Digital Commons Network^™

The Fate Of Early Perichondrial Cells In Developing Bones, Yuki Matsushita, Angel Ka Yan Chu, Chiaki Tsutsumi-Arai, Shion Orikasa, Mizuki Nagata, Sunny Y Wong, Joshua D Welch, Wanida Ono, Noriaki Ono

Faculty, Staff and Student Publications

In endochondral bone development, bone-forming osteoblasts and bone marrow stromal cells have dual origins in the fetal cartilage and its surrounding perichondrium. However, how early perichondrial cells distinctively contribute to developing bones remain unidentified. Here we show using in vivo cell-lineage analyses that Dlx5+ fetal perichondrial cells marked by Dlx5-creER do not generate cartilage but sustainably contribute to cortical bone and marrow stromal compartments in a manner complementary to fetal chondrocyte derivatives under the regulation of Hedgehog signaling. Postnatally, Dlx5+ fetal perichondrial cell derivatives preferentially populate the diaphyseal marrow stroma with a dormant adipocyte-biased state and are refractory to parathyroid …

Inactivation Of Lats1/2 Drives Luminal-Basal Plasticity To Initiate Basal-Like Mammary Carcinomas, Joseph G Kern, Andrew M Tilston-Lunel, Anthony Federico, Boting Ning, Amy Mueller, Grace B Peppler, Eleni Stampouloglou, Nan Cheng, Randy L Johnson, Marc E Lenburg, Jennifer E Beane, Stefano Monti, Xaralabos Varelas

Faculty, Staff and Student Publications

Basal-like breast cancers, an aggressive breast cancer subtype that has poor treatment options, are thought to arise from luminal mammary epithelial cells that undergo basal plasticity through poorly understood mechanisms. Using genetic mouse models and ex vivo primary organoid cultures, we show that conditional co-deletion of the LATS1 and LATS2 kinases, key effectors of Hippo pathway signaling, in mature mammary luminal epithelial cells promotes the development of Krt14 and Sox9-expressing basal-like carcinomas that metastasize over time. Genetic co-deletion experiments revealed that phenotypes resulting from the loss of LATS1/2 activity are dependent on the transcriptional regulators YAP/TAZ. Gene expression analyses of …

Clinical And Molecular Insights Into Gastrointestinal Dysfunction In Myotonic Dystrophy Types 1 & 2, Janel A M Peterson, Thomas A Cooper

Faculty, Staff and Students Publications

Myotonic dystrophy (DM) is a highly variable, multisystemic disorder that clinically affects one in 8000 individuals. While research has predominantly focused on the symptoms and pathological mechanisms affecting striated muscle and brain, DM patient surveys have identified a high prevalence for gastrointestinal (GI) symptoms amongst affected individuals. Clinical studies have identified chronic and progressive dysfunction of the esophagus, stomach, liver and gallbladder, small and large intestine, and rectum and anal sphincters. Despite the high incidence of GI dysmotility in DM, little is known regarding the pathological mechanisms leading to GI dysfunction. In this review, we summarize results from clinical and …

Variation In Human Water Turnover Associated With Environmental And Lifestyle Factors, Yosuke Yamada, Xueying Zhang, Mary E T Henderson, Hiroyuki Sagayama, Herman Pontzer, Daiki Watanabe, Tsukasa Yoshida, Misaka Kimura, Philip N Ainslie, Lene F Andersen, Liam J Anderson, Lenore Arab, Issad Baddou, Kweku Bedu-Addo, Ellen E Blaak, Stephane Blanc, Alberto G Bonomi, Carlijn V C Bouten, Pascal Bovet, Maciej S Buchowski, Nancy F Butte, Stefan G Camps, Graeme L Close, Jamie A Cooper, Richard Cooper, Sai Krupa Das, Lara R Dugas, Simon Eaton, Ulf Ekelund, Sonja Entringer, Terrence Forrester, Barry W Fudge, Annelies H Goris, Michael Gurven, Lewis G Halsey, Catherine Hambly, Asmaa El Hamdouchi, Marije B Hoos, Sumei Hu, Noorjehan Joonas, Annemiek M Joosen, Peter Katzmarzyk, Kitty P Kempen, William E Kraus, Wantanee Kriengsinyos, Robert F Kushner, Estelle V Lambert, William R Leonard, Nader Lessan, Corby K Martin, Anine C Medin, Erwin P Meijer, James C Morehen, James P Morton, Marian L Neuhouser, Theresa A Nicklas, Robert M Ojiambo, Kirsi H Pietiläinen, Yannis P Pitsiladis, Jacob Plange-Rhule, Guy Plasqui, Ross L Prentice, Roberto A Rabinovich, Susan B Racette, David A Raichlen, Eric Ravussin, Leanne M Redman, John J Reilly, Rebecca M Reynolds, Susan B Roberts, Albertine J Schuit, Luis B Sardinha, Analiza M Silva, Anders M Sjödin, Eric Stice, Samuel S Urlacher, Giulio Valenti, Ludo M Van Etten, Edgar A Van Mil, Jonathan C K Wells, George Wilson, Brian M Wood, Jack A Yanovski, Alexia J Murphy-Alford, Cornelia U Loechl, Amy H Luke, Jennifer Rood, Klaas R Westerterp, William W Wong, Motohiko Miyachi, Dale A Schoeller, John R Speakman

Children’s Nutrition Research Center Staff Publications

Water is essential for survival, but one in three individuals worldwide (2.2 billion people) lack access to safe drinking water. Water intake requirements largely reflect water turnover (WT), the water used by the body each day. We investigated the determinants of human WT in 5,604 people from the ages of 8 days to 96 years from 26 countries using isotope tracking (2H) methods. Age, body size, and composition were significantly associated with WT as were physical activity, athletic status, pregnancy, socioeconomic status, and environmental characteristics (latitude, altitude, air temperature, and humidity). People in countries with low human development index (HDI) …

The Innate Immune System In Cardiovascular Diseases And Its Role In Doxorubicin-Induced Cardiotoxicity, Anchit Bhagat, Pradeep Shrestha, Eugenie S Kleinerman

Faculty, Staff and Student Publications

Innate immune cells are the early responders to infection and tissue damage. They play a critical role in the initiation and resolution of inflammation in response to insult as well as tissue repair. Following ischemic or non-ischemic cardiac injury, a strong inflammatory response plays a critical role in the removal of cell debris and tissue remodeling. However, persistent inflammation could be detrimental to the heart. Studies suggest that cardiac inflammation and tissue repair needs to be tightly regulated such that the timely resolution of the inflammation may prevent adverse cardiac damage. This involves the recognition of damage; activation and release …

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

Faculty Research 2022

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

Methylone And Mdma Pharmacokinetics Following Controlled Administration In Humans, Lourdes Poyatos, Alfredo Fabrizio Lo Faro, Diletta Berardinelli, Giorgia Sprega, Sara Malaca, Simona Pichini, Marilyn A. Huestis, Esther Papaseit, Clara Pérez-Mañá, Francesco Paolo Busardò, Magí Farré

Institute of Emerging Health Professions Faculty Papers

The aim of this study is to define, for the first time, human methylone and HMMC plasma pharmacokinetics following controlled administration of 50–200 mg methylone to 12 male volunteers. A new LC-MS/MS method was validated to quantify methylone, MDMA, and their metabolites in plasma. The study was a randomized, cross-over, double-blinded and placebo-controlled study, with a total of 468 plasma samples collected. First, 10 µL of MDMA-d5, MDA-d5 and methylone-d3 internal standards were added to 100 µL of plasma. Two mL of chloroform and ethyl acetate 9:1 (v/v) were then added, mixed well and centrifuged. The supernatant was fortified with …

Muscle-Specific Ablation Of Glucose Transporter 1 (Glut1) Does Not Impair Basal Or Overload-Stimulated Skeletal Muscle Glucose Uptake, Shawna L Mcmillin, Parker L Evans, William M Taylor, Luke A Weyrauch, Tyler J Sermersheim, Steven S Welc, Monique R Heitmeier, Richard C Hresko, Paul W Hruz, Francoise Koumanov, Geoffrey D Holman, E Dale Abel, Carol A Witczak

2020-Current year OA Pubs

Glucose transporter 1 (GLUT1) is believed to solely mediate basal (insulin-independent) glucose uptake in skeletal muscle; yet recent work has demonstrated that mechanical overload, a model of resistance exercise training, increases muscle GLUT1 levels. The primary objective of this study was to determine if GLUT1 is necessary for basal or overload-stimulated muscle glucose uptake. Muscle-specific GLUT1 knockout (mGLUT1KO) mice were generated and examined for changes in body weight, body composition, metabolism, systemic glucose regulation, muscle glucose transporters, and muscle [

Myostatin Is A Negative Regulator Of Adult Neurogenesis After Spinal Cord Injury In Zebrafish, Vishnu Muraleedharan Saraswathy, Lili Zhou, Anthony R Mcadow, Brooke Burris, Deepika Dogra, Sven Reischauer, Mayssa H Mokalled

2020-Current year OA Pubs

Intrinsic and extrinsic inhibition of neuronal regeneration obstruct spinal cord (SC) repair in mammals. In contrast, adult zebrafish achieve functional recovery after complete SC transection. While studies of innate SC regeneration have focused on axon regrowth as a primary repair mechanism, how local adult neurogenesis affects functional recovery is unknown. Here, we uncover dynamic expression of zebrafish myostatin b (mstnb) in a niche of dorsal SC progenitors after injury. mstnb mutants show impaired functional recovery, normal glial and axonal bridging across the lesion, and an increase in the profiles of newborn neurons. Molecularly, neuron differentiation genes are upregulated, while the …

Oleuropein Suppresses Endometriosis Progression And Improves The Fertility Of Mice With Endometriosis, Yuri Park, Yeon Jean Cho, Nuri Sung, Mi Jin Park, Xiaoming Guan, William E Gibbons, Bert W O'Malley, Sang Jun Han

Faculty, Staff and Students Publications

BACKGROUND: Endometriosis is an estrogen-dependent inflammatory reproductive disease. Therefore, systematic estrogen depletion and anti-inflammatory drugs are the current treatment for endometriosis. However, current endometriosis treatments have low efficacy and cause adverse effects in endometriosis patients. Consequently, alternative endometriosis treatments targeting endometriosis-specific factors are in demand. In this context, ERβ was selected as a druggable target for endometriosis due to its critical role in progression. Therefore, selective targeting of ERβ without inhibiting ERα activity would be a new paradigm for endometriosis treatment to overcome the low efficacy and adverse effects of hormonal endometriosis therapy.

METHODS: Cell-based ERβ and ERα activity assay …

From Model Organisms To Humans, The Opportunity For More Rigor In Methodologic And Statistical Analysis, Design, And Interpretation Of Aging And Senescence Research, Daniella E Chusyd, Steven N Austad, Andrew W Brown, Xiwei Chen, Stephanie L Dickinson, Keisuke Ejima, David Fluharty, Lilian Golzarri-Arroyo, Richard Holden, Yasaman Jamshidi-Naeini, Doug Landsittel, Stella Lartey, Edward Mannix, Colby J Vorland, David B Allison

Children’s Nutrition Research Center Staff Publications

This review identifies frequent design and analysis errors in aging and senescence research and discusses best practices in study design, statistical methods, analyses, and interpretation. Recommendations are offered for how to avoid these problems. The following issues are addressed: (a) errors in randomization, (b) errors related to testing within-group instead of between-group differences, (c) failing to account for clustering, (d) failing to consider interference effects, (e) standardizing metrics of effect size, (f) maximum life-span testing, (g) testing for effects beyond the mean, (h) tests for power and sample size, (i) compression of morbidity versus survival curve squaring, and (j) other …

Privacy-Aware Estimation Of Relatedness In Admixed Populations, Su Wang, Miran Kim, Wentao Li, Xiaoqian Jiang, Han Chen, Arif Harmanci

Faculty, Staff and Student Publications

BACKGROUND: Estimation of genetic relatedness, or kinship, is used occasionally for recreational purposes and in forensic applications. While numerous methods were developed to estimate kinship, they suffer from high computational requirements and often make an untenable assumption of homogeneous population ancestry of the samples. Moreover, genetic privacy is generally overlooked in the usage of kinship estimation methods. There can be ethical concerns about finding unknown familial relationships in third-party databases. Similar ethical concerns may arise while estimating and reporting sensitive population-level statistics such as inbreeding coefficients for the concerns around marginalization and stigmatization.

RESULTS: Here, we present SIGFRIED, which makes …

A Genomically And Clinically Annotated Patient-Derived Xenograft Resource For Preclinical Research In Non-Small Cell Lung Cancer., Xing Yi Woo, Anuj Srivastava, Philip C Mack, Joel H. Graber, Brian J Sanderson, Michael W Lloyd, Mandy Chen, Sergii Domanskyi, Regina Gandour-Edwards, Rebekah A Tsai, James G. Keck, Mingshan Cheng, Margaret Bundy, Emily L Jocoy, Jonathan W Riess, William Holland, Stephen C. Grubb, James G Peterson, Grace Stafford, Carolyn Paisie, Steven Neuhauser, Radha Krishna Murthy Karuturi, Joshy George, Allen K. Simons, Margaret Chavaree, Clifford G Tepper, Neal Goodwin, Susan Airhart, Primo N Lara, Thomas H Openshaw, Edison Liu, David R Gandara, Carol J Bult

Faculty Research 2022

UNLABELLED: Patient-derived xenograft (PDX) models are an effective preclinical in vivo platform for testing the efficacy of novel drugs and drug combinations for cancer therapeutics. Here we describe a repository of 79 genomically and clinically annotated lung cancer PDXs available from The Jackson Laboratory that have been extensively characterized for histopathologic features, mutational profiles, gene expression, and copy-number aberrations. Most of the PDXs are models of non-small cell lung cancer (NSCLC), including 37 lung adenocarcinoma (LUAD) and 33 lung squamous cell carcinoma (LUSC) models. Other lung cancer models in the repository include four small cell carcinomas, two large cell neuroendocrine …

Transposon Mutagenesis Reveals Rbms3 Silencing As A Promoter Of Malignant Progression Of Brafv600e-Driven Lung Tumorigenesis, Aria Vaishnavi, Joseph Juan, Maebh Jacob, Christopher Stehn, Eric E Gardner, Michael T Scherzer, Sophia Schuman, J Edward Van Veen, Brandon Murphy, Christopher S Hackett, Adam J Dupuy, Steven A Chmura, Louise Van Der Weyden, Justin Y Newberg, Annie Liu, Karen Mann, Alistair G Rust, William A Weiss, Conan G Kinsey, David J Adams, Allie Grossmann, Michael B Mann, Martin Mcmahon

Faculty, Staff and Student Publications

Mutationally activated BRAF is detected in approximately 7% of human lung adenocarcinomas, with BRAFT1799A serving as a predictive biomarker for treatment of patients with FDA-approved inhibitors of BRAFV600E oncoprotein signaling. In genetically engineered mouse (GEM) models, expression of BRAFV600E in the lung epithelium initiates growth of benign lung tumors that, without additional genetic alterations, rarely progress to malignant lung adenocarcinoma. To identify genes that cooperate with BRAFV600E for malignant progression, we used Sleeping Beauty-mediated transposon mutagenesis, which dramatically accelerated the emergence of lethal lung cancers. Among the genes identified was Rbms3, which encodes an RNA-binding protein previously implicated as a …

Cerebral Blood Flow And Cardiovascular Risk Effects On Resting Brain Regional Homogeneity, Bhim M Adhikari, L Elliot Hong, Zhiwei Zhao, Danny J J Wang, Paul M Thompson, Neda Jahanshad, Alyssa H Zhu, Stefan Holiga, Jessica A Turner, Theo G M Van Erp, Vince D Calhoun, Kathryn S Hatch, Heather Bruce, Stephanie M Hare, Joshua Chiappelli, Eric L Goldwaser, Mark D Kvarta, Yizhou Ma, Xiaoming Du, Thomas E Nichols, Alan R Shuldiner, Braxton D Mitchell, Juergen Dukart, Shuo Chen, Peter Kochunov

Faculty, Staff and Student Publications

Regional homogeneity (ReHo) is a measure of local functional brain connectivity that has been reported to be altered in a wide range of neuropsychiatric disorders. Computed from brain resting-state functional MRI time series, ReHo is also sensitive to fluctuations in cerebral blood flow (CBF) that in turn may be influenced by cerebrovascular health. We accessed cerebrovascular health with Framingham cardiovascular risk score (FCVRS). We hypothesize that ReHo signal may be influenced by regional CBF; and that these associations can be summarized as FCVRS→CBF→ReHo. We used three independent samples to test this hypothesis. A test-retest sample of N = 30 healthy …

Anti-Diabetic Effects Of Glp1 Analogs Are Mediated By Thermogenic Interleukin-6 Signaling In Adipocytes, Absalon D Gutierrez, Zhanguo Gao, Vala Hamidi, Liang Zhu, Karla Bermudez Saint Andre, Kayla Riggs, Monika Ruscheinsky, Hongyu Wang, Yongmei Yu, Charles Miller, Hernan Vasquez, Heinrich Taegtmeyer, Mikhail G Kolonin

Faculty, Staff and Student Publications

Mechanisms underlying anti-diabetic effects of GLP1 analogs remain incompletely understood. We observed that in prediabetic humans exenatide treatment acutely induces interleukin-6 (IL-6) secretion by monocytes and IL-6 in systemic circulation. We hypothesized that GLP1 analogs signal through IL-6 in adipose tissue (AT) and used the mouse model to test if IL-6 receptor (IL-6R) signaling underlies the effects of the GLP1-IL-6 axis. We show that liraglutide transiently increases IL-6 in mouse circulation and IL-6R signaling in AT. Metronomic liraglutide treatment resulted in AT browning and thermogenesis linked with STAT3 activation. IL-6-blocking antibody treatment inhibited STAT3 activation in AT and suppressed liraglutide-induced …

Human Dectin-1 Deficiency Impairs Macrophage-Mediated Defense Against Phaeohyphomycosis, Rebecca A. Drummond, Jigar V. Desai, Amy P. Hsu, Vasileios Oikonomou, Donald C. Vinh, Joshua A. Acklin, Michael S. Abers, Magdalena A. Walkiewicz, Sarah L. Anzick, Muthulekha Swamydas, Simon Vautier, Mukil Natarajan, Andrew J. Oler, Daisuke Yamanaka, Katrin D. Mayer-Barber, Yoichiro Iwakura, David Bianchi, Brian Driscoll, Ken Hauck, Ahnika Kline, Nicholas S.P. Viall, Christa S. Zerbe, Elise M.N. Ferré, Monica M. Schmitt, Tom Dimaggio, Stefania Pittaluga, John A. Butman, Adrian M. Zelazny, Yvonne R. Shea, Cesar A. Arias, Cameron Ashbaugh, Maryam Mahmood, Zelalem Temesgen, Alexander G. Theofiles, Masayuki Nigo, Varsha Moudgal, Karen C. Bloch, Sean G. Kelly, M. Suzanne Whitworth, Ganesh Rao, Cindy J. Whitener, Neema Mafi, Juan Gea-Banacloche, Lawrence C. Kenyon, William R. Miller, Katia Boggian, Andrea Gilbert, Matthew Sincock, Alexandra F. Freeman, John E. Bennett, Rodrigo Hasbun, Constantinos M. Mikelis, Kyung J. Kwon-Chung, Yasmine Belkaid, Gordon D. Brown, Jean K. Lim, Douglas B. Kuhns, Steven M. Holland, Michail S. Lionakis

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, β-glucan-binding receptor, Dectin-1. The patient's PBMCs failed to produce TNF-α and IL-1β in response to β-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1β and …

A, B, C'S Of Trk Receptors And Their Ligands In Ocular Repair, Akash Gupta, Jeremias G Galletti, Zhiyuan Yu, Kevin Burgess, Cintia S De Paiva

Faculty, Staff and Students Publications

Neurotrophins are a family of closely related secreted proteins that promote differentiation, development, and survival of neurons, which include nerve growth factor (NGF), brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4. All neurotrophins signal through tropomyosin receptor kinases (TrkA, TrkB, and TrkC) which are more selective to NGF, brain-derived neurotrophic factor, and neurotrophin-3, respectively. NGF is the most studied neurotrophin in the ocular surface and a human recombinant NGF has reached clinics, having been approved to treat neurotrophic keratitis. Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 are less studied neurotrophins in the ocular surface, even though brain-derived neurotrophic factor is well characterized in …

The Quality Of Energy- And Macronutrient-Balanced Diets Regulates Host Susceptibility To Influenza In Mice, Taylor A Cootes, Nayan D Bhattacharyya, Susie S Y Huang, Lina Daniel, Kim S Bell-Anderson, Sebastian A Stifter, Tracy Chew, Samantha M Solon-Biet, Luis R Saraiva, Yi Cai, Xinchun Chen, Stephen J Simpson, Carl G Feng

2020-Current year OA Pubs

Modulation of individual macronutrients or caloric density is known to regulate host resistance to infection in mice. However, the impact of diet composition, independent of macronutrient and energy content, on infection susceptibility is unclear. We show that two laboratory rodent diets, widely used as standard animal feeds and experimental controls, display distinct abilities in supporting mice during influenza infection. Mice placed on the highly processed AIN93G showed increased mortality to infection compared with those on a grain-based chow diet, suggesting a detrimental role for highly processed food in host defense. We further demonstrate that the heightened susceptibility of AIN93G-fed mice …

Microbiome Insights Into Pediatric Familial Adenomatous Polyposis., Thomas M. Attard, Seth Septer, Caitlin E. Lawson, Mark I. Attard, Sonny T M Lee, Shahid Umar

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Individuals with familial adenomatous polyposis (FAP) harbor numerous polyps with inevitable early progression to colon cancer. Complex microbiotic-tumor microenvironment perturbations suggest a dysbiotic relationship between polyp and microbiome. In this study, we performed comprehensive analyses of stool and tissue microbiome of pediatric FAP subjects and compared with unaffected cohabiting relatives through 16S V4 region amplicon sequencing and machine learning platforms.

RESULTS: Within our FAP and control patient population, Firmicutes and Bacteroidetes were the predominant phyla in the tissue and stool samples, while Proteobacteria dominated the polyp/non-polyp mucosa. A decline in Faecalibacterium in polyps contrasted with a decline in Bacteroides …

Tumor-Intrinsic Sirpa Promotes Sensitivity To Checkpoint Inhibition Immunotherapy In Melanoma, Zhicheng Zhou, Mei-Ju May Chen, Yikai Luo, Kamalika Mojumdar, Xin Peng, Hu Chen, Shweta V Kumar, Rehan Akbani, Yiling Lu, Han Liang

Faculty, Staff and Student Publications

Checkpoint inhibition immunotherapy has revolutionized cancer treatment, but many patients show resistance. Here we perform integrative transcriptomic and proteomic analyses on emerging immuno-oncology targets across multiple clinical cohorts of melanoma under anti-PD-1 treatment, on both bulk and single-cell levels. We reveal a surprising role of tumor-intrinsic SIRPA in enhancing antitumor immunity, in contrast to its well-established role as a major inhibitory immune modulator in macrophages. The loss of SIRPA expression is a marker of melanoma dedifferentiation, a key phenotype linked to immunotherapy efficacy. Inhibition of SIRPA in melanoma cells abrogates tumor killing by activated CD8+ T cells in a co-culture …

Increased Circulating Cortisol After Vaginal Birth Is Associated With Increased Fgf19 Secretion In Neonatal Pigs, Caitlin Vonderohe, Gregory Guthrie, Barbara Stoll, Valeria Melendez Hebib, Harry Dawson, Douglas Burrin

Children’s Nutrition Research Center Staff Publications

The influence of birth modality (scheduled cesarean or spontaneous vaginal) on the development of the newborn has been a source of controversy in neonatology. The impact of cesarean vs vaginal birth on the development of bile acid and fibroblast growth factor 19 (FGF19) signaling is unknown. Our aim was to determine the effect of birth modality and gestational age (preterm vs term) on plasma hormone levels, bile acid pool distribution, expression of genes in the bile acid-FXR-FGF19 pathway, and plasma levels of FGF19 at birth and on day 3 of life in neonatal pigs. Four sows underwent cesarean delivery on …

Inhibiting Ack1-Mediated Phosphorylation Of C-Terminal Src Kinase Counteracts Prostate Cancer Immune Checkpoint Blockade Resistance, Dhivya Sridaran, Surbhi Chouhan, Kiran Mahajan, Arun Renganathan, Cody Weimholt, Shambhavi Bhagwat, Melissa Reimers, Eric H Kim, Manish K Thakur, Muhammad A Saeed, Russell K Pachynski, Markus A Seeliger, W Todd Miller, Felix Y Feng, Nupam P Mahajan

2020-Current year OA Pubs

Solid tumours are highly refractory to immune checkpoint blockade (ICB) therapies due to the functional impairment of effector T cells and their inefficient trafficking to tumours. T-cell activation is negatively regulated by C-terminal Src kinase (CSK); however, the exact mechanism remains unknown. Here we show that the conserved oncogenic tyrosine kinase Activated CDC42 kinase 1 (ACK1) is able to phosphorylate CSK at Tyrosine 18 (pY18), which enhances CSK function, constraining T-cell activation. Mice deficient in the Tnk2 gene encoding Ack1, are characterized by diminished CSK Y18-phosphorylation and spontaneous activation of CD8

Sex Differences In Brain Tumor Glutamine Metabolism Reveal Sex-Specific Vulnerabilities To Treatment, Jasmin Sponagel, Jill K Jones, Cheryl Frankfater, Shanshan Zhang, Olivia Tung, Kevin Cho, Kelsey L Tinkum, Hannah Gass, Elena Nunez, Gary J Patti, Jingqin Luo, Joshua B Rubin, Joseph E Ippolito, Et Al.

2020-Current year OA Pubs

BACKGROUND: Brain cancer incidence and mortality rates are greater in males. Understanding the molecular mechanisms that underlie those sex differences could improve treatment strategies. Although sex differences in normal metabolism are well described, it is currently unknown whether they persist in cancerous tissue.

METHODS: Using positron emission tomography (PET) imaging and mass spectrometry, we assessed sex differences in glioma metabolism in samples from affected individuals. We assessed the role of glutamine metabolism in male and female murine transformed astrocytes using isotope labeling, metabolic rescue experiments, and pharmacological and genetic perturbations to modulate pathway activity.

FINDINGS: We found that male glioblastoma …

Repeated Out-Of-Africa Expansions Of Helicobacter Pylori Driven By Replacement Of Deleterious Mutations, Harry A Thorpe, Elise Tourrette, Koji Yahara, Filipa F Vale, Siqi Liu, Mónica Oleastro, Teresa Alarcon, Tsachi-Tsadok Perets, Saeid Latifi-Navid, Yoshio Yamaoka, Beatriz Martinez-Gonzalez, Ioannis Karayiannis, Timokratis Karamitros, Dionyssios N Sgouras, Wael Elamin, Ben Pascoe, Samuel K Sheppard, Jukka Ronkainen, Pertti Aro, Lars Engstrand, Lars Agreus, Sebastian Suerbaum, Kaisa Thorell, Daniel Falush

Faculty, Staff and Students Publications

Helicobacter pylori lives in the human stomach and has a population structure resembling that of its host. However, H. pylori from Europe and the Middle East trace substantially more ancestry from modern African populations than the humans that carry them. Here, we use a collection of Afro-Eurasian H. pylori genomes to show that this African ancestry is due to at least three distinct admixture events. H. pylori from East Asia, which have undergone little admixture, have accumulated many more non-synonymous mutations than African strains. European and Middle Eastern bacteria have elevated African ancestry at the sites of these mutations, implying …

Imprinted Antibody Responses Against Sars-Cov-2 Omicron Sublineages, Young-Jun Park, Zhuoming Liu, Javier Janer, Sean P J Whelan, Herbert W Virgin, Et Al.

2020-Current year OA Pubs

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters elicit plasma-neutralizing antibodies against Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5, and that breakthrough infections, but not vaccination alone, induce neutralizing antibodies in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1, BA.2, and BA.4/5 receptor-binding domains, whereas Omicron primary infections elicit B cells of narrow specificity up to 6 months after …

Gzmk(High) Cd8(+) T Effector Memory Cells Are Associated With Cd15(High) Neutrophil Abundance In Non-Metastatic Colorectal Tumors And Predict Poor Clinical Outcome, Silvia Tiberti, Carlotta Catozzi, Ottavio Croci, Mattia Ballerini, Danilo Cagnina, Chiara Soriani, Caterina Scirgolea, Zheng Gong, Jiatai He, Angeli D Macandog, Amir Nabinejad, Carina B Nava Lauson, Arianna Quinte', Giovanni Bertalot, Wanda L Petz, Simona P Ravenda, Valerio Licursi, Paola Paci, Marco Rasponi, Luca Rotta, Nicola Fazio, Guangwen Ren, Uberto Fumagalli-Romario, Martin H Schaefer, Stefano Campaner, Enrico Lugli, Luigi Nezi, Teresa Manzo

Faculty Research 2022

CD8+ T cells are a major prognostic determinant in solid tumors, including colorectal cancer (CRC). However, understanding how the interplay between different immune cells impacts on clinical outcome is still in its infancy. Here, we describe that the interaction of tumor infiltrating neutrophils expressing high levels of CD15 with CD8+ T effector memory cells (TEM) correlates with tumor progression. Mechanistically, stromal cell-derived factor-1 (CXCL12/ SDF-1) promotes the retention of neutrophils within tumors, increasing the crosstalk with CD8+ T cells. As a consequence of the contact-mediated inter- action with neutrophils, CD8+ T cells are skewed to produce high levels of GZMK, …

Omics Analyses Of A Somatic Trp53r245w/+ Breast Cancer Model Identify Cooperating Driver Events Activating Pi3k/Akt/Mtor Signaling, Xiaojie Yu, Yun Zhang, Shunbin Xiong, Joy M Mcdaniel, Chang Sun, Gilda P Chau, Jovanka Gencel-Augusto, Dhruv Chachad, Rhiannon L Morrissey, Xiayu Rao, Jing Wang, Guillermina Lozano

Faculty, Staff and Student Publications

Alterations of the tumor suppressor

A High-Resolution 3d Atlas Of The Spectrum Of Tuberculous Andcovid-19 Lung Lesions, Gordon Wells, Joel N Glasgow, Kievershen Nargan, Kapongo Lumamba, Rajhmun Madansein, Kameel Maharaj, Leon Y Perumal, Malcolm Matthew, Robert L Hunter, Hayden Pacl, Jacelyn E Peabody Lever, Denise D Stanford, Satinder P Singh, Prachi Bajpai, Upender Manne, Paul V Benson, Steven M Rowe, Stephan Le Roux, Alex Sigal, Muofhe Tshibalanganda, Carlyn Wells, Anton Du Plessis, Mpumelelo Msimang, Threnesan Naidoo, Adrie J C Steyn

Faculty, Staff and Student Publications

Our current understanding of the spectrum of TB and COVID-19 lesions in the human lung is limited by a reliance on low-resolution imaging platforms that cannot provide accurate 3D representations of lesion types within the context of the whole lung. To characterize TB and COVID-19 lesions in 3D, we applied micro/nanocomputed tomography to surgically resected, postmortem, and paraffin-embedded human lung tissue. We define a spectrum of TB pathologies, including cavitary lesions, calcium deposits outside and inside necrotic granulomas and mycetomas, and vascular rearrangement. We identified an unusual spatial arrangement of vasculature within an entire COVID-19 lobe, and 3D segmentation of …

Tuft-Cell-Intrinsic And -Extrinsic Mediators Of Norovirus Tropism Regulate Viral Immunity, Madison S Strine, Mia Madel Alfajaro, Vincent R Graziano, Jaewon Song, Leon L Hsieh, Ryan Hill, Jun Guo, Kelli L Vandussen, Robert C Orchard, Megan T Baldridge, Sanghyun Lee, Craig B Wilen

2020-Current year OA Pubs

Murine norovirus (MNoV) is a model for human norovirus and for interrogating mechanisms of viral tropism and persistence. We previously demonstrated that the persistent strain MNoV