Digital Commons Network^™

Steroid Receptor Coactivator 3-Deficient Regulatory T Cells Eradicate Multiple Solid Tumors In Syngeneic Mouse Models, Nuri Sung, Eunsu Kim, Yosef Gilad, Yuri Park, Adam M Dean, Yan Xia, Jianming Xu, Clifford C Dacso, David M Lonard, Sang Jun Han

Faculty, Staff and Students Publications

Steroid receptor coactivator 3 (SRC-3) is highly expressed in regulatory T cells (Tregs) and is important for their immunosuppressive activity. Recently, we demonstrated that disrupting SRC-3 expression in Tregs eliminates triple-negative breast cancer (TNBC) and prostate cancer in syngeneic animal models by generating an anti-tumor immune microenvironment without inducing immune-related adverse events (irAEs). Further analysis of these mice revealed that SRC-3 knockout (KO) Tregs infiltrated breast tumors and facilitated the infiltration of CD8

Mtorc2-Nav1.2 Signaling Drives Early Hyperexcitability In Alzheimer’S Disease Mouse Model, Nolan M Dvorak, Jeffrey L Noebels

Faculty, Staff and Students Publications

Hyperexcitability is a biomarker of early-stage Alzheimer’s Disease (AD) and hastens cognitive decline later in its course. Mechanistic target of rapamycin (mTOR) signaling contributes to the slope of this trajectory, as evidenced by early increased brain expression and the rescue of hyperexcitability by genetic deletion of mTOR complex 2 (mTORC2); however, a molecular mechanism directly linking mTOR signaling to membrane hyperexcitability in early-stage AD remains elusive. Here, we show that hyperactive mTOR signaling stimulates the voltage-gated Na+ channel 1.2 (Nav1.2), a previously identified downstream phosphorylation target of mTORC2 and a key regulator of membrane electrogenesis. Augmented Nav1.2 channel function induced …

Nf1 Loss In Estrogen Receptor-Positive Breast Cancer Induces Osteoclast Formation And Immunosuppression To Promote Bone Metastasis, Zifan Zhao, Ze-Yi Zheng, Jonathan T Lei, Matthew J Baik, Yi-Hsuan Wu, Lauren K Somes, Andres F Mosquera Paternina, Omar A Harb, Owen A Chang, Fengshuo Liu, Matthew V Holt, Junkai Wang, Igor Bado, Hai Wang, George Miles, Zbigniew Gugala, Meenakshi Anurag, Ahmed Elkhanany, Yi Li, Valentina Hoyos, Xiang H-F Zhang, Eric C Chang

Faculty, Staff and Students Publications

Estrogen receptor-positive (ER+) breast cancer exhibits a marked propensity for skeletal metastasis; however, the molecular drivers of bone colonization remain incompletely defined. We investigated the tumor suppressor neurofibromin (NF1), a dual repressor for RAS and ER signaling, whose inactivation promotes endocrine therapy (ET) resistance and is associated with inferior relapse-free survival. NF1 copy number loss was detected in 62% of ER+ patients who subsequently developed metastases and was associated with an increased likelihood of bone metastases at initial diagnosis. In mouse xenograft models, NF1-depleted ER+ breast cancer cells demonstrated enhanced dissemination to skeletal sites following surgical resection of primary tumors. …

Neuronal Expression Of Bromodomain Proteins Alters Neuronal Health And Peripheral Protein Homeostasis To Promote Longevity, Naibedya Dutta, Daniel Hicks, Edgar Esparza, Anna Entin, Priyadharshini Vijayakumar, Caitlin M Lange, Tripti Nair, Elijah A Roditi, Athena Alcala, Maxim Averbukh, Matthew Vega, Rebecca Aviles Barahona, Caitlin Mctygue, Veronica Kuo, Juri Kim, Herbert Anson, Aeowynn J Coakley, George Wang, Steven E Pilley, Max A Thorwald, Whitaker Cohn, Sean P Curran, Nicolas Brouilly, Caroline Kumsta, Rachel N Arey, Peter J Mullen, Gilberto Garcia, Ryo Higuchi-Sanabria

Faculty, Staff and Students Publications

Longevity and stress resilience require precise coordination of gene expression programs across tissues. Here, we demonstrate that overexpression of the chromatin reader bet-1 specifically in neurons of Caenorhabditis elegans promotes organismal longevity and stress resistance via cell-nonautonomous signaling. Neuronal bet-1 elicits a neurotransmitter-dependent signal that activates the conserved stress-responsive transcription factor HSF-1 in the intestine, enhancing proteostasis, oxidative stress resistance, metabolic remodeling, and immune defense. Life span extension by neuronal bet-1 requires both hsf-1 and daf-16 in neurons but only requires hsf-1 in peripheral tissues. Using bulk RNA sequencing, we reveal distinct prolongevity pathways that include enhanced heat-shock response, proteostasis, …

Cigarette Smoke Induces Fasn-Dependent Fatty Acid Metabolic Rewiring To Drive Bladder Cancer Progression, Chandra Sekhar Amara, Danthasinghe Waduge Badrajee Piyarathna, Abu Hena Mostafa Kamal, Yuen San Chan, Karthik Reddy Kami Reddy, Chandra Shekar R Ambati, Mohammed Khurshidul Hassan, Pratik Shriwas, Tanmay Gandhi, Antrix Jain, Tanja Gangnus, Pooja Popli, Roshan Borkar, Sung Wook Kang, Silvia L Summers, Vasanta Putluri, Sandra L Grimm, Sharan Venkatesh, Ningxin Song, Erin H Seeley, Jenna Hedlich-Dwyer, Shu-Hsia Chen, Nupam P Mahajan, Abhinav K Jain, Lacey Elizabeth Dobrolecki, Gabrielle A Wells, Hugo Villanueva, Jenny Li, Xuefeng Liu, Roni J Bollag, Anna Malovannaya, Sung Yun Jung, Hyun-Sung Lee, Irfan A Asangani, Martha K Terris, Chad J Creighton, Leomar Y Ballester, Balasubramanyam Karanam, Suyu Liu, Minjae Lee, Rajeeva R Raju, M Minhaj Siddiqui, Livia S Eberlin, Ramakrishna Kommagani, Arun Sreekumar, Jianjun Gao, Nicolas L Young, H Courtney Hodges, Cristian Coarfa, Natalie R Gassman, Seth P Lerner, Yair Lotan, Nagireddy Putluri

Faculty, Staff and Students Publications

Cigarette smoke promotes bladder tumor growth by enhancing cancer cell survival and proliferation through smoke mediated carcinogens. FASN, a key enzyme in fatty acid synthesis, is dysregulated in many cancers and correlates with aggressive phenotypes. In this study, we demonstrate elevated fatty acid levels and FASN specifically in smokers with bladder cancer. Elevated FASN under smoke exposure imparted epigenetic alterations, particularly histone acetylation, impacts DNA repair and DNA-binding transcription factors which regulate metabolic pathways. Under cigarette smoke, bladder cancer cells undergo a metabolic shift, utilizing glutamine as a major carbon source through reductive carboxylation to fuel fatty acid biosynthesis via …

Indications, Techniques, And Safety Of Cryotherapy And Cryobiopsy Via Flexible Bronchoscopy In Pediatric Patients, Alex J Katz, Haley Haskett, Kubra M Bozkanat, Aoife Corcoran, Lauren M C Grant, Antoinette Wannes Daou, Sin Tran, Esra Caylan, Alfin Vicencio, Dan T Benscoter, Cherie A Torres-Silva, Sara M Zak, Gregory Burg, Lisa R Young, Pelton Phinizy, Shailendra Das, Richard Paul Boesch, Erik B Hysinger, Joseph Piccione

Faculty, Staff and Students Publications

Rationale: Cryotherapy and its diagnostic analogue, cryobiopsy, are emerging techniques via bronchoscopy with a wide range of clinical applications. While the use of cryotherapy and cryobiopsy has been established in adult pulmonary medicine, pediatric data describing the indications, procedural specifics, outcomes, and complications are limited.

Objective: To describe the indications, procedural specifics, outcomes, and complications of cryotherapy and cryobiopsy use in pediatric bronchoscopy.

Methods: A multicenter retrospective observational study was conducted at 5 pediatric hospitals in the United States. Patients aged 0 to 21 years who underwent cryotherapy or cryobiopsy via bronchoscopy between January 2017 and January 2025 were included. …

Quantitative Imaging Of Pyruvate Metabolism In A Patient With Anaplastic Thyroid Cancer, James A Bankson, Joshua S Niedzielski, Collin J Harlan, Yunyun Chen, Christopher M Walker, Philip L Lorenzi, Lin Tan, Vikas Kundra, Matthew E Merritt, Mukundan Ragavan, Dawid Schellingerhout, Renjie He, Yao Ding, Sahana Datar, Qing Wang, Christine B Peterson, Clifton D Fuller, Vlad C Sandulache, Stephen Y Lai

Faculty, Staff and Students Publications

Purpose: Magnetic resonance imaging using hyperpolarized (HP) [1-13C]-pyruvate enables assessment of pyruvate metabolism in vivo and offers new insight into metabolic changes in response to cancer therapy. Widely used semi-quantitative metrics of pyruvate metabolism can be affected by physiological factors that are extrinsic to intracellular metabolism. A validated pharmacokinetic (PK) model for analysis of intracellular pyruvate metabolism is needed to enhance the accuracy of quantitative metrics and clinical translation of metabolic MRI using HP pyruvate.

Methods: A PK model with two physical compartments and two chemical pools was developed to analyze the conversion of labeled pyruvate into lactate in vitro. …

Pathogenic Myeloid Phenotypes Drive Disease Pathology In A Novel Human Neurohistiocytosis Model, Shivakumar Rajamanickam, Samantha Trescott, Samantha Mak, Anna S Warden, Amanda M Wilpitz, Bing Xia, Celina Nguyen, Hilda Ding, Jennifer Picarsic, Christopher K Glass, Carl E Allen, Nicole G Coufal

Faculty, Staff and Students Publications

Innate immunity is increasingly recognized as a driver of neurodegeneration, although pathogenic mechanisms are incompletely understood. Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplastic disorder caused by activating somatic mutations in MAPK pathway genes, most commonly BRAFV600E, in myeloid precursors. A subset of patients with LCH develop progressive neurodegeneration (LCH-ND). We generated a human induced pluripotent stem cell (iPSC) model from patients with somatic hematologic mosaicism for BRAFV600E. Brain macrophages/microglia from LCH iPSCs exhibit unique disease-specific pathogenic features. Stepwise differentiation identified hematopoietic progenitors as hyperproliferative, whereas brain macrophages were apoptosis resistant. Through application of cerebral organoids and a humanized …

Rsv Can Infect The Human Nasal Epithelium Via The Basolateral Route And Shows Distinct Subgroup Infectivity And Basal Cell Tropism, Ashley Murray, Divya Nagaraj, Emily M Schultz, Gina Aloisio, Erin Nicholson, Sarah E Blutt, Vasanthi Avadhanula, Pedro A Piedra

Faculty, Staff and Students Publications

Respiratory syncytial virus (RSV) causes millions of lower respiratory tract infections (LRTIs) in young children, older adults, and immunocompromised populations every year. RSV infection initiates in the upper respiratory tract and can progress to the lower airways, resulting in bronchiolitis, pneumonia, and even death. RSV primarily infects epithelial cells apically, but we hypothesized that basolateral exposure of the respiratory epithelium could provide an alternative mechanism of infection that contributes to LRTI development. Using a human nose organoid-air-liquid interface (HNO-ALI) model, we performed apical and basolateral inoculations with contemporaneous RSV strains (RSV/A/Ontario [RSV/A/ON] and RSV/B/Buenos Aires [RSV/B/BA]) representing the two RSV …

Functional Divergence Of Capicua Isoforms Explains Differential Tissue Vulnerability In Neurological Disease, Hamin Lee, Esmeralda Villavicencio Gonzalez, Elias M Rivera, Mark A Durham, Ronald Richman, Elizabeth H-Y Chu, Kailey Xia, Hu Chen, Zhandong Liu, Surabi Veeraragavan, Binoy Shivanna, Huda Y Zoghbi

Faculty, Staff and Students Publications

Many neurological diseases impact specific brain regions despite widespread expression of the disease-related protein. Spinocerebellar ataxia type 1 (SCA1) primarily affects the cerebellum, though Ataxin-1 (ATXN1) is widely expressed. We previously showed that intensified interaction between mutant ATXN1 and Capicua (CIC) drives SCA1 pathogenesis in the cerebellum, whereas ATXN1 loss augments amyloid β production in the hippocampus and cortex. CIC, however, forms a complex with ATXN1 and its paralog, Ataxin-1-like (ATXN1L), yet knockout of either yields completely different phenotypes. To determine whether this could be due to CIC having two isoforms, we generated mice bearing either the long (CIC-L) or …

Epilepsy-Associated Digenic Variants Affecting An Actin-Mitochondria-Glutamate Pathway Promote Seizure Susceptibility, Shenzhao Lu, Mengqi Ma, Shabab B Hannan, Mingxi Deng, Hu Chen, Zhijian Yu, Lindsey D Goodman, Haein Kim, Yun Zhao, Sandeep Kumar Dubey, Wen-Wen Lin, Xueyang Pan, Debdeep Dutta, Vishnu Anand Cuddapah, Jill A Rosenfeld, Xi Luo, Zhandong Liu, Joshua M Shulman, Hugo J Bellen

Faculty, Staff and Students Publications

Epilepsy affects approximately 50 million people worldwide, yet more than half of individuals with a presumed genetic cause still lack a molecular diagnosis despite the identification of over 1,000 monogenic epilepsy genes. This diagnostic gap is unlikely to be resolved by improved variant detection alone, suggesting that variants affecting the same biological pathway may combine to cause disease. By studying epilepsy-associated actin regulatory genes, we identified a conserved "actin-mitochondria-glutamate (AMG) pathway". We demonstrate that reduced actin polymerization promotes DRP1-mediated mitochondrial fission, increases reactive oxygen species (ROS) levels, and enhances glutamatergic transmission, leading to seizures. The glial innate immune pathway, a …

Lig1 Loss In Tp53-Mutant Triple Negative Breast Cancer Rewires Dna Repair And Confers Sensitivity To Parp-Atr Inhibitor Combinations, Anh Minh Tran Huynh, Jonathan T Lei, Rachel Brough, Christina Sallas, Jun Xu, Jacob B Pilcher, Xuxu Gou, Junkai Wang, Lacey E Dobrolecki, Diana M Fandino, Mariah J Berner, Allison Greer, Fei Fei Song, Sarah Latka, Hugo Villanueva, Sumimasa Arimura, Sufeng Mao, Zhongqiu Guo, Sofía I Aramburu, Anran Chen, Thanh Nguyen, Carolina Gutierrez, Dolores H Lopez-Terrada, Bora Lim, Susan G Hilsenbeck, Michael T Lewis, George Miles, Jason C Mills, Gloria V Echeverria, Stephen J Pettitt, Simon N Powell, Susan M Rosenberg, Andrew N J Tutt, Christopher J Lord, Matthew J Ellis, Meenakshi Anurag

Faculty, Staff and Students Publications

Proteogenomic analyses have identified an association between LIG1 (DNA Ligase I) loss and chemotherapy resistance in a subset of triple negative breast cancer (TNBC) enriched for TP53 mutations. Here, we demonstrate that co-occurrence of TP53 mutations and LIG1 loss is associated with upregulated DDR activity, including homologous recombination, likely contributing to reduced platinum sensitivity. Unbiased genetic and monotherapy drug screens identified PARP inhibitors (PARPi) as a potential treatment for LIG1-depleted tumors; however, the increase in sensitivity was modest and lower than that observed in TNBC models with homologous recombination deficiency. Subsequently, a screen of PARP inhibition in combination with each …

Uncovering Phenotypic Expansion In Axin2-Related Disorders Through Precision Animal Modeling, Nathalie M Aceves-Ewing, Denise G Lanza, Paul C Marcogliese, Di Lu, Chih-Wei Hsu, Hirokazu Hashimoto, Matthew Gonzalez, Audrey E Christiansen, Tara L Rasmussen, Alex J Ho, Angelina Gaspero, Cher Sha, Mary E Dickinson, Bo Yuan, Brian J Shayota, Stephanie Pachter, Xiaolin Hu, Debra Lynn Day-Salvatore, Laura Mackay, Oguz Kanca, Michael F Wangler, Lorraine Potocki, Jill A Rosenfeld, Richard Alan Lewis, Hsiao-Tuan Chao, Brendan Lee, Lauren Blieden, Barry N Wasserman, Dorine A Bax, Nicola K Ragge, Sukyeong Lee, Undiagnosed Diseases Network, Baylor College Of Medicine Center For Precision Medicine Models, Shinya Yamamoto, Hugo J Bellen, Lindsay C Burrage, Jason D Heaney

Faculty, Staff and Students Publications

Purpose: Heterozygous pathogenic variants in AXIN2 (HGNC 904) cause oligodontia-colorectal cancer syndrome (ODCRCS). We identified five individuals with de novo, heterozygous variants (NM_004655.4:c.196G>A p.(Glu66Lys), c.197A>G p.(Glu66Gly), and c.199G>A p.(Gly67Arg)) in AXIN2. Common phenotypes among these individuals included ectodermal dysplasia, global developmental delay, microcephaly, and limb, ophthalmologic, and genitourinary abnormalities.

Methods: Structural modeling was performed to predict the impact of these variants on AXIN2. A prime editing N1 screen of mouse embryos was performed to test whether the p.Glu66Lys variant produces a phenotype. Drosophila models were used to test the effect of this variant on Wnt signaling.

Results: …

Tau Pathology In Epilepsy: Emerging Mechanisms And Translational Opportunities, Arjune Sen, Xin You Tai, Aristea Galanopoulou, Maria Thom, Eleonora Aronica, Lucy Vivash, Martin Hardmeier, Action Amos, Stephan Rueegg, Matthias Koepp, Yaroslav Winter, Christoph Helmstaedter, Jeffrey L Noebels, Hilal A Lashuel, Terence J O'Brien

Faculty, Staff and Students Publications

The onset of epilepsy in adulthood occurs most commonly after 55 years of age. Given the ageing global population, this disorder represents an increasing burden on healthcare and society. The bidirectional link between epilepsy and dementia is a focus of intense research with underlying tau pathology highlighted as a potential mechanistic link. In this review, we examine the evidence for tau-related neurodegenerative processes in epilepsy beginning with how changes in biochemical and structural properties of the tau protein can lead to abnormal phosphorylation and pathological aggregation. We consider the role of tau in seizure occurrence and cognitive difficulties in experimental …

Bi-Allelic Loss-Of-Function Variants In Tmem63b Cause Syndromic Surfactant Dysfunction Disorder, Sock Hoai Chan, Audra N Iness, Jill A Rosenfeld, Mir Reza Bekheirnia, Lindsay C Burrage, Matthew Hoi Kin Chau, Chaerish Eint Myet Chae Htoo, Eric C Kao, Shamika Ketkar, Wan Wan Lim, Xi Luo, Rifhan Mazlan, Elizabeth Mizerik, Kein Seong Mun, Kalyani R Patel, Lorraine Potocki, Christina K Rapp, Xavier Roca, Ana Saianda, Ignacio Iglesias-Serrano, Everlyn C Siew, Donald Yuhui Sim, David R Spielberg, Sok-Kun Tae, Jing Xian Teo, Julian Warfsmann, Fan Xia, Child-Eu Registry, Saumya S Jamuar, Ee Shien Tan, Matthias Griese, Weng Khong Lim, Meow-Keong Thong, Keren Machol

Faculty, Staff and Students Publications

Transmembrane protein 63B gene (TMEM63B) encodes a mechanosensitive ion channel expressed in alveolar type II epithelial cells, where it mediates stretch-induced surfactant secretion. While heterozygous gain-of-function variants in TMEM63B have been associated with developmental and epileptic encephalopathy, no human disorder has previously been linked to bi-allelic loss-of-function variants. Here, we report five individuals from four unrelated families with childhood interstitial lung disease and bi-allelic predicted loss-of-function variants in TMEM63B. Affected individuals presented with early-onset respiratory distress, chronic hypoxemia, and diffuse parenchymal lung abnormalities on chest imaging. One individual died in infancy, two underwent bilateral lung transplantation, and two require oxygen …

Human Exposure To Spirochete-Infected Ornithodoros Turicata In A Residential Setting In The Austin, Texas Metropolitan Area, Serhii Filatov, Bonny Mayes, Sarah M Gunter, Alexander R Kneubehl, Job E Lopez

Faculty, Staff and Students Publications

A central Texas resident found an engorged Ornithodoros turicata tick attached to their ankle while at home. The tick tested positive for Borrelia turicatae, an agent for soft tick-borne relapsing fever. Three weeks earlier, the patient started experiencing febrile episodes, rash, and nausea, yet the etiological agent went undiagnosed.

Helminth-Infected Mozambican Children With Malaria Have Increased Anaemia, Cytokines And Helminth-Specific Antibodies, Inocência Cuamba, Rebeca Santano, Berta Grau-Pujol, Marta Vidal, Anélsio Cossa, Chenjerai Jairoce, Rojelio Mejía, José Muñoz, Ruth Aguilar, Bin Zhan, Augusto Nhabomba, Gemma Moncunill, Carlota Dobaño

Faculty, Staff and Students Publications

Owing to their overlapping geographical distribution and the consequent occurrence of coinfections, several studies have evaluated the impact of helminth infections on malaria immune responses and clinical outcomes. However, little has been reported on how malaria coinfection affects anthelmintic responses in children harbouring worm infections. We therefore aimed to assess the impact of malaria coinfection on helminth-related clinical and immune outcomes in children. Here, we measured in plasma the levels of 30 cytokines, total IgE, and helminth-specific IgM, IgA, IgG, IgG1-4, and IgE antibodies to a panel of 11 helminth antigens by Luminex. Samples were obtained from 441 children aged …

Quality Domains In Home-Based Pediatric Hospice And Palliative Care: Adolescent And Young Adult Perspectives, Daniel H Grossoehme, Claire A Crawford, Jhansi Chandra Ellakula, Toluwalase Ajayi, Justin N Baker, Sarah Friebert, Lisa Humphrey, Jillann Jarrell, Rachel Thienprayoon, Pamela S Hinds

Faculty, Staff and Students Publications

Background: Current United States palliative care practice guidelines are intended to cover care across all age groups. Previous research with pediatric providers and caregivers concluded that pediatric hospice and palliative care have unique attributes. Not known is how adolescent hospice and palliative care patients understand quality palliative care. The purpose of this study was to characterize and define quality of care domains as described by adolescent and young adult patients receiving home-based hospice and palliative care.

Methods: Semi-structured interviews with 10-26 year-olds who received home-based hospice and/or palliative care visits in the prior three years at six diverse sites in …

Na-Gst-1 Adsorbed On Alhydrogel Co-Administered With Different Toll-Like Receptor Agonists In Hookworm-Naive Adults Using A Controlled Human Infection Model In The Usa: A Phase 2, Double-Blind, Randomised Controlled Trial, Caroline K Dirosato, Elissa M Malkin, Sean M Lee, Guacyara Erwin, Lara Hoeweler, Larissa Scholte, Maria Elena Bottazzi, David I Pritchard, Peter J Hotez, Jeffrey M Bethony, David J Diemert

Faculty, Staff and Students Publications

Background: Necator americanus glutathione S-transferase-1 (Na-GST-1) performs a crucial enzymatic step in hookworm blood feeding and is a leading target for vaccine development. Phase 1 trials in Brazil, Gabon, and the USA of recombinant Na-GST-1 adsorbed on Alhydrogel (Na-GST-1/Al), co-administered with or without AP 10-701 (Toll-like receptor [TLR] 4 agonist) or CpG 10104 (TLR9 agonist), showed the vaccine was well tolerated, safe, and immunogenic. A controlled human hookworm infection (CHHI) model was previously developed to evaluate the effect of candidate hookworm vaccines on infection. We aimed to assess the effect of vaccination with three different Na-GST-1 vaccine formulations on subsequent …

A Nationwide Central Diagnosis For Pediatric Cns Tumors In Japan: The Jccg Brain Tumor And Pathology Committees, Yoshiko Nakano, Junko Hirato, Takako Yoshioka, Tetsuya Takimoto, Sumihito Nobusawa, Kaishi Satomi, Ran Tomomasa, Seiji Yamada, Taku Homma, Shoh Sasaki, Ayako Yamazaki, Maki Sakaguchi, Yasuhide Takeuchi, Nei Fukazawa, Kai Yamasaki, Kohei Fukuoka, Yui Shinohara Kimura, Yuki Nagayama, Yohei Inoue, Akira Miyahira, Ema Yoshioka, Asako Katsuma, Hayato Fukusumi, Tomoko Shofuda, Yuko Hibiya, Yuko Matsushita, Mai Honda Kitahara, Yuki Yomoda, Miho Kato, Michael D Taylor, Yasuhito Arai, Tatsuhiro Shibata, Hiroaki Sakamoto, Keita Terashima, Yoshiki Arakawa, Toshihiro Kumabe, Ryo Nishikawa, Junichi Hara, Yonehiro Kanemura, Koichi Ichimura

Faculty, Staff and Students Publications

In 2016, the Japan Children's Cancer Group launched a nationwide research initiative to provide central diagnosis incorporating pathology review and molecular profiling for pediatric central nervous system (CNS) tumors. Over the first eight years, 2224 cases were registered. Non-next-generation sequencing analyzes, such as pyrosequencing and NanoString, were routinely performed, mainly for glioma, medulloblastoma, and ependymoma. Additional analyzes, including methylation profiling and RNA sequencing, were conducted for selected diagnostically challenging cases. The most common diagnoses were low-grade glioma (26%), medulloblastoma (18%), germ cell tumor (16%), high-grade glioma (12%), and ependymoma (11%). Diagnostic or targetable alterations were detected in nearly half of …

Adlm Guidance Document On Incorporating Gender Diversity In Pathology And Laboratory Medicine, Tiffany A Thomas, Gabrielle N Winston-Mcpherson, Ina Amarillo, Alisha D Berry, Caroline J Davidge-Pitts, Sridevi Devaraj, Zil Goldstein, Brad S Karon, Brooke M Katzman, Mahmoud A Khalifa, Hung S Luu, James H Nichols, Tracy L Stockley, Michelle R Stoffel, Dina N Greene, Matthew D Krasowski

Faculty, Staff and Students Publications

Background: The first international clinical standards of care for the gender-diverse population were formulated in the late 1970s. In the last 15 years, multiple subspecialty societies within the United States have developed clinical care guidelines for those with gender dysphoria, including gender-affirming hormone therapy (GAHT) and surgical treatments. To date, there are no pathology- and laboratory medicine-specific recommendations in the United States for the gender-diverse population.

Content: This document outlines pathology- and laboratory medicine-specific recommendations for providing optimal care to the gender-diverse population, with a predominant focus on the adult population. The scope of this document focuses on the following …

Mechanisms Coordinating Exit From The Stem Cell State In Mammals, Emily J Park, Florencia Levin-Ferreyra, Bruno Di Stefano

Faculty, Staff and Students Publications

Differentiation requires coordinated exit from the stem cell state, during which gene regulatory networks sustaining self-renewal are dismantled, while lineage-specific programs are activated. This transition is governed by chromatin modifications, transcriptional networks, RNA processing, translational control, and metabolic rewiring that must operate with temporal precision. Despite significant progress in identifying individual regulatory components, understanding how these layers integrate to orchestrate irreversible cell fate commitment remains a fundamental challenge. This review examines common and unique regulatory principles governing stem cell exit, from totipotency during early embryogenesis to tissue-specific stem cell differentiation in adults. We synthesize recent findings on regulatory mechanisms across …

Statistics Of Natural Scenes Shape Contextual Modulation In The Visual Cortex, Jiakun Fu, Suhas Shrinivasan, Luca Baroni, Zhuokun Ding, Paul G Fahey, Paweł A Pierzchlewicz, Nikos Karantzas, Kayla Ponder, Rachel Froebe, Lydia Ntanavara, Taliah Muhammad, Konstantin F Willeke, Eric Wang, Zhiwei Ding, Dat Tran, Stelios Papadopoulos, Saumil Patel, Jacob Reimer, Alexander S Ecker, Xaq Pitkow, Jan Antolik, Fabian H Sinz, Ralf M Haefner, Andreas S Tolias, Katrin Franke

Faculty, Staff and Students Publications

Vision is context dependent, with neuronal responses shaped not only by local features but also by surrounding visual input. While classical studies, using grating stimuli, show that iso-oriented surrounds suppress responses more than orthogonal surrounds, the role of contextual modulation under natural stimulus conditions remains less clear. Using recordings from mouse primary visual cortex (V1), we trained convolutional neural network models to predict neuronal responses to natural images and synthesized surround stimuli that selectively suppressed or facilitated responses to optimal center inputs. In vivo experiments confirmed these predictions. Facilitatory surrounds resembled naturalistic continuations of the optimal center stimulus, consistent with …

Altered Glr-1 Expression After Etoh Withdrawal Is Linked To Associative Behavior Deficits In C. Elegans, Katie Brandel-Ankrapp, Rachel N Arey

Faculty, Staff and Students Publications

Chronic ethanol (EtOH) exposure and withdrawal are linked to worsened memory and cognitive outcomes. One target of EtOH is the glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Both EtOH exposure and withdrawal influences AMPAR expression, function, and broad glutamate signaling. Previous work suggests that EtOH regulation of AMPARs drives behaviors related to dependence and memory phenotypes. However, due to the complexity of the mammalian brain, it is difficult to unravel the precise mechanism by which EtOH regulates AMPARs in mammals to modify specific memory behaviors. In Caenorhabditis elegans, GLR-1, an AMPAR ortholog, has tightly defined expression in relatively few neurons, conserved …

Evidence-Based Classification Of Genes Implicated In Skeletal Disorders Using The Clingen Curation Framework, Ryan F Webb, Hannah Mccurry, Amanda Girod, Madeline Hughes, Emma Wilcox, Mayher Patel, Eleanor C Broeren, Kezang C Tshering, Marina Distefano, Lorenzo D Botto, Lindsay C Burrage, Valérie Cormier-Daire, Juan Dong, Nadja Ehmke, Deborah Krakow, Shahida Moosa, Geert Mortier, Sandesh Nagamani, Loren Pena, Pedro A Sanchez-Lara, Andrea Superti-Furga, Sheila Unger, Danita Velasco, Matthew L Warman, Kerry Brown, Deepika D'Cunha Burkardt, Carlos R Ferreira

Faculty, Staff and Students Publications

More than 770 genetic skeletal disorders have been described, most with disease-causing variants reported in 1 of over 550 different genes. The ClinGen Skeletal Disorders Gene Curation Expert Panel was established to determine the strength of the evidence that supports specific gene-disease relationships (GDRs). Such information can assist clinical testing laboratories in choosing genes that should be included on diagnostic panels. Nine genes accounting for the most frequently encountered skeletal dysplasias (COL1A1, COL1A2, COL2A1, FGFR3, SLC26A2, TRPV4, COMP, ALPL, and SOX9) associated in the medical literature with 26 different skeletal disorders were reviewed using a semi-quantitative scoring framework. This framework …

Chemotherapeutic Induction Of Cytosolic Single-Stranded Dna Accumulation Sensitizes Triple-Negative Breast Cancer To Immunotherapy, Yong Du, Li Yang, Hui Dai, Jianli Zhou, Zhicheng Zhou, Ruoxi Yuan, Rui Ye, Anh Thai Quynh Nguyen, Kishor Bhatia, Shiaw-Yih Lin

Faculty, Staff and Students Publications

Background: Despite the widespread adoption of chemoimmunotherapy in triple-negative breast cancer (TNBC), the mechanisms by which cytotoxic chemotherapy engages antitumor immunity remain poorly defined. Identifying tumor-intrinsic immunogenic programs that predict and enhance responsiveness to immune checkpoint blockade (ICB) is therefore of critical clinical importance.

Methods: Transcriptomic signatures of TREX1 deficiency were generated from CRISPR-engineered TNBC models and applied to multiple independent TNBC cohorts treated with chemoimmunotherapy. Cytosolic single-stranded DNA (ssDNA) accumulation was quantified using a flow cytometry-based assay to functionally screen chemotherapeutic agents. Immune activation and therapeutic efficacy were evaluated using in vitro assays, syngeneic mouse tumor models, flow cytometry, …

Early-Stage Corticostriatal Hyperactivity Impairs Cognitive Flexibility Alongside Striatal Cholinergic Dysfunction In An Alzheimer's Disease Model, Yufei Huang, Xueyi Xie, Zhenbo Huang, Ruifeng Chen, Himanshu Gangal, Xuehua Wang, Karienn Souza, Julia Hunter, Xin Wu, Doodipala Samba Reddy, Jeannie Chin, Jun Wang

Faculty, Staff and Students Publications

Cognitive flexibility declines early in Alzheimer's disease, yet the underlying circuit mechanisms remain unknown. Here, we report that young 5xFAD mice exhibit deficits in instrumental reversal learning prior to spatial memory impairment. This behavioral inflexibility is associated with abnormal neuronal reactivation in the medial prefrontal cortex and dorsomedial striatum. Electrophysiological recordings reveal that medial prefrontal cortex neurons are hyperexcitable and receive increased excitatory input. Furthermore, glutamatergic transmission from the medial prefrontal cortex to striatal direct-pathway medium spiny neurons is enhanced and coincides with strengthened inhibitory transmission onto striatal cholinergic interneurons, reduced spontaneous firing, and diminished striatal acetylcholine release. Critically, sustained …

Human Milk Small Extracellular Vesicles Elicit Changes In Inflammatory Response In Infant Human Intestinal Enteroids, Kacie D Waiters, Anthony S Peidl, Hailey A Mcandrew, Ashfia F Khan, Grace Adeniyi-Ipadeola, Hephzibah Nwanosike, Sana Sharif, M Funmi Babajide, Micah Castillo, Preethi H Gunaratne, Samaneh Karami, Hoa Nguyen-Phuc, Xinli Liu, Sasirekha Ramani, Tasneem Bawa-Khalfe

Faculty, Staff and Students Publications

Human milk (HM) is the key nutritional source for infants and the most effective preventative approach against serious gastrointestinal inflammatory diseases like necrotizing enterocolitis (NEC) in preterm infants. Numerous studies in animal models indicate HM-derived small extracellular vesicles (HMEV) reduce severity of inflammation; however, data on human-specific models are limited. Isolated HMEV were characterized from early-HM (colostrum and transitional), mature-HM, and a combined, pasteurized donor bank-like HM sample (pool-); pool-HMEV retains a profile aligned with HMEV from both early- and mature-HM samples. Exposure to pool-HMEV initiates unique gene signatures associated with reduction of inflammation including NFkB-driven TNFα signaling in human …

Evaluating The Reproducibility And Verifiability Of Nutrition Research: A Case Study Of Studies Assessing The Relationship Between Potatoes And Colorectal Cancer, Yasaman Jamshidi-Naeini, Colby J Vorland, Pranav Kapoor, Bailey Ortyl, Jocelyn Mineo, Luke Still, Korlu Sorsor, Shelby Rodney, Xander Tooze, Brent Flickinger, Beate Henschel, Stephanie L Dickinson, David B Allison

Faculty, Staff and Students Publications

The credibility of nutritional research is dependent on the rigor with which studies are conducted and the ability for independent assessment to be performed. Despite the importance of these, more work is needed in the field of nutrition to buttress the trustworthiness of nutrition research. To develop and apply a process for evaluating the rigor, reproducibility, and verifiability of nutritional research, using the relationship between potato consumption and Colorectal Cancer (CRC) as a case study. We updated existing systematic reviews to include studies on potatoes and CRC, assessing their design, execution, and reporting quality. We attempted to reproduce and verify …

Neddylation Maintains Oocyte Quality By Stabilizing Mitochondrial Transcription, Avery A Ahmed, Tessa E Steenwinkel, Bethany K Patton, Peixin Jiang, Matthew D Meyer, Jaspreet K Rishi, Mei Leng, Alexander B Saltzman, Elizabeth S Anaya, Momal Sharif, Laurie J Mckenzie, Laura Detti, Anna Malovannaya, Sean M Hartig, Stephanie A Pangas

Faculty, Staff and Students Publications

Age-related decline in oocyte quality increases the risk of infertility, miscarriage, and birth defects. Mitochondrial dysfunction is a key contributor to this decline. Here, we report that oocyte-specific deletion of Uba3, which encodes the catalytic subunit of the E1 NEDDylation-activating complex, causes sterility in mice. Fully grown, germinal vesicle–stage Uba3 conditional knockout oocytes exhibit mitochondrial dysfunction, including elevated reactive oxygen species, impaired oxidative phosphorylation, and depletion of mitochondrially encoded RNA transcripts. Proteomic analysis identified alterations in mitochondrial-associated proteins, including enrichment of mitochondrial matrix and respiratory chain components and reduced abundance of electron transport chain complexes. These defects were associated …