR binding was increased in distal intergenic regions but decreased in promoter regions in Atp7b-/- versus wild-type mice. …

Large-Scale Plasma Proteomic Profiling Unveils Diagnostic Biomarkers And Pathways For Alzheimer’S Disease, Gyujin Heo, Ying Xu, Erming Wang, Muhammad Ali, Hamilton Se-Hwee Oh, Patricia Moran-Losada, Federica Anastasi, Armand González Escalante, Raquel Puerta, Soomin Song, Jigyasha Timsina, Menghan Liu, Daniel Western, Katherine Gong, Yike Chen, Pat Kohlfeld, Allison Flynn, Alvin G Thomas, Joseph Lowery, John C Morris, David M Holtzman, Joel S Perlmutter, Suzanne E Schindler, Natalia Vilor-Tejedor, Marc Suárez-Calvet, Pablo García-González, Marta Marquié, Maria Victoria Fernández, Mercè Boada, Amanda Cano, Agustín Ruiz, Bin Zhang, David A Bennett, Tammie Benzinger, Tony Wyss-Coray, Laura Ibanez, Yun Ju Sung, Carlos Cruchaga

Faculty, Staff and Student Publications

Proteomic studies have been instrumental in identifying brain, cerebrospinal fluid and plasma proteins associated with Alzheimer's disease (AD). Here, we comprehensively examined 6,905 aptamers corresponding to 6,106 unique proteins in plasma in more than 3,300 well-characterized individuals to identify new proteins, pathways and predictive models for AD. We identified 416 proteins (294 new) associated with clinical AD status and validated the findings in two external datasets representing more than 7,000 samples. AD-related proteins reflected blood-brain barrier disruption and other processes implicated in AD, such as lipid dysregulation or immune responses. A machine learning model was used to identify a set …

The Association Of Vision And Hearing Impairment On Cognitive Function And Loneliness: Evidence From The Mexican Health And Aging Study, Kimberly Hreha, Rafael Samper-Ternent, Heather E Whitson, L P Downer, Jessica S West, Brian Downer

Faculty, Staff and Student Publications

Objectives: We investigated whether self-reported vision and hearing were associated with cognitive function and loneliness among Mexican adults aged 50 and older.

Methods: Mexican Health and Aging Study data. Vision/hearing status was self-reported (excellent-very good, good, fair-poor). Cognition was measured using nine tasks. Loneliness was measured using the UCLA Loneliness Scale. Analyses controlled for demographic and health characteristics.

Results: Among 12,353 participants (mean age = 67, 58% female), poor vision, but not hearing, was associated with lower global cognition (β = -0.03, p < .05). Poor vision (OR = 1.57, 95% CI = 1.30-1.91) and hearing (OR = 1.35, 95% CI = 1.14-1.61) were associated with higher odds of being lonely after adjusting for demographics and comorbidities, but not when adjusting for limitations in daily activities and depressive symptoms.

Discussion: Poor vision is a potentially modifiable risk factor for lower cognition and loneliness among Mexican adults. …

Validity And Reliability Of The Tampa Scale For Kinesiophobia For Adolescents With Heart Disease., David A. White, William R. Black, Emily Cramer, Lindsey Malloy-Walton, Mollie Walton, Laura Martis, Brandy Enneking, Kelli M. Teson, Jessica S. Watson, Jami Gross-Toalson

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: To assess the validity and reliability of a newly adapted Tampa Scale for KP for adolescents with HD (TSK-Heart-A).

METHODS: The TSK-Heart-A survey consists of 17 Likert scale items, producing a summary score (SS) ranging from 17 (low KP) to 68 (high KP). Following content and face validity, adolescents (age 12-18 yr) with arrhythmia disorders or Fontan palliation were recruited. The PROMIS pediatric anxiety and depression short forms, Pediatric Quality of Life Inventory (PedsQL) generic core and cardiac module, and a PA questionnaire for adolescents (PAQ-A) were used for criterion validity. The TSK-Heart-A was completed twice (20.4 ± 6.3 …

Nf2 Loss-Of-Function And Hypoxia Drive Radiation Resistance In Grade 2 Meningiomas, Bhuvic Patel, Sangami Pugazenthi, Collin W English, Vijay Nitturi, Shree S Pari, Tatenda Mahlokozera, William A Leidig, Hsiang-Chih Lu, Alicia Yang, Kaleigh Roberts, Patrick Desouza, Kyle P Mcgeehan, Diane D Mao, Namita Sinha, Joseph E Ippolito, Sonika Dahiya, Allegra Petti, Hiroko Yano, Tiemo J Klisch, Akdes S Harmanci, Akash J Patel, Albert H Kim

Duncan NRI Faculty and Staff Publications

Background: World Health Organization Grade 2 meningiomas (G2Ms) often recur and resist therapies. Grade 2 meningiomas with histopathological necrosis have been associated with worse local control (LC) after radiation therapy, but the drivers and biomarkers of radiation resistance in G2Ms remain unknown.

Methods: We performed genetic sequencing and histopathological analysis of 113 G2Ms and investigated the role of genetic and microenvironmental factors on clonogenic survival after ionizing radiation. We performed transcriptional profiling of our in vitro model and 18 human G2M tumors by bulk RNA sequencing as well as 8 G2Ms by single nuclei RNA sequencing.

Results: NF2 loss-of-function (LOF) …

Psychometric Properties Of The Spanish Yale-Brown Obsessive-Compulsive Scale - Second Edition, Eric A Storch, Jessica Sc Cheng, Miranda Higham, Josselyn S Muñoz, Vanessa Zavala Cruz, Dayan Berrones, Diana P Obando, Jacey L Anderberg, Renee M Frederick, Vissente Tapia-Cuevas, Macarena Churruca Muñoz, Constanza Uribe Villar, Pablo R Moya, Marcos E Ochoa-Panaifo, Mayra C Martinez Mallen, Andrew D Wiese, Caitlin M Pinciotti, Melisa N Sagarnaga, Joseph F Mcguire, Ogechi C Onyeka, María B Moyano, Latin American Trans-Ancestry Initiative For Ocd Genomics (Latino), Brazilian Obsessive-Compulsive Spectrum Disorder Working Group (Gttoc), Wayne K Goodman, James J Crowley

Faculty, Staff and Students Publications

The Yale-Brown Obsessive-Compulsive Scale, Second Edition (Y-BOCS-II) is an evidence-based clinician-rated measure for assessing the presence and severity of obsessive-compulsive symptoms. The Spanish version of the Y-BOCS-II has not yet been validated. The present study examines the psychometric properties of the Spanish Y-BOCS-II (Spanish-Y-BOCS-II) in adults with obsessive-compulsive disorder (OCD) who are of Hispanic/Latino ancestry. The Spanish-Y-BOCS-II was administered to 1805 adults with OCD. Participants also completed a battery of measures assessing OCD, depression, and anxiety symptoms. The internal consistency for the Symptom Checklist (Kuder-Richardson-20=0.92), Obsession Severity (α=0.87), Compulsion Severity (α=0.86), and Total Severity (α=0.92) were high. The inter-rater reliability …