Medical Specialties Commons^™

Ubiquitous Dysregulation Of The Wnt Pathway In Immune Thrombocytopenia Genetic Susceptibility, Estelle Lecluze, Stennio Da Silva Faria, Manon Saby, Jason Yu, Véronique Lisi, Vincent-Philippe Lavallée, Taylor Olmsted Kim, Michael E Scheurer, Amanda B Grimes, Thomas Pincez

Faculty, Staff and Students Publications

The pathogenesis of immune thrombocytopenia (ITP) is complex and incompletely understood. Multiple cell types have been implicated, and their respective contribution is unclear. A recent genome-wide association study identified single-nucleotide polymorphisms (SNPs) associated with pediatric ITP within or near 5 genes in the canonical Wnt signaling pathway. To investigate whether this pathway was dysregulated in ITP and identify which cell types were involved, we leveraged extensive functional genomics and single-cell RNA sequencing (scRNA-seq) data. By linking the identified SNPs to likely regulated genes, we showed an enrichment in the Wnt pathway and identified 2 additional genes in this pathway involved …

Mutations In The Key Autophagy Tethering Factor Epg5 Link Neurodevelopmental And Neurodegenerative Disorders Including Early-Onset Parkinsonism, Hormos Salimi Dafsari, Celine Deneubourg, Kritarth Singh, Reza Maroofian, Zita Suprenant, Ay Lin Kho, Neil J Ingham, Karen P Steel, Preethi Sheshadri, Franciska Baur, Lea Hentrich, Birgit Gerisch, Mina Zamani, Cesar Alves, Ata Siddiqui, Haidar S Dafsari, Mehri Salari, Anthony E Lang, Michael Harris, Alice Abdelaleem, Saeid Sadeghian, Reza Azizimalamiri, Hamid Galehdari, Gholamreza Shariati, Alireza Sedaghat, Jawaher Zeighami, Daniel Calame, Dana Marafi, Ruizhi Duan, Adrian Boehnke, Gary D Clark, Jill A Rosenfeld, Carrie A Mohila, Dora Steel, Saurabh Chopra, Suvasini Sharma, Nicolai Kohlschmidt, Steffi Patzer, Afshin Saffari, Darius Ebrahimi-Fakhari, Büşra Eser Çavdartepe, Irene J Chang, Erika Beckman, Renate Peters, Andrew Paul Fennell, Bernice Lo, Luisa Averdunk, Felix Distelmaier, Martina Baethmann, Frances Elmslie, Kairit Joost, Sheela Nampoothiri, Dhanya Yesodharan, Hanna Mandel, Amy Kimball, Antonie D Kline, Cyril Mignot, Boris Keren, Vincent Laugel, Katrin Õunap, Kalpana Devadathan, Frederique M C Van Berkestijn, Arpana Silwal, Saskia Koene, Sumit Verma, Mohammed Yousuf Karim, Chahynez Boubidi, Majid Aziz, Gehad Elghazali, Lauren Mattas, Mohammad Miryounesi, Farzad Hashemi-Gorji, Shahryar Alavi, Nayereh Nouri, Mehrdad Noruzinia, Saeideh Kavousi, Arveen Kamath, Sandeep Jayawant, Russell Saneto, Nourelhoda A Haridy, Pinar Ozkan Kart, Ali Cansu, Madeleine Joubert, Claire Beneteau, Kyra E Stuurman, Martina Wilke, Tahsin Stefan Barakat, Homa Tajsharghi, Annarita Scardamaglia, Sadeq Vallian, Semra Hız, Ali Shoeibi, Reza Boostani, Narges Hashemi, Meisam Babaei, Norah Saleh Alsaleh, Julie Porter, Tania Attié-Bitach, Pauline Marzin, Dorota Wicher, Jessica I Gold, Elisabeth Schuler, Amna Kashgari, Rakan F Alanazi, Wafaa Eyaid, Marc Engelen, Mirjam Langeveld, Burkhard Stüve, Yun Li, Gökhan Yigit, Bernd Wollnik, Mariana H G Monje, Dimitri Krainc, Niccolò E Mencacci, Somayeh Bakhtiari, Michael Kruer, Emanuela Argilli, Elliott Sherr, Yalda Jamshidi, Ehsan Ghayoor Karimiani, Yiu Wing Sunny Cheung, Ivan Karin, Giovanni Zifarelli, Peter Bauer, Wendy K Chung, James R Lupski, Manju A Kurian, Jörg Dötsch, Jürgen-Christoph Von Kleist-Retzow, Thomas Klopstock, Matias Wagner, Calvin Yip, Andreas Roos, Rita Carsetti, Carlo Dionisi-Vici, Mathias Gautel, Michael R Duchen, Adam Antebi, Henry Houlden, Manolis Fanto, Heinz Jungbluth

Faculty, Staff and Students Publications

Objective: Autophagy is a fundamental biological pathway with vital roles in intracellular homeostasis. During autophagy, defective cargoes including mitochondria are targeted to lysosomes for clearance and recycling. Recessive truncating variants in the autophagy gene EPG5 have been associated with Vici syndrome, a severe early-onset neurodevelopmental disorder with extensive multisystem involvement. Here, we aimed to delineate the extended, age-dependent EPG5-related disease spectrum.

Methods: We investigated clinical, radiological, and molecular features from the largest cohort of EPG5-related patients identified to date, complemented by experimental investigation of cellular and animal models of EPG5 defects.

Results: Through worldwide collaboration, we identified 211 patients, 97 …

Apol2 Stabilizes Ku80 To Confer Nhej-Mediated Radioresistance In Gastric Cancer, Dan Zu, Qimei Bao, Hanyi He, Yuke Zhong, Mingcong Deng, Yangchan Hu, Chunkai Zhang, Chen Liang, Yixing Huang, Haidong Liu, Xiao Li, Yanhua He, Guoyan Luo, Weixin Wu, Fenghui Guan, Shengfeng Xu, Min Liu, Albino Bacolla, Ji Jing, Yian Du, John A Tainer, Yin Shi, Zu Ye, Xiangdong Cheng

Faculty, Staff and Student Publications

Radiotherapy is one of the most important adjuvant treatment methods for gastric cancer (GC). However, radioresistance remains a major clinical obstacle. In this study, APOL2 is identified as a key player in promoting non-homologous end joining (NHEJ)-mediated double-strand break (DSB) repair and enhancing radioresistance in GC. Bioinformatics and clinical data revealed that high APOL2 expression is correlated with poor prognosis in GC patients. Functional experiments showed that APOL2 overexpression enhances genomic stability by accelerating DSB repair via the NHEJ pathway, while APOL2 knockout impairs repair capacity. Mechanistically, APOL2 binds to and stabilizes Ku80 by enhancing USP7-mediated deubiquitylation, thereby increasing Ku80 …

Genome Sequencing Reveals The Impact Of Pseudoexons In Rare Genetic Disease, Georgia Pitsava, Megan Hawley, Light Auriga, Ivan De Dios, Arthur Ko, Sofia Marmolejos, Miguel Almalvez, Ingrid Chen, Kaylee Scozzaro, Jianhua Zhao, Rebekah Barrick, Nicholas Ah Mew, Vincent A Fusaro, Jonathan Lotempio, Matthew Taylor, Luisa Mestroni, Sharon Graw, Dianna Milewicz, Dongchuan Guo, David R Murdock, Kinga M Bujakowska, Changrui Xiao, Emmanuèle C Délot, Seth I Berger, Eric Vilain

Faculty, Staff and Student Publications

Purpose: Advancements in sequencing technologies have significantly improved clinical genetic testing; yet, the diagnostic yield remains around 30% to 40%. Emerging technologies are now being deployed to address the remaining diagnostic gap.

Methods: We tested whether short-read genome sequencing could increase the diagnostic yield in individuals enrolled into the UCI-GREGoR research study, who had suspected Mendelian conditions and prior inconclusive testing. Two other collaborative research cohorts, focused on aortopathy and dilated cardiomyopathy, consisted of individuals who were undiagnosed but had not undergone harmonized prior testing.

Results: We sequenced 353 families (754 participants) and found a molecular diagnosis in 54 (15.3%) …

Risk Score Roulette: A Cautionary Tale Of Polygenic Risk Score Reliability, Diane Xue, Elizabeth E Blue, Alexis C Wood, Jerome I Rotter, Alison E Fohner

Children’s Nutrition Research Center Staff Publications

Genetic risk prediction for Alzheimer's disease (AD) has high potential impact, yet few studies have assessed the reliability of various polygenic risk score (PRS) methods at the individual level. Here, we evaluated the reliability of AD PRS estimates among 6338 participants from the Multi-Ethnic Study of Atherosclerosis. We compared four PRS models that have been previously associated with dementia risk. Despite similar population-level performance metrics, inter-model reliability of individual-level risk assessment was low, even among individuals classified in the top and bottom deciles. These findings raise serious concerns about the downstream application of PRS for guiding interventions for AD.

Low Socioeconomic Status Adversely Influences Outcomes After Coronary Artery Bypass Grafting, Paige E Brlecic, Christopher B Sylvester, Katie J Hogan, Qianzi Zhang, Joseph S Coselli, Marc R Moon, Todd K Rosengart, Subhasis Chatterjee, Ravi K Ghanta

Faculty, Staff and Students Publications

Objectives: Although socioeconomic status (SES) is believed to affect patient outcomes after coronary artery bypass grafting (CABG), readmission data are sparse. In a national cohort, we analyzed the influence of SES on readmission, resource utilization, and mortality after CABG.

Methods: We queried the Nationwide Readmissions Database to identify patients who underwent isolated CABG from January 2016 through December 2018. We derived low, middle, and high SES from International Classification of Diseases, 10th Revision, Clinical Modification codes, patient demographics, and neighborhood-level factors. The effect of SES on risk-adjusted outcomes was assessed with multivariable analysis.

Results: Of 523,042 patients who underwent CABG, …

Two Decades Of Diagnostic Safety Research: Advances, Challenges, And Next Steps, Sundas Khan, Andrea Bradford, Christina L Cifra, Hardeep Singh

Faculty, Staff and Students Publications

Since the National Academies of Sciences, Engineering, and Medicine (NASEM) report Improving Diagnosis in Health Care, various research efforts have accelerated progress to understand and improve diagnostic safety. In this opinion piece, we summarize two decades of progress in methods for identifying and learning from diagnostic errors and provide recommendations for future research. Multiple methods have been used to quantify diagnostic errors in various clinical settings, thereby facilitating a deeper understanding of the nature and magnitude of the problem and enabling studies of contributing factors. However, the use of standardized definitions of a diagnostic error and/or diagnostic safety event, …

Foreword: Addressing Diagnostic Error: The First 10 Years, Mark L Graber, Edward P Hoffer, Hardeep Singh

Faculty, Staff and Students Publications

No abstract provided.

Upper Respiratory Tract Infection Leading To A New Diagnosis Of Sweet Syndrome And Monoclonal Gammopathy Of Unknown Significance, Nidhi Rawat, Meron Gebrehiwot, Jason Raw, Jeyaprakash Ramachandran

HCA Healthcare Journal of Medicine

Background

We present a rare case of Sweet syndrome with underlying monoclonal gammopathy of unknown significance (MGUS) which initially presented as upper respiratory tract infection.

Case Presentation

A 52-year-old woman presented with a complaint of sore throat for 6 days, productive cough and fever for 5 days, and red, pruritic, circular, tender rashes on face, arms and trunk for 2 days. There was a past history of similar self-limiting rashes presenting intermittently for 1.5 years. She also reported to be taking tablet ibuprofen, as required for the past 1-2 years, for cervical spondylosis. On integumentary examination, widespread, red, tender, annular …

Safety And Efficacy Of Liver-Directed Radiotherapy After Chemoimmunotherapy For Advanced Cholangiocarcinoma: An Early Report From A Large Tertiary Cancer Center, Abdulmoiz Asif, Abdulmoid Asif, Michael K Rooney, Enoch Chang, Felicity Namayanja, Kimana Quentin, Sunyoung Lee, Ian Hu, Vincent Bernard, Prajnan Das, Emma B Holiday, Sonal Noticewala, Grace L Smith, Albert C Koong, Ethan B Ludmir, Milind Javle, Lianchun Xiao, Eugene J Koay

Faculty, Staff and Student Publications

BACKGROUND: Recent randomized controlled trials have established chemoimmunotherapy as the standard of care for patients with advanced biliary cancers with a median overall survival (OS) of about thirteen months. No data exist to demonstrate the safety and efficacy of liver-directed radiotherapy (RT) for extrahepatic and intrahepatic cholangiocarcinoma (CCA) in the era of chemoimmunotherapy. The purpose of this study is to report our early experience treating patients with CCA using RT and chemoimmunotherapy.

METHODS: Twenty-eight patients with CCA who received chemoimmunotherapy sequentially and/or concurrently with RT were retrospectively analyzed. The median biologic equivalent dose (BED) of RT was 84.0 [interquartile range …

Urinary Vitamin D Binding Protein And Kidney Injury Molecule-1 Are Potent Predictors Of Acute Kidney Injury After Left Ventricular Assist Device Implantation, Shiyi Li, Iván Murrieta-Álvarez, Katherine V Nordick, Zachary Gray, Camila Hochman-Mendez, Alexis E Shafii, Kenneth K Liao, Carl P Walther, Nandan K Mondal

Faculty, Staff and Students Publications

Background/Objectives: Acute kidney injury (AKI) is a frequent and serious complication following left ventricular assist device (LVAD) implantation. This study aimed to predict AKI within 90 days post-LVAD by evaluating urinary levels of vitamin D binding protein (VDBP) and kidney injury molecule-1 (KIM-1).

Methods: We prospectively enrolled 29 advanced heart failure patients undergoing LVAD implantation and categorized them into four groups based on pre-LVAD kidney function and hemodynamic stability. Early-morning urine samples were collected 24 h before and 1 week after surgery. Urinary VDBP and KIM-1 levels, normalized to creatinine, were measured.

Results: Thirteen patients developed AKI …

Pediatric Non-Down Syndrome Acute Megakaryoblastic Leukemia Patients Have Dismal Outcomes Irrespective Of Allogeneic Hematopoietic Stem Cell Transplant: A Single-Center Experience, Gabriela Llaurador, Matthew Willis, Michele S Redell, M Monica Gramatges, Andrea N Marcogliese, Swati Naik, Robert Krance, Erin Doherty, Alexandra M Stevens

Faculty, Staff and Students Publications

Background: Pediatric non-Down Syndrome Acute Megakaryoblastic Leukemia (non-DS-AMKL) is a rare subtype of Acute Myeloid Leukemia (AML) arising from primitive megakaryocytes and is associated with poor outcomes. Given its high incidence of relapse, this subpopulation of children is frequently referred for allogeneic hematopoietic stem cell transplant (allo-HSCT) in first complete remission (CR1).

Objectives: The objective of this study was to describe the clinical outcomes of non-DS-AMKL pediatric patients in a large, single-institution cohort.

Methods: A retrospective review of the medical records of thirty-six patients diagnosed with non-DS-AMKL treated at Texas Children's Hospital from 2000 to 2022 was conducted.

Results: Twenty-nine …

Resolving Slc6a1 Variable Expressivity With Deep Clinical Phenotyping And Drosophila Models, Kristy L Jay, Nikhita Gogate, Paige I Hall, Kimberly M Ezell, Jonathan C Andrews, Sharayu V Jangam, Hongling Pan, Kelvin Pham, Ryan German, Vanessa Gomez, Emily Jellinek-Russo, Eric A Storch, Brain Gene Registry Consortium, Undiagnosed Diseases Network, Shinya Yamamoto, Oguz Kanca, Hugo J Bellen, Herman A Dierick, Joy D Cogan, John A Phillips, Rizwan Hamid, Thomas Cassini, Lynette Rives, Sumit Pruthi, Hua-Chang Chen, Jennifer E Posey, Michael F Wangler

Faculty, Staff and Students Publications

Variants in SLC6A1 result in a rare neurodevelopmental disorder characterized by a variable clinical presentation of symptoms including developmental delay, epilepsy, motor dysfunction, and autism spectrum disorder. SLC6A1 haploinsufficiency has been confirmed as the predominant pathway of SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD); however, the molecular mechanism underlying the variable clinical presentation remains unclear. Here, through work of the Undiagnosed Diseases Network, we identify an individual with an inherited p.A334S variant of uncertain significance. To resolve this variant and better understand the variable expressivity associated with SLC6A1, we assess the phenotypes of the proband in comparison with a cohort of 13 individuals …

Erratum To <[Transplant Cell Ther 2023 Jul;29(7):438e1-438e16 Epub 2023 Mar 9]>, Melissa R Hines, Tristan E Knight, Kevin O Mcnerney, Mark B Leick, Tania Jain, Sairah Ahmed, Matthew J Frigault, Joshua A Hill, Michael D Jain, William T Johnson, Yi Lin, Kris M Mahadeo, Gabriela M Maron, Rebecca A Marsh, Sattva S Neelapu, Sarah Nikiforow, Amanda K Ombrello, Nirav N Shah, Aimee C Talleur, David Turicek, Anant Vatsayan, Sandy W Wong, Marcela V Maus, Krishna V Komanduri, Nancy Berliner, Jan-Inge Henter, Miguel-Angel Perales, Noelle V Frey, David T Teachey, Matthew J Frank, Nirali N Shah

Faculty, Staff and Student Publications

No abstract provided.

Final Analysis Of The Resonate-2 Study: Up To 10 Years Of Follow-Up Of First-Line Ibrutinib Treatment For Cll/Sll, Jan A Burger, Paul M Barr, Tadeusz Robak, Carolyn Owen, Alessandra Tedeschi, Anita Sarma, Piers E M Patten, Sebastian Grosicki, Helen Mccarthy, Fritz Offner, Edith Szafer-Glusman, Cathy Zhou, Anita Szoke, Lynne Neumayr, James P Dean, Paolo Ghia, Thomas J Kipps

Faculty, Staff and Student Publications

With up to 10 years of follow-up, we report results from the final analysis of RESONATE- 2, a phase 3 study of first-line ibrutinib vs chlorambucil for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients aged ≥65 years with previously untreated CLL/SLL without del(17p) were randomly assigned to receive either single-agent ibrutinib (420 mg/d; n = 136) or chlorambucil (0.5-0.8 mg/kg; ≤12 cycles; n = 133). With a median follow-up of 9.6 years in the ibrutinib arm, the median progression-free survival (PFS) was 8.9 years (95% confidence interval [CI], 7.0 to not estimable [NE]) vs 1.3 years (95% …

Longitudinal Characterization Of Males With X-Linked Creatine Transporter Deficiency: Final Results Of A Multiyear Observational Study, Judith S Miller, Cristan Farmer, Susan Blair, Simona Bianconi, Natacha Akshoomoff, Irina Anselm, Bruce A Barshop, Lindsey Becker, Amanda E Bennett, Leandra N Berry, Elizabeth M Berry-Kravis, Aleksandra Bruchey, Anna W Byars, Tricia Cimms, Kim M Cecil, Maxine Covello, Laura S Cubit, Tanvi Das, Robert J Davis, Madison Drye, Can Ficicioglu, John B Fulton, Robin P Goin-Kochel, Whitney Guthrie, Barbara E Hallinan, Fady Hannah-Shmouni, Kathryn E Gustafson, Dwight D Koeberl, Nicola Longo, Eva Mamak, Saadet Mercimek-Andrews, Claire Michalak, Forbes D Porter, Samar Rahhal, Linda Rees, Gail A Spiridigliozzi, Caitlin Stone, Nancy R Sullivan, V Reid Sutton, Rebecca P Thomas, Manisha Udhnani, Susan Waisbren, Michelle Xu, Lin Zhang, Melanie Brandabur, Audrey Thurm

Faculty, Staff and Students Publications

Background: The purpose of the Vigilan observational study (ClinicalTrials.gov, NCT02931682) was to prospectively assess the natural history and developmental course of creatine transporter deficiency (CTD).

Methods: Males with CTD aged 6 months to 65 years were evaluated at 6-month intervals for up to 4 years. Evaluations included neurodevelopmental assessments of intellectual functioning, adaptive functioning, and challenging behaviors and the onset and progression of medical comorbidities.

Results: Fifty participants (median age, 7.6 years) were enrolled. The predominant CTD phenotype consisted of significant intellectual disabilities and limited skill development over time. Most participants had a history of febrile or nonfebrile seizures, …

A Single-Nucleus Transcriptomic Atlas Of The Adult Aedes Aegypti Mosquito, Olivia V Goldman, Alexandra E Defoe, Yanyan Qi, Yaoyu Jiao, Shih-Che Weng, Brittney Wick, Leah Houri-Zeevi, Priyanka Lakhiani, Takeshi Morita, Jacopo Razzauti, Adriana Rosas-Villegas, Yael N Tsitohay, Madison M Walker, Ben R Hopkins, Aedes Aegypti Mosquito Cell Atlas Consortium, Maximilian Haeussler, Omar S Akbari, Laura B Duvall, Helen White-Cooper, Trevor R Sorrells, Roshan Sharma, Hongjie Li, Leslie B Vosshall, Nadav Shai

Faculty, Staff and Students Publications

The female Aedes aegypti mosquito's remarkable ability to hunt humans and transmit pathogens relies on her unique biology. Here, we present the Aedes aegypti Mosquito Cell Atlas, a comprehensive single-nucleus RNA sequencing dataset of more than 367,000 nuclei from 19 dissected tissues of adult female and male Aedes aegypti, providing cellular-level resolution of mosquito biology. We identify novel cell types and expand our understanding of sensory neuron organization of chemoreceptors across all sensory tissues. Our analysis uncovers male-specific cells and sexually dimorphic gene expression in the antenna and brain. In female mosquitoes, we find that glial cells, rather than neurons, …

Cohesin Haploinsufficiency Is Tolerated In Cbfb::Myh11-Driven Murine Acute Myeloid Leukemia, Shannon E Conneely, Alexis Quezada, Kristen J Kurtz, Nenggang Zhang, Josephine De La Fuente, Nesa Mercer, Jason H Rogers, Rogelio Aguilar, Geraldo Medrano, Margaret A Goodell, Paul P Liu, Debananda Pati, Rachel E Rau

Faculty, Staff and Students Publications

Cohesin gene mutations occur in many malignancies, including acute myeloid leukemia (AML). Loss-of-function mutations in the four major cohesin complex genes (RAD21, SMC3, SMC1a, and STAG2) occur across most major genetic subtypes of AML but are notably absent in AML harboring CBFB::MYH11, suggesting that cohesin mutations yield distinct biological outcomes dependent on the genetic AML driver. We hypothesized that CBFB::MYH11-expressing leukemias would be dependent on intact cohesin genes given their near-mutual exclusivity. To investigate this, we combined either germline or inducible heterozygous deletions in cohesin genes Smc3 or Rad21, respectively, with an inducible murine model of Cbfb::MYH11 AML. This approach …

Distinct Molecular Responses Of Human Intestinal Organoids To Proton And Photon Radiation, Victoria Poplaski, Tajhal D Patel, Hoa Nguyen-Phuc, Amal Kambal, Lawrence Bronk, Mary K Estes, Cristian Coarfa, Sarah E Blutt

Faculty, Staff and Students Publications

Radiation exposure impairs rapidly renewing tissues like the intestinal epithelium, yet translational insights from murine models have been limited by species-specific responses. Here, we use human intestinal organoids (HIOs) derived from jejunal epithelium to evaluate human epithelial responses to low dose proton and photon (gamma) radiation. Gamma irradiation induces a unique developmental and metabolic shift in crypt-like organoids, including enrichment of amino acid metabolism pathways and activation of fetal-associated transcription factors and morphology. Integrated multi-omic profiling reveals serotonin biosynthesis as a central regenerative node. Human intestinal organoids can complement animal models and are emerging as a powerful tool in modeling …

Sensitivity And Specificity Of The Cobas Liat Ct/Ng/Mg Nucleic Acid Test In A Clinical Laboratory Setting And Point-Of-Care Location, B Van Der Pol, R Arcenas, C Boraas, S Chavoustie, L L. Crane, N D'Empaire, A C. Ermel, G Harnett, F Hinestrosa, S House, Rebecca A. Lillis, J Miller, A Mills, R Poblete, S A. Young

School of Medicine Faculty Publications

Sexually transmitted infections, e.g., Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Mycoplasma genitalium (MG), present with similar signs/symptoms and are often treated empirically due to delays in receiving diagnostic test results. This study evaluated the clinical performance of the Cobas Liat CT/NG/MG nucleic acid amplification test (NAAT) in detecting these pathogens in a point-of-care (POC) setting. This non-interventional, multicenter study recruited symptomatic/asymptomatic participants from 13 geographically diverse POC sites across the USA. Prospective clinician- and self-collected specimens (urine/vaginal swabs) were used to determine the sensitivity and specificity of the Cobas Liat CT/NG/MG test relative to the composite reference standard (CRS), …

Scrotal Temperature Change During Running In Naked Humans, Yasuho Takii, Makoto Fukuda, Kazuyuki Kanosue, Tamae Yoda

Children’s Nutrition Research Center Staff Publications

Male reproductive organs are functionally affected by high body temperature. This study aimed to clarify the thermoregulation mechanisms of the human scrotum during running, and experiments were conducted to investigate temperature changes in the whole body and the scrotum. Eleven male long-distance runners performed treadmill running at 60%[Formula: see text] for 60 min in an indoor environment at 27 °C and 40% relative humidity. Immediately after the start of the run, the skin temperatures in areas other than the scrotum decreased or showed a tendency to decrease. In contrast, the scrotal temperature increased immediately after the start of the run. …

Epdevatlas: Mapping Gabaergic Cells And Microglia In The Early Postnatal Mouse Brain, Josephine K. Liwang, Fae N. Kronman, Hyun-Jae Pi, Yuan-Ting Wu, Daniel J. Vanselow, Steffy B. Manjila, Deniz Parmaksiz, Donghui Shin, Yoav Ben-Simon, Michael Taormina, Sharon W. Way, Hongkui Zeng, Bosiljka Tasic, Lydia Ng, Yongsoo Kim

School of Graduate Studies Faculty Publications

During development, brain regions follow encoded growth trajectories. Compared to classical brain growth charts, high-definition growth charts could quantify regional volumetric growth and constituent cell types, improving our understanding of typical and pathological brain development. Here, we create high-resolution 3D atlases of the early postnatal mouse brain, using Allen CCFv3 anatomical labels, at postnatal days (P) 4, 6, 8, 10, 12, and 14, and determine the volumetric growth of different brain regions. We utilize 11 different cell type-specific transgenic animals to validate and refine anatomical labels. Moreover, we reveal region-specific density changes in γ-aminobutyric acid-producing (GABAergic) neurons, cortical layer-specific cell …

Prevalence And Clinical Impact Of Pseudohypercalcemia In Paraproteinemia: A Case And Cohort Study, Usman Sunusi, Li Chen, Nianyi Li, Jason K Y Lee, Irmeen Siddiqui, Erin Goodhue, Rongrong Huang, Jieli Li

Faculty, Staff and Students Publications

Background: Hypercalcemia is a common and serious complication of malignancy, often contributing to morbidity and mortality. In patients with paraproteinemia, elevated total calcium with normal ionized calcium, termed pseudohypercalcemia, can complicate diagnosis and lead to inappropriate treatment. While this phenomenon has been described in case reports, its prevalence and clinical impact in routine practice remain poorly defined.

Methods: We report a case of pseudohypercalcemia in a patient with IgG κ multiple myeloma and conducted a retrospective review of de-identified data to assess the prevalence and biochemical associations of pseudohypercalcemia in paraproteinemia. Available data included serum protein electrophoresis (SPEP), …

Translational Framework Linking Perfluoroheptanoic Acid (Pfhpa) Exposure To Metabolic Dysfunction Associated Steatotic Liver Disease In Adolescents, Brittney O Baumert, Ana C Maretti-Mira, Douglas I Walker, Zhenjiang Li, Nikos Stratakis, Hongxu Wang, Yinqi Zhao, Fabian Christoph Fischer, Qiran Jia, Damaskini Valvi, Scott M Bartell, Jiawen Carmen Chen, Thomas Inge, Justin R Ryder, Todd Jenkins, Stephanie Sisley, Stavra Xanthakos, David E Kleiner, Rohit Kohli, Sarah Rock, Sandrah P Eckel, Michele A La Merrill, Max M Aung, Matthew P Salomon, Rob Mcconnell, Jesse Goodrich, David V Conti, Lucy Golden-Mason, Lida Chatzi

Faculty, Staff and Students Publications

Background: The rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), particularly among pediatric populations, requires identification of modifiable risk factors to control disease progression. Per- and polyfluoroalkyl substances (PFAS) have emerged as potential contributors to liver damage; however, their role in MASLD remains underexplored. This study aimed to develop a translational framework integrating human and in vitro data to elucidate the effect of PFAS on MASLD development.

Methods: We measured PFAS plasma levels in the Teen-LABS cohort (n = 136), comprising adolescents with obesity (mean age = 16.8 years) undergoing bariatric surgery. Plasma samples were also analyzed using proteomic …

Microglia Sensing Of Peripheral Signals That Bridge The Brain And Body, Claire E Young, Melanie A Samuel

Faculty, Staff and Students Publications

Microglia are the resident immune cell of the brain, and alterations in microglia signaling have been implicated in many neurodegenerative disorders. While microglia responses to central cues and other brain cell types are well documented, studies are increasingly investigating the impact of peripherally derived signals on microglia function. A diverse array of peripheral cues, including dietary components, hormones, and bacteria metabolites and components from the microbiome cross the blood brain barrier and directly influence microglia state through ligand-receptor interactions. This review highlights the complexity of brain-body interactions from the perspective of microglia function and proposes the idea that microglia could …

Insights Into Spheroid Formation: Interaction Of Ovarian Cancer Cells With Macrophage Populations In The Tumor Microenvironment, Simone Pisano, Yajaira Sofia Jimenez, Paul Rees, Jing Xiao, Deyarina Gonzalez, Robert Steven Conlan, Bruna Corradetti

Faculty, Staff and Students Publications

Background: Treating advanced ovarian cancer (OC) is challenging due to the immunosuppressive tumor microenvironment. This study investigates tumor-immune cell interactions using organotypic spheroid models that simulate the in vivo microenvironment.

Methods: A dual-model spheroid system was established combining serous adenocarcinoma SKOV-3 cells with monocytes, pro-inflammatory (MΦ1) or anti-inflammatory (MΦ2) macrophages, or their derived exosomes (EXOs). In Model A, immune cells or EXOs were co-seeded with tumor cells to replicate early heterotypic aggregation. In Model B, immune cells or EXOs were introduced 24 h post-spheroid formation to simulate immune infiltration into established spheroids. Spheroid morphology was quantified by diameter and circularity, …

Nasal Microbionts Differentially Colonize And Elicit Cytokines In Human Nasal Epithelial Organoids, Andrea I Boyd, Leah A Kafer, Isabel F Escapa, Amal Kambal, Hira Tariq, Susan G Hilsenbeck, Hoa Nguyen-Phuc, Anubama Rajan, Joshua M Lensmire, Kathryn A Patras, Pedro A Piedra, Sarah E Blutt, Katherine P Lemon

Faculty, Staff and Students Publications

Nasal colonization by Staphylococcus aureus or Streptococcus pneumoniae is associated with an increased risk of infection by these pathobionts, whereas nasal colonization by Dolosigranulum species is associated with health. Human nasal epithelial organoids (HNOs) differentiated at air-liquid interface (ALI) physiologically recapitulate human nasal respiratory epithelium with a robust mucociliary blanket. Due to their natural stem-like properties, HNO lines are a long-term experimental resource that offers genetic diversity based on the different donors. To develop HNOs as a new model system for bacterial nasal colonization, we reproducibly monocolonized HNOs differentiated at ALI with S. aureus, S. pneumoniae, or Dolosigranulum …

Effect Of Valemetostat On The Pharmacokinetics Of Midazolam And Digoxin: A Phase 1 Drug-Drug Interaction Study In Patients With Non-Hodgkin Lymphoma, Masaya Tachibana, Steven Horwitz, Eric Jacobsen, Francine Foss, Pamela Allen, Pierluigi Porcu, Tatyana Feldman, Jia Ruan, Jonathan Brammer, Jie Wang, Shinichi Inaba, Yuka Iko, Keiko Nakajima, Yasuyuki Kakurai, Noriaki Kitami, Yang Chen, Yvonne Lau

Department of Medicine Faculty Papers

Valemetostat tosylate (valemetostat) is an oral, potent, dual inhibitor of enhancer of zeste homolog (EZH)2/1, under investigation in non-Hodgkin lymphomas (NHLs) and solid tumors. In vitro, it inhibits cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) when combined with sensitive CYP3A or P-gp substrates. This drug–drug interaction (DDI) sub-study is part of the phase 1 trial of valemetostat monotherapy (DS3201-A-J101; NCT02732275), assessing the effect of valemetostat on the pharmacokinetics (PK) of sensitive CYP3A and P-gp substrates midazolam and digoxin, respectively, in patients with relapsed or refractory NHL, and its safety and efficacy. Patients received two simultaneous single doses of midazolam and …

Factor Structure Of Food And Physical Activity Parenting Practices Among Us Fathers By Ethnicity And Survey Language: A Cross Sectional Study, Salma M A Musaad, Louise C Mâsse, Alicia Beltran, Oriana Perez, Teresia M O'Connor

Children’s Nutrition Research Center Staff Publications

Background: Parenting practices contribute to children’s eating and physical activity behaviors, and thereby their risk of obesity and associated medical conditions. Fathers may engage in different parenting practices than mothers. The objective of this study was therefore to establish psychometrically sound tools in English and Spanish for measuring Physical Activity Parenting Practices (PAPP) and Food Parenting Practices (FPP) for Hispanic and non-Hispanic fathers of diverse races for use in future studies, such as evaluations of family-based obesity interventions targeted at fathers.

Methods: We conducted a preliminary assessment of the psychometric properties of a reduced version of the PAPP and FPP …

Nuclear Poly(A)-Binding Protein And Nucleolin Utilize Their Rna Recognition Motifs To Read Par Chains, Leilei Shi, Morgan Dasovich, John R Horton, Hongrui Liu, Qiansheng Zhan, Swarnalatha Manickavinayaham, Collene R Jeter, Isaiah J Mixon, Nicholas M Zehrbach, Charles A Ishak, Je-Hyun Yoon, Xiaodong Cheng, Anthony K L Leung, Mark T Bedford

Faculty, Staff and Student Publications

Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification mediated by ADP-ribosyltransferases, known as PARPs, which attach ADP-ribose units onto proteins, forming negatively charged multimeric chains. This modification relaxes chromatin at DNA damage sites, facilitating repair machinery access. Additionally, PAR polymers serve as docking platforms for effector proteins, termed PAR "readers", commonly involved in DNA repair. The recruitment of these proteins is mediated through conserved protein domains, including RNA recognition motifs (RRMs). Using an array of hundreds of recombinant RNA-binding domains, we systematically examined RRM interactions with PAR chains of varying lengths. Despite their chemical similarity to RNA, only a small subset of …