Medicine and Health Sciences Commons^™

Key Variants Via The Alzheimer's Disease Sequencing Project Whole Genome Sequence Data, Yanbing Wang, Chloé Sarnowski, Honghuang Lin, Achilleas N Pitsillides, Nancy L Heard-Costa, Seung Hoan Choi, Dongyu Wang, Joshua C Bis, Elizabeth E Blue, Eric Boerwinkle, Philip L De Jager, Myriam Fornage, Ellen M Wijsman, Sudha Seshadri, Josée Dupuis, Gina M Peloso, Anita L Destefano

Journal Articles

INTRODUCTION: Genome-wide association studies (GWAS) have identified loci associated with Alzheimer's disease (AD) but did not identify specific causal genes or variants within those loci. Analysis of whole genome sequence (WGS) data, which interrogates the entire genome and captures rare variations, may identify causal variants within GWAS loci.

METHODS: We performed single common variant association analysis and rare variant aggregate analyses in the pooled population (N cases = 2184, N controls = 2383) and targeted analyses in subpopulations using WGS data from the Alzheimer's Disease Sequencing Project (ADSP). The analyses were restricted to variants within 100 kb of 83 previously …

Decorin Suppresses Tumor Lymphangiogenesis: A Mechanism To Curtail Cancer Progression, Dipon K. Mondal, Christopher Xie, Gabriel J. Pascal, Simone Buraschi, Renato V. Iozzo

Kimmel Cancer Center Faculty Papers

The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a prosurvival program and to sustain a proangiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, …

An Approach To Identify Gene-Environment Interactions And Reveal New Biological Insight In Complex Traits, Xiaofeng Zhu, Yihe Yang, Noah Lorincz-Comi, Gen Li, Amy R Bentley, Paul S De Vries, Michael Brown, Alanna C Morrison, Charles N Rotimi, W James Gauderman, Dabeeru C Rao, Hugues Aschard

Journal Articles

There is a long-standing debate about the magnitude of the contribution of gene-environment interactions to phenotypic variations of complex traits owing to the low statistical power and few reported interactions to date. to address this issue, the Gene-Lifestyle Interactions Working Group within the Cohorts for Heart and Aging Research in Genetic Epidemiology Consortium has been spearheading efforts to investigate G × E in large and diverse samples through meta-analysis. Here, we present a powerful new approach to screen for interactions across the genome, an approach that shares substantial similarity to the Mendelian randomization framework. We identify and confirm 5 loci …

A Representative Clinical Course Of Progression, With Molecular Insights, Of Hormone Receptor-Positive, Her2-Negative Bone Metastatic Breast Cancer, Elizabeth Magno, Karen M. Bussard

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Despite treatment advances, breast cancer remains a leading cause of death of women in the United States, mostly due to metastatic disease. Bone is a preferential site for breast cancer metastasis, and most metastatic breast cancer patients experience bone involvement at the time of death. The majority of patients with bone metastatic breast cancer are first diagnosed with and treated for early-stage disease, and from development of early-stage breast cancer to the recurrence of cancer in the bones, up to 30 years may elapse. Throughout this timeframe, a typical patient undergoes many treatments that have effects on the bone microenvironment. …

Prevalence, Morbidity, And Mortality Of Men With Sex Chromosome Aneuploidy In The Million Veteran Program Cohort, Shanlee Davis, Craig Teerlink, Julie Lynch, Bryan Gorman, Meghana Pagadala, Aoxing Liu, Matthew Panizzon, Victoria Merritt, Giulio Genovese, Judith Ross, Richard Hauger

Department of Pediatrics Faculty Papers

IMPORTANCE: The reported phenotypes of men with 47,XXY and 47,XYY syndromes include tall stature, multisystem comorbidities, and poor health-related quality of life (HRQOL). However, knowledge about these sex chromosome aneuploidy (SCA) conditions has been derived from studies in the less than 15% of patients who are clinically diagnosed and also lack diversity in age and genetic ancestry.

OBJECTIVES: To determine the prevalence of clinically diagnosed and undiagnosed X or Y chromosome aneuploidy among men enrolled in the Million Veteran Program (MVP); to describe military service metrics of men with SCAs; and to compare morbidity and mortality outcomes between men with …

Protecting Human And Animal Health: The Road From Animal Models To New Approach Methods, Barbara L F Kaplan, Alan M Hoberman, William Slikker, Mary Alice Smith, Emanuela Corsini, Thomas B Knudsen, M Sue Marty, Sonya K Sobrian, Suzanne C Fitzpatrick, Marcia H Ratner, Donna L Mendrick

Journal Articles

Animals and animal models have been invaluable for our current understanding of human and animal biology, including physiology, pharmacology, biochemistry, and disease pathology. However, there are increasing concerns with continued use of animals in basic biomedical, pharmacological, and regulatory research to provide safety assessments for drugs and chemicals. There are concerns that animals do not provide sufficient information on toxicity and/or efficacy to protect the target population, so scientists are utilizing the principles of replacement, reduction, and refinement (the 3Rs) and increasing the development and application of new approach methods (NAMs). NAMs are any technology, methodology, approach, or assay used …

Comparing Cognitive Tests And Smartphone-Based Assessment In 2 Us Community-Based Cohorts., Ileana De Anda-Duran, Preeti Sunderaraman, Edward Searls, Shirine Moukaled, Xuanyi Jin, Zachary Popp, Cody Karjadi, Phillip H Hwang, Huitong Ding, Sherral Devine, Ludy C Shih, Spencer Low, Honghuang Lin, Vijaya B Kolachalama, Lydia Bazzano, David J Libon, Rhoda Au

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

BACKGROUND: Smartphone-based cognitive assessments have emerged as promising tools, bridging gaps in accessibility and reducing bias in Alzheimer disease and related dementia research. However, their congruence with traditional neuropsychological tests and usefulness in diverse cohorts remain underexplored.

METHODS AND RESULTS: A total of 406 FHS (Framingham Heart Study) and 59 BHS (Bogalusa Heart Study) participants with traditional neuropsychological tests and digital assessments using the Defense Automated Neurocognitive Assessment (DANA) smartphone protocol were included. Regression models investigated associations between DANA task digital measures and a neuropsychological global cognitive

CONCLUSIONS: Our findings demonstrate that smartphone-based cognitive assessments exhibit concurrent validity with a …

Joint Problem-Solving Orientation, Mutual Value Recognition, And Performance In Fluid Teamwork Environments, Michaela Kerrissey, Zhanna Novikov

Journal Articles

INTRODUCTION: Joint problem-solving orientation (JPS) has been identified as a factor that promotes performance in fluid teamwork, but research on this factor remains nascent. This study pushes the frontier of understanding about JPS in fluid teamwork environments by applying the concept to within-organization work and exploring its relationships with performance, mutual value recognition (MVR), and expertise variety (EV).

METHODS: This is a longitudinal, survey-based field study within a large United States healthcare organization

RESULTS: Our results affirm a moderated mediation model wherein JPS enhances performance, both directly and through MVR; EV serves as a moderator in the JPS-MVR relationship. JPS …

Identification And Characterization Of Two Novel Kcnh2 Mutations Contributing To Long Qt Syndrome, Anthony Owusu-Mensah, Jacqueline Treat, Joyce Bernardi, Ryan Pfeiffer, Robert Goodrow, Bright Tsevi, Victoria Lam, Michel Audette, Jonathan M. Cordeiro, Makarand Deo

Electrical & Computer Engineering Faculty Publications

We identified two different inherited mutations in KCNH2 gene, or human ether-a-go-go related gene (hERG), which are linked to Long QT Syndrome. The first mutation was in a 1-day-old infant, whereas the second was in a 14-year-old girl. The two KCNH2 mutations were transiently transfected into either human embryonic kidney (HEK) cells or human induced pluripotent stem-cell derived cardiomyocytes. We performed associated multiscale computer simulations to elucidate the arrhythmogenic potentials of the KCNH2 mutations. Genetic screening of the first and second index patients revealed a heterozygous missense mutation in KCNH2, resulting in an amino acid change (P632L) in the …

Listeria Adhesion Protein Orchestrates Caveolae-Mediated Apical Junctional Remodeling Of Epithelial Barrier For Listeria Monocytogenes Translocation, Rishi Drolia, Donald B. Bryant, Shivendra Tenguria, Zuri A. Jules-Culver, Jessie Thind, Breanna Amelunke, Donqi Liu, Nicholas L. F. Gallina, Krishna K. Mishra, Manalee Samaddar, Manoj R. Sawale, Dharmendra K. Mishra, Abigail D. Cox, Arun K. Bhunia

Biological Sciences Faculty Publications

The cellular junctional architecture remodeling by Listeria adhesion protein-heat shock protein 60 (LAP-Hsp60) interaction for Listeria monocytogenes (Lm) passage through the epithelial barrier is incompletely understood. Here, using the gerbil model, permissive to internalin (Inl) A/B-mediated pathways like in humans, we demonstrate that Lm crosses the intestinal villi at 48 h post-infection. In contrast, the single isogenic (lap− or ΔinlA) or double (lap−ΔinlA) mutant strains show significant defects. LAP promotes Lm translocation via endocytosis of cell-cell junctional complex in enterocytes that do not display luminal E-cadherin. In comparison, InlA facilitates …

Needle Biopsy Accelerates Pro-Metastatic Changes And Systemic Dissemination In Breast Cancer: Implications For Mortality By Surgery Delay, Hiroyasu Kameyama, Priya Dondapati, Reese Simmons, Macall Leslie, John Langenheim, Yunguang Sun, Misung Yi, Aubrey Rottschaefer, Rashmi Pathak, Shreya Nuguri, Kar-Ming Fung, Shirng-Wern Tsaih, Inna Chervoneva, Hallgeir Rui, Takemi Tanaka

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

ncreased breast cancer (BC) mortality risk posed by delayed surgical resection of tumor after diagnosis is a growing concern, yet the underlying mechanisms remain unknown. Our cohort analyses of early-stage BC patients reveal the emergence of a significantly rising mortality risk when the biopsy-to-surgery interval was extended beyond 53 days. Additionally, histology of post-biopsy tumors shows prolonged retention of a metastasis-permissive wound stroma dominated by M2-like macrophages capable of promoting cancer cell epithelial-to-mesenchymal transition and angiogenesis. We show that needle biopsy promotes systemic dissemination of cancer cells through a mechanism of sustained activation of the COX-2/PGE₂/EP2 feedforward loop, …

Nucleus Accumbens Core Single Cell Ensembles Bidirectionally Respond To Experienced Versus Observed Aversive Events, Oyku Dinckol, Noah Harris Wenger, Jennifer E Zachry, Munir Gunes Kutlu

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Fear learning is a critical feature of survival skills among mammals. In rodents, fear learning manifests itself through direct experience of the aversive event or social transmission of aversive stimuli such as observing and acting on conspecifics' distress. The neuronal network underlying the social transmission of information largely overlaps with the brain regions that mediate behavioral responses to aversive and rewarding stimuli. In this study, we recorded single cell activity patterns of nucleus accumbens (NAc) core neurons using in vivo optical imaging of calcium transients via miniature scopes. This cutting-edge imaging methodology not only allows us to record activity patterns …

Dietary Habits, Meal Timing, And Meal Frequency In Kuwaiti Adults: Analysis Of The Kuwait National Nutrition Surveillance Data, Fatema Alkhulaifi, Suad Al-Hooti, Sameer Al-Zenki, Husam Alomirah, Charles Darkoh

Journal Articles

Dietary habits, including meal frequency, meal timing, and skipping meals, have been extensively studied due to their association with the development of noncommunicable diseases (NCDs). This study describes dietary habits, meal timing, frequency, skipping meals, and late-night eating in Kuwaiti adults. Kuwait National Nutrition Surveillance System data were utilized to reach the objectives of this study. The findings reveal that approximately 54% of the adults in Kuwait eat after 10 p.m., 29% skip breakfast, and 9.8% skip dinner. Furthermore, adults in Kuwait consume 4.4 meals per day on average. Women skip breakfast more often and have more extended night fasting …

Rare Variant Enrichment Analysis Supports, Angad Jolly, Haowei Du, Christelle Borel, Na Chen, Sen Zhao, Christopher M Grochowski, Ruizhi Duan, Jawid M Fatih, Moez Dawood, Sejal Salvi, Shalini N Jhangiani, Donna M Muzny, André Koch, Konstantinos Rouskas, Stavros Glentis, Efthymios Deligeoroglou, Flora Bacopoulou, Carol A Wise, Jennifer E Dietrich, Ignatia B Van Den Veyver, Antigone S Dimas, Sara Brucker, V Reid Sutton, Richard A Gibbs, Stylianos E Antonarakis, Nan Wu, Zeynep H Coban-Akdemir, Lan Zhu, Jennifer E Posey, James R Lupski

Journal Articles

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by aplasia of the female reproductive tract; the syndrome can include renal anomalies, absence or dysgenesis, and skeletal anomalies. While functional models have elucidated several candidate genes, only

Developing A National-Scale Exposure Index For Combined Environmental Hazards And Social Stressors And Applications To The Environmental Influences On Child Health Outcomes (Echo) Cohort., Sheena E. Martenies, Mingyu Zhang, Anne E. Corrigan, Anton Kvit, Timothy Shields, William Wheaton, Deana Around Him, Judy Aschner, Maria M. Talavera-Barber, Emily S. Barrett, Theresa M. Bastain, Casper Bendixsen, Carrie V. Breton, Nicole R. Bush, Ferdinand Cacho, Carlos A. Camargo, Kecia N. Carroll, Brian S. Carter, Andrea E. Cassidy-Bushrow, Whitney Cowell, Lisa A. Croen, Dana Dabelea, Cristiane S. Duarte, Anne L. Dunlop, Todd M. Everson, Rima Habre, Tina V. Hartert, Jennifer B. Helderman, Alison E. Hipwell, Margaret R. Karagas, Barry M. Lester, Kaja Z. Lewinn, Sheryl Magzamen, Rachel Morello-Frosch, Thomas G. O'Connor, Amy M. Padula, Michael Petriello, Sheela Sathyanarayana, Joseph B. Stanford, Tracey J. Woodruff, Rosalind J. Wright, Amii M. Kress, Program Collaborators For Environmental Influences On Child Health Outcomes

Manuscripts, Articles, Book Chapters and Other Papers

Tools for assessing multiple exposures across several domains (e.g., physical, chemical, and social) are of growing importance in social and environmental epidemiology because of their value in uncovering disparities and their impact on health outcomes. Here we describe work done within the Environmental influences on Child Health Outcomes (ECHO)-wide Cohort Study to build a combined exposure index. Our index considered both environmental hazards and social stressors simultaneously with national coverage for a 10-year period. Our goal was to build this index and demonstrate its utility for assessing differences in exposure for pregnancies enrolled in the ECHO-wide Cohort Study. Our unitless …

Invited Review: Adrenocortical Function In Avian And Non-Avian Reptiles: Insights From Dispersed Adrenocortical Cells., Rocco V. Carsia, Patrick J. Mcilroy, Henry B John-Alder

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Herein we review our work involving dispersed adrenocortical cells from several lizard species: the Eastern Fence Lizard (Sceloporus undulatus), Yarrow's Spiny Lizard (Sceloporus jarrovii), Striped Plateau Lizard (Sceloporus virgatus) and the Yucatán Banded Gecko (Coleonyx elegans). Early work demonstrated changes in steroidogenic function of adrenocortical cells derived from adult S. undulatus associated with seasonal interactions with sex. However, new information suggests that both sexes operate within the same steroidogenic budget over season. The observed sex effect was further explored in orchiectomized and ovariectomized lizards, some supported with exogenous testosterone. Overall, a suppressive effect of testosterone was evident, especially in cells …

Assessment Of The First Presentations Of Common Variable Immunodeficiency In A Large Cohort Of Patients, Hossein Esmaeilzadeh, Armita Jokar-Derisi, Amir Hossein Hassani, Reza Yazdani, Samaneh Delavari, Hassan Abolhassani, Negar Mortazavi, Aida Askarisarvestani

Department of Neurology Faculty Papers

BACKGROUND: Common Variable Immunodeficiency (CVID) is a primary immunodeficiency syndrome resulting in recurrent infections, autoimmunity, and granulomatous manifestations.

METHODS AND MATERIALS: This retrospective study was conducted on an Iranian national registry of immunodeficient patients from 2010 to 2021. The frequency of first presentations of CVID and its association with sex, age of onset, and family history of CVID was evaluated.

RESULTS: A total of 383 patients entered the study, 164 of whom were female, and the rest were male. The mean age of the patients was 25.3 ± 14.5 years. The most frequent first presentations of CVID were pneumonia (36.8%) …

Climate Change Imperils Pediatric Health: Child Advocacy Through Fossil Fuel Divestment., Sandra H. Jee, Elizabeth Friedman, Ruth A. Etzel, Vi T. Nguyen, Todd L. Sack, Kathi J. Kemper

Manuscripts, Articles, Book Chapters and Other Papers

Climate change poses an existential threat to children's health. Divestment of ownership stakes in fossil fuel companies is one tool available to pediatricians to address climate change. Pediatricians are trusted messengers regarding children's health and therefore bear a unique responsibility to advocate for climate and health policies that affect children. Among the impacts of climate change on pediatric patients are allergic rhinitis and asthma; heat-related illnesses; premature birth; injuries from severe storms and fires; vector-borne diseases; and mental illnesses. Children are disproportionately affected as well by climate-related displacement of populations, drought, water shortages, and famine. The human-generated burning of fossil …

Voluntary Wheel Running Promotes Resilience To The Behavioral Effects Of Unpredictable Chronic Mild Stress In Male And Female Mice., Elias Elias, Ariel Y Zhang, Abigail G White, Matthew J Pyle, Melissa T Manners

Faculty Scholarship for the College of Science & Mathematics

Besides significant benefits to physical health, exercise promotes mental health, reduces symptoms of mental illness, and enhances psychological development. Exercise can offset the impact of chronic stress, which is a major precursor to the development of mental disorders. The effects of exercise on chronic stress-induced behaviors are contradictory in preclinical studies, primarily due to the lack of data and sex-specific investigations. We sought to evaluate the effects of exercise on chronic stress-induced behavioral changes in both male and female mice. Mice were subjected to an Unpredictable Chronic Mild Stress (UCMS) paradigm with accessibility to running wheels for 2 h daily. …

Association Of Mitochondrial Dna Copy Number With Brain Mri Markers And Cognitive Function: A Meta-Analysis Of Community-Based Cohorts, Yuankai Zhang, Xue Liu, Kerri L Wiggins, Nuzulul Kurniansyah, Xiuqing Guo, Amanda L Rodrigue, Wei Zhao, Lisa R Yanek, Scott M Ratliff, Achilleas Pitsillides, Juan Sebastian Aguirre Patiño, Tamar Sofer, Dan E Arking, Thomas R Austin, Alexa S Beiser, John Blangero, Eric Boerwinkle, Jan Bressler, Joanne E Curran, Lifang Hou, Timothy M Hughes, Sharon L R Kardia, Lenore J Launer, Daniel Levy, Thomas H Mosley, Ilya M Nasrallah, Stephen S Rich, Jerome I Rotter, Sudha Seshadri, Wassim Tarraf, Kevin A González, Vasan Ramachandran, Kristine Yaffe, Paul A Nyquist, Bruce M Psaty, Charles S Decarli, Jennifer A Smith, David C Glahn, Hector M González, Joshua C Bis, Myriam Fornage, Susan R Heckbert, Annette L Fitzpatrick, Chunyu Liu, Claudia L Satizabal

Journal Articles

BACKGROUND AND OBJECTIVES: Previous studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.

METHODS: We included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear …

Diet, Physical Activity, And Stress Among Wheelchair Users With Multiple Sclerosis: Examining Individual And Co-Occurring Behavioral Risk Factors, Stephanie L Silveira, Brenda Jeng, Gary Cutter, Robert W Motl

Journal Articles

OBJECTIVE: This study examined individual and co-occurring behavioral risk factors (diet, exercise, and stress) in wheelchair users with multiple sclerosis (MS) and potential association with MS symptoms (ie, fatigue, depression, anxiety, pain, sleep, and health-related quality of life [HRQOL]).

DESIGN: Survey.

SETTING: General Community.

PARTICIPANTS: One hundred twenty-three wheelchair users with MS completed this study (N=123).

INTERVENTIONS: Not applicable.

MAIN OUTCOME MEASURES: Participants were mailed instructions for accessing online questionnaires (demographic and clinical characteristics, Godin Leisure-Time Exercise Questionnaire, Perceived Stress Scale, Automated Self-Administered 24-Hour Dietary Assessment Tool, and MS symptoms).

RESULTS: Standard cut-points were used to categorize behavioral risk factors …

Differences In Startle And Prepulse Inhibition In Contactin-Associated Protein-Like 2 Knock-Out Rats Are Associated With Sex-Specific Alterations In Brainstem Neural Activity, Alice Zheng, Kaela E Scott, Ashley L Schormans, Rajkamalpreet Mann, Brian L Allman, Susanne Schmid

Anatomy and Cell Biology Publications

The contactin-associated protein-like 2 (CNTNAP2) gene encodes for the CASPR2 protein, which plays an essential role in neurodevelopment. Mutations in CNTNAP2 are associated with neurodevelopmental disorders, including autism spectrum disorder and schizophrenia. Rats with a loss of function mutation in the Cntnap2 gene show increased acoustic startle response (ASR) and decreased prepulse inhibition (PPI). The neural basis of this altered auditory processing in Cntnap2 knock-out rats is currently unknown. Auditory brainstem recordings previously revealed no differences between the genotypes. The next step is to investigate brainstem structures outside of the primary auditory pathway that mediate ASR and PPI, which are …

Exposure To Pcb126 During The Nursing Period Reversibly Impacts Early-Life Glucose Tolerance, Brittany B. Rice, Keegan W. Sammons, Sara Y. Ngo Tenlep, Madeline T. Weltzer, Leryn J. Reynolds, Cetewayo S. Rashid, Hollie I. Swanson, Kevin J. Pearson

Human Movement Sciences & Special Education Faculty Publications

Polychlorinated biphenyls (PCBs) are persistent environmental organic pollutants known to have detrimental health effects. Using a mouse model, we previously demonstrated that PCB126 exposure before and during pregnancy and throughout the perinatal period adversely affected offspring glucose tolerance and/or body composition profiles. The purpose of this study was to investigate the glucose tolerance and body composition of offspring born to dams exposed to PCB126 during the nursing period only. Female ICR mice were bred, and half of the dams were exposed to either vehicle (safflower oil) or 1 µmole PCB126 per kg of body weight via oral gavage on postnatal …

Research Note: Association Of Single Nucleotide Polymorphism Of Akt3 With Egg Production Traits In White Muscovy Ducks (Cairina Moschata)., Semiu Folaniyi Bello, Haiping Xu, Kan Li, Lijin Guo, Siyu Zhang, Ridwan Olawale Ahmed, Endashaw Jebessa Bekele, Ming Zheng, Mingjian Xian, Bahareldin Ali Abdalla, Adeniyi Charles Adeola, Adeyinka Abiola Adetula, Raman Akinyanju Lawal, Weijian Zhu, Dexiang Zhang, Xiquan Zhang, Congliang Ji, Qinghua Nie

Faculty Research 2022

Prior studies on transcriptomes of hypothalamus and ovary revealed that AKT3 is one of the candidate genes that might affect egg production in White Muscovy ducks. The role of AKT3 in the uterus during reproductive processes cannot be overemphasized. However, functional role of this gene in the tissues and on egg production traits of Muscovy ducks remains unknown. To identify the relationship between AKT3 and egg production traits in ducks, relative expression profile was first examined prior to identifying the variants within AKT3 that may underscore egg production traits [age at first egg (AFE), number of eggs at 300 d …

Lifespan Benefits For The Combination Of Rapamycin Plus Acarbose And For Captopril In Genetically Heterogeneous Mice., Randy Strong, Richard A Miller, Catherine J Cheng, James F Nelson, Jonathan Gelfond, Shailaja Kesaraju Allani, Vivian Diaz, Angela Olsen Dorigatti, Jonathan Dorigatti, Elizabeth Fernandez, Andrzej Galecki, Brett Ginsburg, Karyn L Hamilton, Martin A Javors, Kerry Kornfeld, Matt Kaeberlein, Suja Kumar, David B Lombard, Marisa Lopez-Cruzan, Benjamin F Miller, Peter Rabinovitch, Peter C. Reifsnyder, Nadia Rosenthal, Molly A. Bogue, Adam B Salmon, Yousin Suh, Eric Verdin, Herbert Weissbach, John Newman, Francesca Maccchiarini, David E. Harrison

Faculty Research 2022

Mice bred in 2017 and entered into the C2017 cohort were tested for possible lifespan benefits of (R/S)-1,3-butanediol (BD), captopril (Capt), leucine (Leu), the Nrf2-activating botanical mixture PB125, sulindac, syringaresinol, or the combination of rapamycin and acarbose started at 9 or 16 months of age (RaAc9, RaAc16). In male mice, the combination of Rapa and Aca started at 9 months and led to a longer lifespan than in either of the two prior cohorts of mice treated with Rapa only, suggesting that this drug combination was more potent than either of its components used alone. In females, lifespan in mice …

Metformin Is Associated With Reduced Covid-19 Severity In Patients With Prediabetes., Lauren E Chan, Elena Casiraghi, Bryan Laraway, Ben D Coleman, Hannah Blau, Adnin Zaman, Nomi L Harris, Kenneth Wilkins, Blessy Antony, Michael Gargano, Giorgio Valentini, David Sahner, Melissa Haendel, Peter N Robinson, Carolyn Bramante, Justin Reese

Faculty Research 2022

AIMS: Studies suggest that metformin is associated with reduced COVID-19 severity in individuals with diabetes compared to other antihyperglycemics. We assessed if metformin is associated with reduced incidence of severe COVID-19 for patients with prediabetes or polycystic ovary syndrome (PCOS), common diseases that increase the risk of severe COVID-19.

METHODS: This observational, retrospective study utilized EHR data from 52 hospitals for COVID-19 patients with PCOS or prediabetes treated with metformin or levothyroxine/ondansetron (controls). After balancing via inverse probability score weighting, associations with COVID-19 severity were assessed by logistic regression.

RESULTS: In the prediabetes cohort, when compared to levothyroxine, metformin was …

Blackcurrants Reduce The Risk Of Postmenopausal Osteoporosis: A Pilot Double-Blind, Randomized, Placebo-Controlled Clinical Trial., Briana M Nosal, Junichi R Sakaki, Zachary Macdonald, Kyle Mahoney, Kijoon Kim, Matthew Madore, Staci Thornton, Thi Dong Binh Tran, George M. Weinstock, Elaine Choung-Hee Lee, Ock K Chun

Faculty Research 2022

Beneficial effects of blackcurrant supplementation on bone metabolism in mice has recently been demonstrated, but no studies are available in humans. The current study aimed to examine the dose-dependent effects of blackcurrant in preventing bone loss and the underlying mechanisms of action in adult women. Forty peri- and early postmenopausal women were randomly assigned into one of three treatment groups for 6 months: (1) a placebo (control group, n = 13); (2) 392 mg/day of blackcurrant powder (low blackcurrant, BC, group, n = 16); and (3) 784 mg/day of blackcurrant powder (high BC group, n = 11). The significance of …

Myc Regulates A Pan-Cancer Network Of Co-Expressed Oncogenic Splicing Factors., Laura M Urbanski, Mattia Brugiolo, Sunghee Park, Brittany Lynn Angarola, Nathan Leclair, Marina Yurieva, Phil Palmer, Sangram Keshari Sahu, Olga Anczuków

Faculty Research 2022

MYC is dysregulated in >50% of cancers, but direct targeting of MYC has been clinically unsuccessful. Targeting downstream MYC effector pathways represents an attractive alternative. MYC regulates alternative mRNA splicing, but the mechanistic links between MYC and the splicing machinery in cancer remain underexplored. Here, we identify a network of co-expressed splicing factors (SF-modules) in MYC-active breast tumors. Of these, one is a pan-cancer SF-module correlating with MYC activity across 33 tumor types. In mammary cell models, MYC activation leads to co-upregulation of pan-cancer module SFs and to changes in >4,000 splicing events. In breast cancer organoids, co-overexpression of the …

Mendelian Gene Identification Through Mouse Embryo Viability Screening., Pilar Cacheiro, Carl Henrik Westerberg, Jesse Mager, Mary E Dickinson, Lauryl M J Nutter, Violeta Muñoz-Fuentes, Chih-Wei Hsu, Ignatia B Van Den Veyver, Ann M Flenniken, Colin Mckerlie, Stephen A Murray, Lydia Teboul, Jason D Heaney, K C Kent Lloyd, Louise Lanoue, Robert E Braun, Jacqueline K White, Amie K Creighton, Valerie Laurin, Ruolin Guo, Dawei Qu, Sara Wells, James Cleak, Rosie Bunton-Stasyshyn, Michelle Stewart, Jackie Harrisson, Jeremy Mason, Hamed Haseli Mashhadi, Helen Parkinson, Ann-Marie Mallon, International Mouse Phenotyping Consortium, Genomics England Research Consortium, Damian Smedley

Faculty Research 2022

BACKGROUND: The diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful. A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property.

METHODS: Here we further dissected this spectrum by assessing the embryonic stage at which homozygous …

Cost-Effectiveness Frameworks For Comparing Genome And Exome Sequencing Versus Conventional Diagnostic Pathways: A Scoping Review And Recommended Methods, Bart S Ferket, Zach Baldwin, Priyanka Murali, Akila Pai, Kathleen F Mittendorf, Heidi V Russell, Flavia Chen, Frances L Lynch, Kristen Hassmiller Lich, Lucia A Hindorff, Renate Savich, Anne Slavotinek, Hadley Stevens Smith, Bruce D Gelb, David L Veenstra

Journal Articles

PURPOSE: Methodological challenges have limited economic evaluations of genome sequencing (GS) and exome sequencing (ES). Our objective was to develop conceptual frameworks for model-based cost-effectiveness analyses (CEAs) of diagnostic GS/ES.

METHODS: We conducted a scoping review of economic analyses to develop and iterate with experts a set of conceptual CEA frameworks for GS/ES for prenatal testing, early diagnosis in pediatrics, diagnosis of delayed-onset disorders in pediatrics, genetic testing in cancer, screening of newborns, and general population screening.

RESULTS: Reflecting on 57 studies meeting inclusion criteria, we recommend the following considerations for each clinical scenario. For prenatal testing, performing comparative analyses …