Digital Commons Network^™

Preventive And Therapeutic Reduction Of Amyloid Deposition And Behavioral Impairments In A Model Of Alzheimer’S Disease By Whole Blood Exchange, Akihiko Urayama, Ines Moreno-Gonzalez, Diego Morales-Scheihing, Vineetkumar Kharat, Sandra Pritzkow, Claudio Soto

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is the major form of dementia in the elderly population. The main neuropathological changes in AD patients are neuronal death, synaptic alterations, brain inflammation, and the presence of cerebral protein aggregates in the form of amyloid plaques and neurofibrillary tangles. Compelling evidence suggests that the misfolding, aggregation, and cerebral deposition of amyloid-beta (Aβ) plays a central role in the disease. Thus, prevention and removal of misfolded protein aggregates is considered a promising strategy to treat AD. In the present study, we describe that the development of cerebral amyloid plaques in a transgenic mice model of AD (Tg2576) …

Handling Informative Premature Treatment Or Study Discontinuation For Assessing Between-Group Differences In A Comparative Oncology Trial, Bo Huang, Ryan Sun, Brian Claggett, Lu Tian, Ethan B Ludmir, Lee-Jen Wei

Faculty, Staff and Student Publications

This decision analytical model study examines premature treatment discontinuation in clinical trials for patients with advanced renal cell carcinoma.

Monkeypox: What Do Dental Professionals Need To Know?, Charifa Zemouri, Edgar O Beltrán, Richard Holliday, Nicholas S Jakubovics, James R Allison

Faculty, Staff and Student Publications

Infection control is critical for the safe delivery of dental care. Infection control practices must be responsive to emerging and re-emerging infectious diseases and outbreaks, as was clearly seen during the peak of the COVID-19 pandemic. An emerging global outbreak of the monkeypox virus has again raised potential challenges for infection control in dentistry. Monkeypox is an infectious disease, characterised by a rash affecting the skin and soft tissues, including the oral cavity. Previously, cases were mostly seen following contact with infected animals in Central and West Africa, with limited human-to-human transmission within and outside of these areas. However, since …

Targeted Inhibition Of Dna-Pkcs, Atm, Atr, Parp, And Rad51 Modulate Response To X Rays And Protons, Scott J Bright, David B Flint, David K J Martinus, Broderick X Turner, Mandira Manandhar, Mariam Ben Kacem, Conor H Mcfadden, Timothy A Yap, Simona F Shaitelman, Gabriel O Sawakuchi

Faculty, Staff and Student Publications

Small molecule inhibitors are currently in preclinical and clinical development for the treatment of selected cancers, particularly those with existing genetic alterations in DNA repair and DNA damage response (DDR) pathways. Keen interest has also been expressed in combining such agents with other targeted antitumor strategies such as radiotherapy. Radiotherapy exerts its cytotoxic effects primarily through DNA damage-induced cell death; therefore, inhibiting DNA repair and the DDR should lead to additive and/or synergistic radiosensitizing effects. In this study we screened the response to X-ray or proton radiation in cell lines treated with DDR inhibitors (DDRis) targeting ATM, ATR, DNA-PKcs, Rad51, …

A Retrospective Analysis Of Ebv-Dna Status With The Prognosis Of Lymphoma, Lihua Qiu, Junqi Si, Junnan Kang, Zehui Chen, Rexidan Nuermaimaiti, Zhengzi Qian, Lanfang Li, Shiyong Zhou, Mingjian James You, Huilai Zhang, Chen Tian

Faculty, Staff and Student Publications

Epstein-Barr virus (EBV) infection is proved to be associated with clinicopathology of lymphoma. However, little is known about the relationship between EBV-DNA status after treatment and prognosis. In this study, real-time polymerase chain reaction (PCR) was used for quantitative detection of EBV-DNA load in peripheral blood of all 26,527 patients with lymphoma, and the clinical characteristics and prognosis of 202 patients were retrospectively analysed, including 100 patients with positive EBV-DNA and 102 randomly selected patients with negative EBV-DNA. We found that the average rate of EBV-DNA positivity in lymphomas was 0.376%, and EBV-DNA-positive patients presented higher risk with elevated lactate …

Systematically Higher Ki67 Scores On Core Biopsy Samples Compared To Corresponding Resection Specimen In Breast Cancer: A Multi-Operator And Multi-Institutional Study, Balazs Acs, Samuel C Y Leung, Kelley M Kidwell, Indu Arun, Renaldas Augulis, Sunil S Badve, Yalai Bai, Anita L Bane, John M S Bartlett, Jane Bayani, Gilbert Bigras, Annika Blank, Henk Buikema, Martin C Chang, Robin L Dietz, Andrew Dodson, Susan Fineberg, Cornelia M Focke, Dongxia Gao, Allen M Gown, Carolina Gutierrez, Johan Hartman, Zuzana Kos, Anne-Vibeke Lænkholm, Arvydas Laurinavicius, Richard M Levenson, Rustin Mahboubi-Ardakani, Mauro G Mastropasqua, Sharon Nofech-Mozes, C Kent Osborne, Frédérique M Penault-Llorca, Tammy Piper, Mary Anne Quintayo, Tilman T Rau, Stefan Reinhard, Stephanie Robertson, Roberto Salgado, Tomoharu Sugie, Bert Van Der Vegt, Giuseppe Viale, Lila A Zabaglo, Daniel F Hayes, Mitch Dowsett, Torsten O Nielsen, David L Rimm, International Ki67 In Breast Cancer Working Group Of The Breast International Group And North American Breast Cancer Group (Big-Nabcg)

Faculty, Staff and Students Publications

Ki67 has potential clinical importance in breast cancer but has yet to see broad acceptance due to inter-laboratory variability. Here we tested an open source and calibrated automated digital image analysis (DIA) platform to: (i) investigate the comparability of Ki67 measurement across corresponding core biopsy and resection specimen cases, and (ii) assess section to section differences in Ki67 scoring. Two sets of 60 previously stained slides containing 30 core-cut biopsy and 30 corresponding resection specimens from 30 estrogen receptor-positive breast cancer patients were sent to 17 participating labs for automated assessment of average Ki67 expression. The blocks were centrally cut …

Incidence And 5-Year Survival Of Children And Adolescents With Hepatoblastoma In The United States, Justin A Kahla, David A Siegel, Shifan Dai, Philip J Lupo, Jennifer H Foster, Michael E Scheurer, Andras A Heczey

Center for Medical Ethics and Health Policy Staff Publications

Objective: Hepatoblastoma (HB) is the most common pediatric primary malignant liver tumor, its incidence has been increasing worldwide, but recent changes in incidence and outcomes with high population coverage are not well characterized.

Methods: We defined the incidence of HB diagnosed during 2003-2017 from United States Cancer Statistics (USCS) database, and survival during 2001-2016 from the National Program of Cancer Registries (NPCR). Data were stratified by sex, race/ethnicity, age, tumor stage, county population, and diagnosis year. Incidence trends were assessed by calculating average annual percent change (AAPC) using Joinpoint regression. Differences in overall 5-year survival were estimated using Cox regression …

Psychiatric Polygenic Risk Scores: Child And Adolescent Psychiatrists’ Knowledge, Attitudes, And Experiences, Stacey Pereira, Katrina A Muñoz, Brent J Small, Takahiro Soda, Laura N Torgerson, Clarissa E Sanchez, Jehannine Austin, Eric A Storch, Gabriel Lázaro-Muñoz

Center for Medical Ethics and Health Policy Staff Publications

Psychiatric polygenic risk scores (PRS) have potential utility in psychiatric care and prevention, but there are concerns about their implementation. We surveyed 960 US-based practicing child and adolescent psychiatrists' (CAP) about their experiences, perspectives, and potential uses of psychiatric PRS. While 23% of CAP reported that they had never heard of PRS, 10 % of respondents have had a patient/family bring PRS to them and 4% have generated PRS for patients. Though 25% stated they would request PRS if a patient/caregiver asked, 35% indicated that nothing would prompt them to request PRS. Most respondents (54%) believed psychiatric PRS are currently …

Genome Interpretation Using In Silico Predictors Of Variant Impact, Panagiotis Katsonis, Kevin Wilhelm, Amanda Williams, Olivier Lichtarge

Faculty, Staff and Students Publications

Estimating the effects of variants found in disease driver genes opens the door to personalized therapeutic opportunities. Clinical associations and laboratory experiments can only characterize a tiny fraction of all the available variants, leaving the majority as variants of unknown significance (VUS). In silico methods bridge this gap by providing instant estimates on a large scale, most often based on the numerous genetic differences between species. Despite concerns that these methods may lack reliability in individual subjects, their numerous practical applications over cohorts suggest they are already helpful and have a role to play in genome interpretation when used at …

Potential Interactions Between Cerebellar Dysfunction And Sleep Disturbances In Dystonia, Luis E Salazar Leon, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Dystonia is the third most common movement disorder. It causes debilitating twisting postures that are accompanied by repetitive and sometimes intermittent co- or over-contractions of agonist and antagonist muscles. Historically diagnosed as a basal ganglia disorder, dystonia is increasingly considered a network disorder involving various brain regions including the cerebellum. In certain etiologies of dystonia, aberrant motor activity is generated in the cerebellum and the abnormal signals then propagate through a "dystonia circuit" that includes the thalamus, basal ganglia, and cerebral cortex. Importantly, it has been reported that non-motor defects can accompany the motor symptoms; while their severity is not …

Identifying Phenotypic Expansions For Congenital Diaphragmatic Hernia Plus (Cdh+) Using Decipher Data, Amy Hardcastle, Aliska M Berry, Ian M Campbell, Xiaonan Zhao, Pengfei Liu, Amanda E Gerard, Jill A Rosenfeld, Saumya D Sisoudiya, Andres Hernandez-Garcia, Sara Loddo, Silvia Di Tommaso, Antonio Novelli, Maria L Dentici, Rossella Capolino, Maria C Digilio, Ludovico Graziani, Cecilie F Rustad, Katherine Neas, Giovanni B Ferrero, Alfredo Brusco, Eleonora Di Gregorio, Diana Wellesley, Claire Beneteau, Madeleine Joubert, Kris Van Den Bogaert, Anneleen Boogaerts, Dominic J Mcmullan, John Dean, Maria G Giuffrida, Laura Bernardini, Vinod Varghese, Nora L Shannon, Rachel E Harrison, Wayne W K Lam, Shane Mckee, Peter D Turnpenny, Trevor Cole, Jenny Morton, Jacqueline Eason, Marilyn C Jones, Rebecca Hall, Michael Wright, Karen Horridge, Chad A Shaw, Wendy K Chung, Daryl A Scott

Duncan NRI Faculty and Staff Publications

Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset of CDH cases. This is due, in part, to an incomplete understanding of the genes that contribute to diaphragm development. Here, we used clinical and molecular data from 36 individuals with CDH+ who are cataloged in the DECIPHER database to identify genes that may play a role in diaphragm development and to discover new phenotypic expansions. Among this group, we identified individuals who carried putatively deleterious sequence or copy number variants affecting CREBBP, SMARCA4, …

Residence In A Latinx Enclave And End-Induction Minimal Residual Disease Positivity Among Children With Acute Lymphoblastic Leukemia, Joshua P Muñiz, John P Woodhouse, Amy E Hughes, Sandi L Pruitt, Karen R Rabin, Michael E Scheurer, Philip J Lupo, Jeremy M Schraw

Center for Medical Ethics and Health Policy Staff Publications

Racial and ethnic inequities in survival persist for children with acute lymphoblastic leukemia (ALL). In the US, there are strong associations between SES, race/ethnicity, and place of residence. This is evidenced by ethnic enclaves: neighborhoods with high concentrations of ethnic residents, immigrants, and language isolation. The Latinx enclave index (LEI) can be used to investigate how residence in a Latinx enclave is associated with health outcomes. We studied the association between LEI score and minimal residual disease (MRD) in 142 pediatric ALL patients treated at Texas Children's Hospital. LEI score was associated with end-induction MRD positivity (OR per unit increase …

Characteristics Of Graft-Versus-Host Disease (Gvhd) After Post-Transplantation Cyclophosphamide Versus Conventional Gvhd Prophylaxis, Rima M Saliba, Amin M Alousi, Joseph Pidala, Mukta Arora, Stephen R Spellman, Michael T Hemmer, Tao Wang, Camille Abboud, Sairah Ahmed, Joseph H Antin, Amer Beitinjaneh, David Buchbinder, Michael Byrne, Jean-Yves Cahn, Hannah Choe, Rabi Hanna, Peiman Hematti, Rammurti T Kamble, Carrie L Kitko, Mary Laughlin, Lazaros Lekakis, Margaret L Macmillan, Rodrigo Martino, Parinda A Mehta, Taiga Nishihori, Sagar S Patel, Miguel-Angel Perales, Hemalatha G Rangarajan, Olov Ringdén, Joseph Rosenthal, Bipin N Savani, Kirk R Schultz, Sachiko Seo, Takanori Teshima, Marjolein Van Der Poel, Leo F Verdonck, Daniel Weisdorf, Baldeep Wirk, Jean A Yared, Jeffrey Schriber, Richard E Champlin, Stefan O Ciurea

Center for Medical Ethics and Health Policy Staff Publications

Post-transplantation cyclophosphamide (PTCy) has been shown to effectively control graft-versus-host disease (GvHD) in haploidentical (Haplo) transplantations. In this retrospective registry study, we compared GvHD organ distribution, severity, and outcomes in patients with GvHD occurring after Haplo transplantation with PTCy GvHD prophylaxis (Haplo/PTCy) versus HLA-matched unrelated donor transplantation with conventional prophylaxis (MUD/conventional). We evaluated 2 cohorts: patients with grade 2 to 4 acute GvHD (aGvHD) including 264 and 1163 recipients of Haplo and MUD transplants; and patients with any chronic GvHD (cGvHD) including 206 and 1018 recipients of Haplo and MUD transplants, respectively. In comparison with MUD/conventional transplantation ± antithymocyte globulin …

Crucial Nuances In Understanding (Mis)Associations Between The Neonatal Microbiome And Cesarean Delivery, Alexa M Sassin, Grace J Johnson, Alison N Goulding, Kjersti M Aagaard

Faculty, Staff and Students Publications

As rates of Cesarean delivery and common non-communicable disorders (NCDs), such as obesity, metabolic disease, and atopy/asthma, have concomitantly increased in recent decades, investigators have attempted to discern a causal link. One line of research has led to a hypothesis that Cesarean birth disrupts the presumed normal process of colonization of the neonatal microbiome with vaginal microbes, yielding NCDs later in life. However, a direct link between a disrupted microbiota transfer at time of delivery and acute and/or chronic illness in infants born via Cesarean has not been causally established. Microbiota seeding from maternal vaginal or stool sources has been …

Towards A Definitive Symptom Structure Of Obsessive-Compulsive Disorder: A Factor And Network Analysis Of 87 Distinct Symptoms In 1366 Individuals, Matti Cervin, Euripedes C Miguel, Ayşegül Selcen Güler, Ygor A Ferrão, Ayşe Burcu Erdoğdu, Luisa Lazaro, Sebla Gökçe, Daniel A Geller, Yasemin Yulaf, Şaziye Senem Başgül, Özlem Özcan, Koray Karabekiroğlu, Leonardo F Fontenelle, Yankı Yazgan, Eric A Storch, James F Leckman, Maria Conceição Do Rosário, David Mataix-Cols

Center for Medical Ethics and Health Policy Staff Publications

Background: The symptoms of obsessive-compulsive disorder (OCD) are highly heterogeneous and it is unclear what is the optimal way to conceptualize this heterogeneity. This study aimed to establish a comprehensive symptom structure model of OCD across the lifespan using factor and network analytic techniques.

Methods: A large multinational cohort of well-characterized children, adolescents, and adults diagnosed with OCD (N = 1366) participated in the study. All completed the Dimensional Yale-Brown Obsessive-Compulsive Scale, which contains an expanded checklist of 87 distinct OCD symptoms. Exploratory and confirmatory factor analysis were used to outline empirically supported symptom dimensions, and interconnections among the …

Cardiac Crises: Cardiac Arrhythmias And Cardiomyopathy During Tango2 Deficiency Related Metabolic Crises, Christina Y Miyake, Erica J Lay, Cheyenne M Beach, Scott R Ceresnak, Caridad M Delauz, Taylor S Howard, Christopher M Janson, Kate Jardine, Prince J Kannankeril, Maina Kava, Jeffrey J Kim, Leonardo Liberman, Scott L Macicek, Tam Dam Pham, Terry Robertson, Santiago O Valdes, Gregory Webster, Sara B Stephens, Diana M Milewicz, Mahshid Azamian, Saad A Ehsan, Kimberly M Houck, Claudia Soler-Alfonso, Kevin E Glinton, Mustafa Tosur, Na Li, Weiyi Xu, Seema R Lalani, Lilei Zhang

Faculty, Staff and Students Publications

BACKGROUND: TANGO2 deficiency disorder (TDD) is an autosomal recessive disease associated with metabolic crisis, lethal cardiac arrhythmias, and cardiomyopathy. Data regarding treatment, management, and outcomes of cardiac manifestations of TDD are lacking.

OBJECTIVE: The purpose of this study was to describe TDD-related cardiac crises.

METHODS: Retrospective multicenter chart review was made of TDD patients admitted with cardiac crises, defined as development of ventricular tachycardia (VT), cardiomyopathy, or cardiac arrest during metabolic crises.

RESULTS: Twenty-seven children were admitted for 43 cardiac crises (median age 6.4 years; interquartile range [IQR] 2.4-9.8 years) at 14 centers. During crisis, QTc prolongation occurred in all …

Psychiatric Polygenic Risk Scores: Child And Adolescent Psychiatrists’ Knowledge, Attitudes, And Experiences, Stacey Pereira, Katrina A Muñoz, Brent J Small, Takahiro Soda, Laura N Torgerson, Clarissa E Sanchez, Jehannine Austin, Eric A Storch, Gabriel Lázaro-Muñoz

Center for Medical Ethics and Health Policy Staff Publications

Psychiatric polygenic risk scores (PRS) have potential utility in psychiatric care and prevention, but there are concerns about their implementation. We surveyed 960 US-based practicing child and adolescent psychiatrists' (CAP) about their experiences, perspectives, and potential uses of psychiatric PRS. While 23% of CAP reported that they had never heard of PRS, 10 % of respondents have had a patient/family bring PRS to them and 4% have generated PRS for patients. Though 25% stated they would request PRS if a patient/caregiver asked, 35% indicated that nothing would prompt them to request PRS. Most respondents (54%) believed psychiatric PRS are currently …

Age Differential Response To Bevacizumab Therapy In Choroidal Neovascularization In Rabbits, Van Phuc Nguyen, Jessica Henry, Josh Zhe, Quynh Kieu, Wei Qian, Yingbin Fu, Xueding Wang, Yannis M Paulus

Faculty, Staff and Students Publications

Choroidal neovascularization (CNV) in young rabbits has been shown to have a rapid, robust response after treatment with bevacizumab, an anti-vascular endothelial growth factor (VEGF) medication. This investigation evaluates an age differential response to bevacizumab in older populations of rabbits using multimodal high resolution molecular imaging. Young (4 months old) and life span (14 months old) rabbits were given subretinal injections of Matrigel and VEGF to produce CNV. All CNV rabbit models were then treated with a bevacizumab intravitreal injection. Rabbits were then monitored longitudinally using photoacoustic microscopy (PAM), optical coherence tomography (OCT), color photography, and fluorescence imaging. Chain-like gold …

Sequencing Individual Genomes With Recurrent Genomic Disorder Deletions: An Approach To Characterize Genes For Autosomal Recessive Rare Disease Traits, Bo Yuan, Katharina V Schulze, Nurit Assia Batzir, Jefferson Sinson, Hongzheng Dai, Wenmiao Zhu, Francia Bocanegra, Chin-To Fong, Jimmy Holder, Joanne Nguyen, Christian P Schaaf, Yaping Yang, Weimin Bi, Christine Eng, Chad Shaw, James R Lupski, Pengfei Liu

Children’s Nutrition Research Center Staff Publications

Background: In medical genetics, discovery and characterization of disease trait contributory genes and alleles depends on genetic reasoning, study design, and patient ascertainment; we suggest a segmental haploid genetics approach to enhance gene discovery and molecular diagnostics.

Methods: We constructed a genome-wide map for nonallelic homologous recombination (NAHR)-mediated recurrent genomic deletions and used this map to estimate population frequencies of NAHR deletions based on large-scale population cohorts and region-specific studies. We calculated recessive disease carrier burden using high-quality pathogenic or likely pathogenic variants from ClinVar and gnomAD. We developed a NIRD (NAHR deletion Impact to Recessive Disease) score for recessive …

Modeling Multivariate Age-Related Imaging Variables With Dependencies, Hwiyoung Lee, Chixiang Chen, Peter Kochunov, Liyi Elliot Hong, Shuo Chen

Faculty, Staff and Student Publications

Neuroimaging techniques have been increasingly used to understand the neural biology of aging brains. The neuroimaging variables from distinct brain locations and modalities can exhibit age-related patterns that reflect localized neural decline. However, it is a challenge to identify the impacts of risk factors (eg, mental disorders) on multivariate imaging variables while simultaneously accounting for the dependence structure and nonlinear age trajectories using existing tools. We propose a mixed-effects model to address this challenge by building random effects based on the latent brain aging status. We develop computationally efficient algorithms to estimate the parameters of new random effects. The simulations …

Pin-Pointing The Key Hubs In The Ifn-Γ Pathway Responding To Sars-Cov-2 Infection, Ayelen Toro, Sofia Lage-Vickers, Juan Bizzotto, Felipe Vilicich, Agustina Sabater, Gaston Pascual, Sabrina Ledesma-Bazan, Pablo Sanchis, Maria Sol Ruiz, Ana Paula Arevalo, Jorge L Porfido, Mercedes Abbate, Rocio Seniuk, Estefania Labanca, Nicolas Anselmino, Nora M Navone, Daniel F Alonso, Elba Vazquez, Martina Crispo, Javier Cotignola, Geraldine Gueron

Faculty, Staff and Student Publications

Interferon gamma (IFN-γ) may be potential adjuvant immunotherapy for COVID-19 patients. In this work, we assessed gene expression profiles associated with the IFN-γ pathway in response to SARS-CoV-2 infection. Employing a case-control study from SARS-CoV-2-positive and -negative patients, we identified IFN-γ-associated pathways to be enriched in positive patients. Bioinformatics analyses showed upregulation of MAP2K6, CBL, RUNX3, STAT1, and JAK2 in COVID-19-positive vs. -negative patients. A positive correlation was observed between STAT1/JAK2, which varied alongside the patient's viral load. Expression of MX1, MX2, ISG15, and OAS1 (four well-known IFN-stimulated genes (ISGs)) …

Sex-Specific Epigenetic Development In The Mouse Hypothalamic Arcuate Nucleus Pinpoints Human Genomic Regions Associated With Body Mass Index, Harry Mackay, Chathura J Gunasekara, Kit-Yi Yam, Dollada Srisai, Hari Krishna Yalamanchili, Yumei Li, Rui Chen, Cristian Coarfa, Robert A Waterland

Duncan NRI Faculty and Staff Publications

Recent genome-wide association studies corroborate classical research on developmental programming indicating that obesity is primarily a neurodevelopmental disease strongly influenced by nutrition during critical ontogenic windows. Epigenetic mechanisms regulate neurodevelopment; however, little is known about their role in establishing and maintaining the brain's energy balance circuitry. We generated neuron and glia methylomes and transcriptomes from male and female mouse hypothalamic arcuate nucleus, a key site for energy balance regulation, at time points spanning the closure of an established critical window for developmental programming of obesity risk. We find that postnatal epigenetic maturation is markedly cell type and sex specific and …

Identification Of An Early Survival Prognostic Gene Signature For Localized Osteosarcoma Patients, Harry Mackay, Chathura J Gunasekara, Kit-Yi Yam, Dollada Srisai, Hari Krishna Yalamanchili, Yumei Li, Rui Chen, Cristian Coarfa, Robert A Waterland

Faculty, Staff and Students Publications

Recent genome-wide association studies corroborate classical research on developmental programming indicating that obesity is primarily a neurodevelopmental disease strongly influenced by nutrition during critical ontogenic windows. Epigenetic mechanisms regulate neurodevelopment; however, little is known about their role in establishing and maintaining the brain's energy balance circuitry. We generated neuron and glia methylomes and transcriptomes from male and female mouse hypothalamic arcuate nucleus, a key site for energy balance regulation, at time points spanning the closure of an established critical window for developmental programming of obesity risk. We find that postnatal epigenetic maturation is markedly cell type and sex specific and …

Impact Of Neighborhood Quality And Recent Life Stressors On Sleep Problems: A Longitudinal Study Of Adolescents At Risk For Maltreatment, Krithika Prakash, Joseph Tu, Angela Staples

Journal of Applied Research on Children: Informing Policy for Children at Risk

It is estimated that around 70% of adolescents are not getting sufficient sleep. The impact of poor sleep during adolescence is related to both increased psychopathology and poorer academic and social functioning. While studies have established a link at the community level between earlier school start times and poorer sleep, there remain open questions about other aspects of community such as neighborhood factors and stressful life events. In this study, we investigated the impact of three neighborhood factors (chaos, stability, and efficacy) and recent life stressors on adolescent (n = 1354) sleep habits at ages 12, 14, and 16 …

Identifying Candidate Genes And Drug Targets For Alzheimer’S Disease By An Integrative Network Approach Using Genetic And Brain Region-Specific Proteomic Data, Andi Liu, Astrid M Manuel, Yulin Dai, Brisa S Fernandes, Nitesh Enduru, Peilin Jia, Zhongming Zhao

Faculty, Staff and Student Publications

Genome-wide association studies (GWAS) have identified more than 75 genetic variants associated with Alzheimer's disease (ad). However, how these variants function and impact protein expression in brain regions remain elusive. Large-scale proteomic datasets of ad postmortem brain tissues have become available recently. In this study, we used these datasets to investigate brain region-specific molecular pathways underlying ad pathogenesis and explore their potential drug targets. We applied our new network-based tool, Edge-Weighted Dense Module Search of GWAS (EW_dmGWAS), to integrate ad GWAS statistics of 472 868 individuals with proteomic profiles from two brain regions from two large-scale ad cohorts [parahippocampal gyrus …

Prognostic Molecular Biomarkers In Chordomas: A Systematic Review And Identification Of Clinically Usable Biomarker Panels, Franco Rubino, Christopher Alvarez-Breckenridge, Kadir Akdemir, Anthony P Conley, Andrew J Bishop, Wei-Lien Wang, Alexander J Lazar, Laurence D Rhines, Franco Demonte, Shaan M Raza

Faculty, Staff and Student Publications

INTRODUCTION AND OBJECTIVE: Despite the improvements in management and treatment of chordomas over time, the risk of disease recurrence remains high. Consequently, there is a push to develop effective systemic therapeutics for newly diagnosed and recurrent disease. In order to tailor treatment for individual chordoma patients and develop effective surveillance strategies, suitable clinical biomarkers need to be identified. The objective of this study was to systematically review all prognostic biomarkers for chordomas reported to date in order to classify them according to localization, study design and statistical analysis.

METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) …

Mucus-Degrading Bacteroides Link Carbapenems To Aggravated Graft-Versus-Host Disease, Eiko Hayase, Tomo Hayase, Mohamed A Jamal, Takahiko Miyama, Chia-Chi Chang, Miriam R Ortega, Saira S Ahmed, Jennifer L Karmouch, Christopher A Sanchez, Alexandria N Brown, Rawan K El-Himri, Ivonne I Flores, Lauren K Mcdaniel, Dung Pham, Taylor Halsey, Annette C Frenk, Valerie A Chapa, Brooke E Heckel, Yimei Jin, Wen-Bin Tsai, Rishika Prasad, Lin Tan, Lucas Veillon, Nadim J Ajami, Jennifer A Wargo, Jessica Galloway-Peña, Samuel Shelburne, Roy F Chemaly, Lauren Davey, Robert W P Glowacki, Chen Liu, Gabriela Rondon, Amin M Alousi, Jeffrey J Molldrem, Richard E Champlin, Elizabeth J Shpall, Raphael H Valdivia, Eric C Martens, Philip L Lorenzi, Robert R Jenq

Faculty, Staff and Student Publications

The intestinal microbiota is an important modulator of graft-versus-host disease (GVHD), which often complicates allogeneic hematopoietic stem cell transplantation (allo-HSCT). Broad-spectrum antibiotics such as carbapenems increase the risk for intestinal GVHD, but mechanisms are not well understood. In this study, we found that treatment with meropenem, a commonly used carbapenem, aggravates colonic GVHD in mice via the expansion of Bacteroides thetaiotaomicron (BT). BT has a broad ability to degrade dietary polysaccharides and host mucin glycans. BT in meropenem-treated allogeneic mice demonstrated upregulated expression of enzymes involved in the degradation of mucin glycans. These mice also had thinning of the colonic …

Testing A Behavioral Activation Gaming App For Depression During Pregnancy: Multimethod Pilot Study, Philipp Karschnia, Jacob S Young, Antonio Dono, Levin Häni, Stephanie T Juenger, Tommaso Sciortino, Francesco Bruno, Nico Teske, Ramin A Morshed, Alexander F Haddad, Yalan Zhang, Sophia Stoecklein, Michael A Vogelbaum, Juergen Beck, Nitin Tandon, Shawn Hervey-Jumper, Annette M Molinaro, Roberta Rudà, Lorenzo Bello, Oliver Schnell, Yoshua Esquenazi, Maximilian I Ruge, Stefan J Grau, Martin Van Den Bent, Michael Weller, Mitchel S Berger, Susan M Chang, Joerg-Christian Tonn

Faculty, Staff and Student Publications

In IDH-wildtype glioblastomas which meet the histopathological or molecular diagnosis criteria, it remains unclear whether the presence of TERT promotor mutations provides additional prognostic information. Based on a multicenter cohort of 466 IDH-wildtype glioblastomas (including 396 with and 70 patients without TERT promotor mutations), we found that TERT promotor mutations were neither associated with progression-free survival nor overall survival. This held true in various treatment-based or molecular subgroups. This argues against standardized analysis for TERT promotor mutation status for the purpose of prognostic or therapeutic relevance in newly diagnosed IDH-wildtype glioblastoma that otherwise meets the histopathological and …

De Novo Variants In Emc1 Lead To Neurodevelopmental Delay And Cerebellar Degeneration And Affect Glial Function In Drosophila, Hyung-Lok Chung, Patrick Rump, Di Lu, Megan R Glassford, Jung-Wan Mok, Jawid Fatih, Adily Basal, Paul C Marcogliese, Oguz Kanca, Michele Rapp, Johanna M Fock, Erik-Jan Kamsteeg, James R Lupski, Austin Larson, Mark C Haninbal, Hugo Bellen, Tamar Harel

Duncan NRI Faculty and Staff Publications

Background: The endoplasmic reticulum (ER)-membrane protein complex (EMC) is a multi-protein transmembrane complex composed of 10 subunits that functions as a membrane-protein chaperone. Variants in EMC1 lead to neurodevelopmental delay and cerebellar degeneration. Multiple families with biallelic variants have been published, yet to date, only a single report of a monoallelic variant has been described, and functional evidence is sparse.

Methods: Exome sequencing was used to investigate the genetic cause underlying severe developmental delay in three unrelated children. EMC1 variants were modeled in Drosophila, using loss-of-function (LoF) and overexpression studies. Glial-specific and neuronal-specific assays were used to determine whether the …

Integration Of Mouse Ovary Morphogenesis With Developmental Dynamics Of The Oviduct, Ovarian Ligaments, And Rete Ovarii, Jennifer Mckey, Dilara N Anbarci, Corey Bunce, Alejandra E Ontiveros, Richard R Behringer, Blanche Capel

Faculty, Staff and Student Publications

Morphogenetic events during the development of the fetal ovary are crucial to the establishment of female fertility. However, the effects of structural rearrangements of the ovary and surrounding reproductive tissues on ovary morphogenesis remain largely uncharacterized. Using tissue clearing and lightsheet microscopy, we found that ovary folding correlated with regionalization into cortex and medulla. Relocation of the oviduct to the ventral aspect of the ovary led to ovary encapsulation, and mutual attachment of the ovary and oviduct to the cranial suspensory ligament likely triggered ovary folding. During this process, the rete ovarii (RO) elaborated into a convoluted tubular structure extending …