Digital Commons Network^™

Aptamers As Potential Therapeutic Tools For Ovarian Cancer: Advancements And Challenges, Wojciech Szymanowski, Anna Szymanowska, Anna Bielawska, Gabriel Lopez-Berestein, Cristian Rodriguez-Aguayo, Paola Amero

Faculty, Staff and Student Publications

Ovarian cancer (OC) is the most common lethal gynecologic cause of death in women worldwide, with a high mortality rate and increasing incidence. Despite advancements in the treatment, most OC patients still die from their disease due to late-stage diagnosis, the lack of effective diagnostic methods, and relapses. Aptamers, synthetic, short single-stranded oligonucleotides, have emerged as promising anticancer therapeutics. Their ability to selectively bind to target molecules, including cancer-related proteins and receptors, has revolutionized drug discovery and biomarker identification. Aptamers offer unique insights into the molecular pathways involved in cancer development and progression. Moreover, they show immense potential as drug …

Mechanistic Toxicology In Light Of Genetic Compensation, Mary Jane Elizalde, Daniel A Gorelick

Faculty, Staff and Students Publications

Mechanistic toxicology seeks to identify the molecular and cellular mechanisms by which toxicants exert their deleterious effects. One powerful approach is to generate mutations in genes that respond to a particular toxicant, and then test how such mutations change the effects of the toxicant. CRISPR is a rapid and versatile approach to generate mutations in cultured cells and in animal models. Many studies use CRISPR to generate short insertions or deletions in a target gene and then assume that the resulting mutation, such as a premature termination codon, causes a loss of functional protein. However, recent studies demonstrate that this …

Molecular Mechanisms Of Twist1-Regulated Transcription In Emt And Cancer Metastasis, Xiaobin Yu, Tao He, Zhangwei Tong, Lan Liao, Shixia Huang, Walid D Fakhouri, Dean P Edwards, Jianming Xu

Faculty, Staff and Students Publications

TWIST1 induces epithelial-to-mesenchymal transition (EMT) to drive cancer metastasis. It is yet unclear what determines TWIST1 functions to activate or repress transcription. We found that the TWIST1 N-terminus antagonizes TWIST1-regulated gene expression, cancer growth and metastasis. TWIST1 interacts with both the NuRD complex and the NuA4/TIP60 complex (TIP60-Com) via its N-terminus. Non-acetylated TWIST1-K73/76 selectively interacts with and recruits NuRD to repress epithelial target gene transcription. Diacetylated TWIST1-acK73/76 binds BRD8, a component of TIP60-Com that also binds histone H4-acK5/8, to recruit TIP60-Com to activate mesenchymal target genes and MYC. Knockdown of BRD8 abolishes TWIST1 and TIP60-Com interaction and TIP60-Com recruitment to …

Machine Learning Methods For Endocrine Disrupting Potential Identification Based On Single-Cell Data, Zahir Aghayev, Adam T Szafran, Anh Tran, Hari S Ganesh, Fabio Stossi, Lan Zhou, Michael A Mancini, Efstratios N Pistikopoulos, Burcu Beykal

Faculty, Staff and Students Publications

Humans are continuously exposed to a variety of toxicants and chemicals which is exacerbated during and after environmental catastrophes such as floods, earthquakes, and hurricanes. The hazardous chemical mixtures generated during these events threaten the health and safety of humans and other living organisms. This necessitates the development of rapid decision-making tools to facilitate mitigating the adverse effects of exposure on the key modulators of the endocrine system, such as the estrogen receptor alpha (ERα), for example. The mechanistic stages of the estrogenic transcriptional activity can be measured with high content/high throughput microscopy-based biosensor assays at the single-cell level, which …

Plasma Metabolomics And Quantitative Interstitial Abnormalities In Ever-Smokers, Bina Choi, Raúl San José Estépar, Suneeta Godbole, Jeffrey L Curtis, Jennifer M Wang, Rubén San José Estépar, Ivan O Rosas, Jared R Mayers, Brian D Hobbs, Craig P Hersh, Samuel Y Ash, Meilan K Han, Russell P Bowler, Kathleen A Stringer, George R Washko, Wassim W Labaki

Faculty, Staff and Students Publications

BACKGROUND: Quantitative interstitial abnormalities (QIA) are an automated computed tomography (CT) finding of early parenchymal lung disease, associated with worse lung function, reduced exercise capacity, increased respiratory symptoms, and death. The metabolomic perturbations associated with QIA are not well known. We sought to identify plasma metabolites associated with QIA in smokers. We also sought to identify shared and differentiating metabolomics features between QIA and emphysema, another smoking-related advanced radiographic abnormality.

METHODS: In 928 former and current smokers in the Genetic Epidemiology of COPD cohort, we measured QIA and emphysema using an automated local density histogram method and generated metabolite profiles …

Identification Of Blood Protein Biomarkers Associated With Prostate Cancer Risk Using Genetic Prediction Models: Analysis Of Over 140,000 Subjects, Hua Zhong, Jingjing Zhu, Shuai Liu, Dalia H Ghoneim, Praveen Surendran, Tao Liu, Sarah Fahle, Adam Butterworth, Md Ashad Alam, Hong-Wen Deng, Herbert Yu, Chong Wu, Lang Wu

Faculty, Staff and Student Publications

Prostate cancer (PCa) brings huge public health burden in men. A growing number of conventional observational studies report associations of multiple circulating proteins with PCa risk. However, the existing findings may be subject to incoherent biases of conventional epidemiologic studies. To better characterize their associations, herein, we evaluated associations of genetically predicted concentrations of plasma proteins with PCa risk. We developed comprehensive genetic prediction models for protein levels in plasma. After testing 1308 proteins in 79 194 cases and 61 112 controls of European ancestry included in the consortia of BPC3, CAPS, CRUK, PEGASUS, and PRACTICAL, 24 proteins showed significant …

Repurposing Egfr Inhibitors For Oral Cancer Pain And Opioid Tolerance, Maria Daniela Santi, Morgan Zhang, Naijiang Liu, Chi T Viet, Tongxin Xie, Dane D Jensen, Moran Amit, Huilin Pan, Yi Ye

Faculty, Staff and Student Publications

Oral cancer pain remains a significant public health concern. Despite the development of improved treatments, pain continues to be a debilitating clinical feature of the disease, leading to reduced oral mobility and diminished quality of life. Opioids are the gold standard treatment for moderate-to-severe oral cancer pain; however, chronic opioid administration leads to hyperalgesia, tolerance, and dependence. The aim of this review is to present accumulating evidence that epidermal growth factor receptor (EGFR) signaling, often dysregulated in cancer, is also an emerging signaling pathway critically involved in pain and opioid tolerance. We presented preclinical and clinical data to demonstrate how …

Identification Of Circulating Proteins Associated With General Cognitive Function Among Middle-Aged And Older Adults, Adrienne Tin, Alison E Fohner, Qiong Yang, Jennifer A Brody, Gail Davies, Jie Yao, Dan Liu, Ilana Caro, Joni V Lindbohm, Michael R Duggan, Osorio Meirelles, Sarah E Harris, Valborg Gudmundsdottir, Adele M Taylor, Albert Henry, Alexa S Beiser, Ali Shojaie, Annabell Coors, Annette L Fitzpatrick, Claudia Langenberg, Claudia L Satizabal, Colleen M Sitlani, Eleanor Wheeler, Elliot M Tucker-Drob, Jan Bressler, Josef Coresh, Joshua C Bis, Julián Candia, Lori L Jennings, Maik Pietzner, Mark Lathrop, Oscar L Lopez, Paul Redmond, Robert E Gerszten, Stephen S Rich, Susan R Heckbert, Thomas R Austin, Timothy M Hughes, Toshiko Tanaka, Valur Emilsson, Ramachandran S Vasan, Xiuqing Guo, Yineng Zhu, Christophe Tzourio, Jerome I Rotter, Keenan A Walker, Luigi Ferrucci, Mika Kivimäki, Monique M B Breteler, Simon R Cox, Stephanie Debette, Thomas H Mosley, Vilmundur G Gudnason, Lenore J Launer, Bruce M Psaty, Sudha Seshadri, Myriam Fornage

Faculty, Staff and Student Publications

Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer's disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets.

In Situ Profiling Reveals Metabolic Alterations In The Tumor Microenvironment Of Ovarian Cancer After Chemotherapy, Sara Corvigno, Sunil Badal, Meredith L Spradlin, Michael Keating, Igor Pereira, Elaine Stur, Emine Bayraktar, Katherine I Foster, Nicholas W Bateman, Waleed Barakat, Kathleen M Darcy, Thomas P Conrads, G Larry Maxwell, Philip L Lorenzi, Susan K Lutgendorf, Yunfei Wen, Li Zhao, Premal H Thaker, Michael J Goodheart, Jinsong Liu, Nicole Fleming, Sanghoon Lee, Livia S Eberlin, Anil K Sood

Faculty, Staff and Student Publications

In this study, we investigated the metabolic alterations associated with clinical response to chemotherapy in patients with ovarian cancer. Pre- and post-neoadjuvant chemotherapy (NACT) tissues from patients with high-grade serous ovarian cancer (HGSC) who had poor response (PR) or excellent response (ER) to NACT were examined. Desorption electrospray ionization mass spectrometry (DESI-MS) was performed on sections of HGSC tissues collected according to a rigorous laparoscopic triage algorithm. Quantitative MS-based proteomics and phosphoproteomics were performed on a subgroup of pre-NACT samples. Highly abundant metabolites in the pre-NACT PR tumors were related to pyrimidine metabolism in the epithelial regions and oxygen-dependent proline …

Discovery, Structure-Activity Relationship And In Vitro Anticancer Activity Of Small-Molecule Inhibitors Of The Protein-Protein Interactions Between Af9/Enl And Af4 Or Dot1l, Xin Li, Xiaowei Wu, Shenyou Nie, Jidong Zhao, Yuan Yao, Fangrui Wu, Chandra Bhushan Mishra, Md Ashraf-Uz-Zaman, Bala Krishna Moku, Yongcheng Song

Faculty, Staff and Students Publications

Simple Summary

Chromosomal translocations involving the mixed lineage leukemia (MLL) gene generate potent fusion oncogenes and cause acute myeloid leukemia or lymphocytic leukemia, which account for ~75% infant and 5–10% child/adult acute leukemia cases with a poor prognosis (5-year survival rates < 45%). Protein–protein interactions between the most frequent MLL fusion partner proteins AF9/ENL and AF4 or histone methyltransferase DOT1L are critical to malignant gene expression and are therefore a potential drug target for cancer. Compound screening followed by medicinal chemistry studies identified several novel small-molecule inhibitors showing strong inhibition of these protein–protein interactions, significant suppression of characteristic gene expression, and robust cellular anticancer activities with negligible cytotoxicity. These compounds are useful chemical probes for biological studies of these protein–protein interactions, as well as pharmacological leads for further drug development against MLL-rearranged and other leukemias.

Abstract

Chromosomal translocations involving the mixed lineage leukemia (MLL) gene cause 5–10% acute leukemias with poor clinical outcomes. Protein–protein interactions (PPI) between the most frequent MLL fusion partner proteins AF9/ENL and AF4 or histone methyltransferase DOT1L are drug targets for MLL-rearranged (MLL-r) leukemia. Several benzothiophene-carboxamide compounds were identified as novel inhibitors of these PPIs with IC₅₀ values as …

Management Of Chronic Pain And Ptsd In Veterans With Tdcs+Prolonged Exposure: A Pilot Study, Melba A Hernandez-Tejada, Kathryn E Cherry, Sheila A M Rauch, Ron Acierno, Gabriel R Fries, Wendy Muzzy, Ellen J Teng, Bethany Wangelin, Hyochol Ahn

Faculty, Staff and Student Publications

Introduction: Chronic pain and posttraumatic stress disorder (PTSD) are prevalent comorbid conditions, particularly in Veterans; however, there are few integrated treatments for chronic pain and PTSD. Instead, interventions are typically implemented separately and may involve addictive opioids. Although there are highly effective, non-pharmacological treatments for PTSD, they are plagued by high dropout, which may be exacerbated by comorbid pain, as these PTSD treatments typically require increased activity. Importantly, a noninvasive pain treatment, tDCS (transcranial direct current stimulation) shows indications of effectiveness and may be integrated with psychological treatments, even when delivered via telehealth. This study examines the feasibility and initial …

Associations Between Rest-Activity Rhythms And Liver Function Tests: The Us National Health And Nutrition Examination Survey, 2011-2014, Chris Ho Ching Yeung, Cici Bauer, Qian Xiao

Faculty, Staff and Student Publications

Liver functions are regulated by the circadian rhythm; however, whether a weakened circadian rhythm is associated with impaired liver function is unclear. This study aims to investigate the association of characteristics of rest-activity rhythms with abnormal levels of biomarkers of liver function. Data were obtained from the National Health and Nutrition Examination Survey 2011-2014. Seven rest-activity rhythm parameters were derived from 24 h actigraphy data using the extended cosine model and non-parametric methods. Multiple logistic regression and multiple linear regression models were used to assess the associations between rest-activity rhythm parameters and alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase …

Racial Disparities In Mit Family Translocation Renal Cell Carcinoma, Xiaofan Lu, Nassim Tawanaie Pour Sedehi, Xiaoping Su, Fangrong Yan, Omar Alhalabi, Nizar M Tannir, Gabriel G Malouf

Faculty, Staff and Student Publications

Racial disparities have been documented in the biology and outcome of certain renal cell carcinomas (RCCs) among Black patients. However, little is known about racial differences in MiT family translocation RCC (TRCC). To investigate this issue, we performed a case-control study using data from The Cancer Genome Atlas (TCGA) and the Chinese OrigiMed2020 cohort. A total of 676 patients with RCC (14 Asian, 113 Black, and 525 White) were identified in TCGA, and TRCC was defined as RCC with TFE3/TFEB translocation or TFEB amplification, leading to 21 patients with TRCC (2 Asian, 8 Black, 10 White, and 1 unknown). Asian …

Tfeb And Tfe3 Control Glucose Homeostasis By Regulating Insulin Gene Expression, Adrien Pasquier, Nunzia Pastore, Luca D'Orsi, Rita Colonna, Alessandra Esposito, Veronica Maffia, Rossella De Cegli, Margherita Mutarelli, Susanna Ambrosio, Gennaro Tufano, Antonio Grimaldi, Marcella Cesana, Davide Cacchiarelli, Nathalie Delalleau, Gennaro Napolitano, Andrea Ballabio

Duncan NRI Faculty and Staff Publications

To fulfill their function, pancreatic beta cells require precise nutrient-sensing mechanisms that control insulin production. Transcription factor EB (TFEB) and its homolog TFE3 have emerged as crucial regulators of the adaptive response of cell metabolism to environmental cues. Here, we show that TFEB and TFE3 regulate beta-cell function and insulin gene expression in response to variations in nutrient availability. We found that nutrient deprivation in beta cells promoted TFEB/TFE3 activation, which resulted in suppression of insulin gene expression. TFEB overexpression was sufficient to inhibit insulin transcription, whereas beta cells depleted of both TFEB and TFE3 failed to suppress insulin gene …

Rare De Novo Gain-Of-Function Missense Variants In Dot1l Are Associated With Developmental Delay And Congenital Anomalies, Zelha Nil, Ashish R Deshwar, Yan Huang, Scott Barish, Xi Zhang, Sanaa Choufani, Polona Le Quesne Stabej, Ian Hayes, Patrick Yap, Chad Haldeman-Englert, Carolyn Wilson, Trine Prescott, Kristian Tveten, Arve Vøllo, Devon Haynes, Patricia G Wheeler, Jessica Zon, Cheryl Cytrynbaum, Rebekah Jobling, Moira Blyth, Siddharth Banka, Alexandra Afenjar, Cyril Mignot, Florence Robin-Renaldo, Boris Keren, Oguz Kanca, Xiao Mao, Daniel J Wegner, Kathleen Sisco, Marwan Shinawi, Undiagnosed Disease Network, Michael F Wangler, Rosanna Weksberg, Shinya Yamamoto, Gregory Costain, Hugo J Bellen

Faculty, Staff and Students Publications

Misregulation of histone lysine methylation is associated with several human cancers and with human developmental disorders. DOT1L is an evolutionarily conserved gene encoding a lysine methyltransferase (KMT) that methylates histone 3 lysine-79 (H3K79) and was not previously associated with a Mendelian disease in OMIM. We have identified nine unrelated individuals with seven different de novo heterozygous missense variants in DOT1L through the Undiagnosed Disease Network (UDN), the SickKids Complex Care genomics project, and GeneMatcher. All probands had some degree of global developmental delay/intellectual disability, and most had one or more major congenital anomalies. To assess the pathogenicity of the DOT1L …

Srcap Mutations Drive Clonal Hematopoiesis Through Epigenetic And Dna Repair Dysregulation, Chun-Wei Chen, Linda Zhang, Ravi Dutta, Abhishek Niroula, Peter G Miller, Christopher J Gibson, Alexander G Bick, Jaime M Reyes, Yi-Tang Lee, Ayala Tovy, Tianpeng Gu, Sarah Waldvogel, Yi-Hung Chen, Bryan J Venters, Pierre-Olivier Estève, Sriharsa Pradhan, Michael-Christopher Keogh, Pradeep Natarajan, Koichi Takahashi, Adam S Sperling, Margaret A Goodell

Faculty, Staff and Students Publications

Somatic mutations accumulate in all cells with age and can confer a selective advantage, leading to clonal expansion over time. In hematopoietic cells, mutations in a subset of genes regulating DNA repair or epigenetics frequently lead to clonal hematopoiesis (CH). Here, we describe the context and mechanisms that lead to enrichment of hematopoietic stem cells (HSCs) with mutations in SRCAP, which encodes a chromatin remodeler that also influences DNA repair. We show that SRCAP mutations confer a selective advantage in human cells and in mice upon treatment with the anthracycline-class chemotherapeutic doxorubicin and bone marrow transplantation. Furthermore, Srcap mutations lead …

Conformational Ensemble-Dependent Lipid Recognition And Segregation By Prenylated Intrinsically Disordered Regions In Small Gtpases, Mussie K Araya, Alemayehu A Gorfe

Faculty, Staff and Student Publications

We studied diverse prenylated intrinsically disordered regions (PIDRs) of Ras and Rho family small GTPases using long timescale atomistic molecular dynamics simulations in an asymmetric model membrane of phosphatidylcholine (PC) and phosphatidylserine (PS) lipids. Here we show that conformational plasticity is a key determinant of lipid sorting by polybasic PIDRs and provide evidence for lipid sorting based on both headgroup and acyl chain structures. We further show that conformational ensemble-based lipid recognition is generalizable to all polybasic PIDRs, and that the sequence outside the polybasic domain (PBD) modulates the conformational plasticity, bilayer adsorption, and interactions of PIDRs with membrane lipids. …

Microfluidic Coaxial 3d Bioprinting Of Cell-Laden Microfibers And Microtubes For Salivary Gland Tissue Engineering, Yu Yin, Ephraim J Vázquez-Rosado, Danielle Wu, Vignesh Viswananthan, Andrew Farach, Mary C Farach-Carson, Daniel A Harrington

Faculty, Staff and Student Publications

Replacement therapy for the salivary gland (SG) remains an unmet clinical need. Xerostomia ("dry mouth") due to hyposalivation can result from injury or disease to the SG, such as salivary acinar death caused by radiation therapy (RT) for head and neck squamous cell carcinoma (HNSCC). Currently, only palliative treatments exist for xerostomia, and many patients endure deteriorated oral health and poor quality of life. Tissue engineering could offer a permanent solution for SG replacement by isolating healthy SG tissues prior to RT, expanding its cells in vitro, and recreating a functional salivary neogland for implantation post-RT. 3D bioprinting methods potentiate …

Ensuring Trust In Genomics Research, Erman Ayday, Jaideep Vaidya, Xiaoqian Jiang, Amalio Telenti

Faculty, Staff and Student Publications

Reproducibility, transparency, representation, and privacy underpin the trust on genomics research in general and genome-wide association studies (GWAS) in particular. Concerns about these issues can be mitigated by technologies that address privacy protection, quality control, and verifiability of GWAS. However, many of the existing technological solutions have been developed in isolation and may address one aspect of reproducibility, transparency, representation, and privacy of GWAS while unknowingly impacting other aspects. As a consequence, the current patchwork of technological tools only partially and in an overlapping manner address issues with GWAS, sometimes even creating more problems. This paper addresses the progress in …

Exercise Training Reduces The Inflammatory Response And Promotes Intestinal Mucosa-Associated Immunity In Lynch Syndrome, Nan Deng, Laura Reyes-Uribe, Johannes F Fahrmann, Whittney S Thoman, Mark F Munsell, Jennifer B Dennison, Eunice Murage, Ranran Wu, Ernest T Hawk, Selvi Thirumurthi, Patrick M Lynch, Christina M Dieli-Conwright, Alexander J Lazar, Sonali Jindal, Khoi Chu, Manoj Chelvanambi, Karen Basen-Engquist, Yisheng Li, Jennifer A Wargo, Florencia Mcallister, James P Allison, Padmanee Sharma, Krishna M Sinha, Samir Hanash, Susan C Gilchrist, Eduardo Vilar

Faculty, Staff and Student Publications

PURPOSE: Lynch syndrome (LS) is a hereditary condition with a high lifetime risk of colorectal and endometrial cancers. Exercise is a non-pharmacologic intervention to reduce cancer risk, though its impact on patients with LS has not been prospectively studied. Here, we evaluated the impact of a 12-month aerobic exercise cycling intervention in the biology of the immune system in LS carriers.

PATIENTS AND METHODS: To address this, we enrolled 21 patients with LS onto a non-randomized, sequential intervention assignation, clinical trial to assess the effect of a 12-month exercise program that included cycling classes 3 times weekly for 45 minutes …

Nanobomb Optical Coherence Elastography In Multilayered Phantoms, Maryam Hatami, Dmitry Nevozhay, Manmohan Singh, Alexander Schill, Paul Boerner, Salavat Aglyamov, Konstantin Sokolov, Kirill V Larin

Faculty, Staff and Student Publications

Many tissues are composed of layered structures, and a better understanding of the changes in the layered tissue biomechanics can enable advanced guidance and monitoring of therapy. The advent of elastography using longitudinally propagating shear waves (LSWs) has created the prospect of a high-resolution assessment of depth-dependent tissue elasticity. Laser activation of liquid-to-gas phase transition of dye-loaded perfluorocarbon (PFC) nanodroplets (a.k.a., nanobombs) can produce highly localized LSWs. This study aims to leverage the potential of photoactivation of nanobombs to incudce LSWs with very high-frequency content in wave-based optical coherence elastography (OCE) to estimate the elasticity gradient with high resolution. In …

A Framework For Standardised Tissue Sampling And Processing During Resection Of Diffuse Intracranial Glioma: Joint Recommendations From Four Rano Groups, Philipp Karschnia, Marion Smits, Guido Reifenberger, Emilie Le Rhun, Benjamin M Ellingson, Norbert Galldiks, Michelle M Kim, Jason T Huse, Oliver Schnell, Patrick N Harter, Malte Mohme, Expert Rater Panel, Louisa Von Baumgarten, Nathalie L Albert, Raymond Y Huang, Minesh P Mehta, Martin Van Den Bent, Michael Weller, Michael A Vogelbaum, Susan M Chang, Mitchel S Berger, Joerg-Christian Tonn

Faculty, Staff and Student Publications

Surgical resection represents the standard of care for people with newly diagnosed diffuse gliomas, and the neuropathological and molecular profile of the resected tissue guides clinical management and forms the basis for research. The Response Assessment in Neuro-Oncology (RANO) consortium is an international, multidisciplinary effort that aims to standardise research practice in neuro-oncology. These recommendations represent a multidisciplinary consensus from the four RANO groups: RANO resect, RANO recurrent glioblastoma, RANO radiotherapy, and RANO/PET for a standardised workflow to achieve a representative tumour evaluation in a disease characterised by intratumoural heterogeneity, including recommendations on which tumour regions should be surgically sampled, …

Once-Weekly Transcon Cnp (Navepegritide) In Children With Achondroplasia (Accomplish): A Phase 2, Multicentre, Randomised, Double-Blind, Placebo-Controlled, Dose-Escalation Trial, Ravi Savarirayan, Daniel G Hoernschemeyer, Merete Ljungberg, Yuri A Zarate, Carlos A Bacino, Michael B Bober, Janet M Legare, Wolfgang Högler, Teresa Quattrin, M Jennifer Abuzzahab, Paul L Hofman, Klane K White, Nina S Ma, Dirk Schnabel, Sérgio B Sousa, Meng Mao, Alden Smith, Mukta Chakraborty, Adebola Giwa, Bent Winding, Birgitte Volck, Aimee D Shu, Ciara Mcdonnell

Faculty, Staff and Students Publications

BACKGROUND: TransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) designed to allow for continuous CNP exposure with once-weekly dosing. This 52-week phase 2 (ACcomplisH) trial assessed the safety and efficacy of TransCon CNP in children with achondroplasia.

METHODS: ACcomplisH is a global, randomised, double-blind, placebo-controlled, dose-escalation trial. Study participants were recruited between June 10, 2020, and September 24, 2021. Eligible participants were prepubertal, aged 2-10 years, with genetically confirmed achondroplasia, and randomised 3:1 to once-weekly subcutaneous injections of TransCon CNP (6, 20, 50, or 100 μg CNP/kg/week) or placebo for 52 weeks. Primary objectives were safety …

Effectiveness Of Icosapent Ethyl On First And Total Cardiovascular Events In Patients With Metabolic Syndrome, But Without Diabetes: Reduce-It Metsyn, Michael Miller, Deepak L Bhatt, Eliot A Brinton, Terry A Jacobson, Philippe Gabriel Steg, Armando Lira Pineda, Steven B Ketchum, Ralph T Doyle, Jean-Claude Tardif, Christie M Ballantyne

Faculty, Staff and Students Publications

Aims: Metabolic syndrome (MetSyn) is associated with high risk of cardiovascular (CV) events, irrespective of statin therapy. In the overall REDUCE-IT study of statin-treated patients, icosapent ethyl (IPE) reduced the risk of the primary composite endpoint (CV death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or unstable angina requiring hospitalization) and the key secondary composite endpoint (CV death, non-fatal myocardial infarction, or non-fatal stroke).

Methods and results: REDUCE-IT was an international, double-blind trial that randomized 8179 high CV risk statin-treated patients with controlled LDL cholesterol and elevated triglycerides, to IPE 4 g/day or placebo. The current study evaluated the pre-specified …

A Human Mitofusin 2 Mutation Can Cause Mitophagic Cardiomyopathy, Antonietta Franco, Jiajia Li, Daniel P Kelly, Ray E Hershberger, Ali J Marian, Renate M Lewis, Moshi Song, Xiawei Dang, Alina D Schmidt, Mary E Mathyer, John R Edwards, Cristina De Guzman Strong, Gerald W Dorn

Faculty, Staff and Student Publications

Cardiac muscle has the highest mitochondrial density of any human tissue, but mitochondrial dysfunction is not a recognized cause of isolated cardiomyopathy. Here, we determined that the rare mitofusin (MFN) 2 R400Q mutation is 15-20× over-represented in clinical cardiomyopathy, whereas this specific mutation is not reported as a cause of MFN2 mutant-induced peripheral neuropathy, Charcot-Marie-Tooth disease type 2A (CMT2A). Accordingly, we interrogated the enzymatic, biophysical, and functional characteristics of MFN2 Q400 versus wild-type and CMT2A-causing MFN2 mutants. All MFN2 mutants had impaired mitochondrial fusion, the canonical MFN2 function. Compared to MFN2 T105M that lacked catalytic GTPase activity and exhibited normal …

Site-Specific Pathophysiology In A Neonatal Mouse Model Of Gastroparesis, Price T Edwards, Krishnakant G Soni, Margaret E Conner, Stephanie W Fowler, Jaime P P Foong, Rhian Stavely, Lily S Cheng, Geoffrey A Preidis

Faculty, Staff and Students Publications

BACKGROUND: Early-life events impact maturation of the gut microbiome, enteric nervous system, and gastrointestinal motility. We examined three regions of gastric tissue to determine how maternal separation and gut microbes influence the structure and motor function of specific regions of the neonatal mouse stomach.

METHODS: Germ-free and conventionally housed C57BL/6J mouse pups underwent timed maternal separation (TmSep) or nursed uninterrupted (controls) until 14 days of life. We assessed gastric emptying by quantifying the progression of gavaged fluorescein isothiocyanate (FITC)-dextran. With isolated rings of forestomach, corpus, and antrum, we measured tone and contractility by force transduction, gastric wall thickness by light …

Breastfeeding And Risk Of Childhood Brain Tumors: A Report From The Childhood Cancer And Leukemia International Consortium, Jeremy M Schraw, Eleni Th Petridou, Audrey Bonaventure, John D Dockerty, Maria Karalexi, Evangelia Ntzani, Claire Infante-Rivard, Jacqueline Clavel, Paige M Bracci, Roberta Mckean-Cowdin, Eve Roman, Eleanor Kane, Friederike Erdmann, Joachim Schüz, Beth A Mueller, Michael E Scheurer

Faculty, Staff and Students Publications

Purpose: Studies report mixed findings regarding the association of breastfeeding with childhood brain tumors (CBT), the leading causes of cancer-related mortality in young people. Our objective was to determine whether breastfeeding is associated with CBT incidence.

Methods: We pooled data on N = 2610 cases with CBT (including 697 cases with astrocytoma, 447 cases with medulloblastoma/primitive neuroectodermal tumor [PNET], 167 cases with ependymoma) and N = 8128 age- and sex-matched controls in the Childhood Cancer and Leukemia International Consortium. We computed unconditional logistic regression models to estimate the odds ratio (OR) and 95% confidence interval (CI) of CBT, astrocytoma, medulloblastoma/PNET, …

Examining Potential Modifiers Of Human Skin And Plasma Carotenoid Responses In A Randomized Trial Of A Carotenoid-Containing Juice Intervention, Stephanie B Jilcott Pitts, Qiang Wu, Nancy E Moran, Melissa N Laska, Lisa Harnack

Children’s Nutrition Research Center Staff Publications

Background: Skin carotenoid measurements are emerging as a valid and reliable indicator of fruit and vegetable intake and carotenoid intake. However, little is known about the extent to which skin carotenoid responsivity to dietary changes differs based on demographic and physiologic characteristics.

Objectives: This study examined potential effect modifiers of skin carotenoid and plasma carotenoid responses to a carotenoid-rich juice intervention.

Methods: We leveraged data from 2 arms of a 3-site randomized controlled trial of a carotenoid-containing juice intervention (moderate dose = 6 ounces juice, 4 mg total carotenoids/d, high dose = 12 ounces juice, 8 mg total carotenoids/d) (n …

Transposable Elements Are Co-Opted As Oncogenic Regulatory Elements By Lineage-Specific Transcription Factors In Prostate Cancer, Giacomo Grillo, Tina Keshavarzian, Simon Linder, Christopher Arlidge, Lisanne Mout, Ankita Nand, Mona Teng, Aditi Qamra, Stanley Zhou, Ken J Kron, Alex Murison, James R Hawley, Michael Fraser, Theodorus H Van Der Kwast, Ganesh V Raj, Housheng Hansen He, Wilbert Zwart, Mathieu Lupien

Faculty, Staff and Student Publications

Transposable elements hold regulatory functions that impact cell fate determination by controlling gene expression. However, little is known about the transcriptional machinery engaged at transposable elements in pluripotent and mature versus oncogenic cell states. Through positional analysis over repetitive DNA sequences of H3K27ac chromatin immunoprecipitation sequencing data from 32 normal cell states, we report pluripotent/stem and mature cell state–specific “regulatory transposable elements.” Pluripotent/stem elements are binding sites for pluripotency factors (e.g., NANOG, SOX2, OCT4). Mature cell elements are docking sites for lineage-specific transcription factors, including AR and FOXA1 in prostate epithelium. Expanding the analysis to prostate tumors, we identify a …

Mechanisms Of Osteoclastogenesis In Orthodontic Tooth Movement And Orthodontically Induced Tooth Root Resorption, Yuta Nakai, Natnicha Praneetpong, Wanida Ono, Noriaki Ono

Faculty, Staff and Student Publications

Orthodontic tooth movement (OTM) is achieved by the simultaneous activation of bone resorption by osteoclasts and bone formation by osteoblasts. When orthodontic forces are applied, osteoclast-mediated bone resorption occurs in the alveolar bone on the compression side, creating space for tooth movement. Therefore, controlling osteoclastogenesis is the fundamental tenet of orthodontic treatment. Orthodontic forces are sensed by osteoblast lineage cells such as periodontal ligament (PDL) cells and osteocytes. Of several cytokines produced by these cells, the most important cytokine promoting osteoclastogenesis is the receptor activator of nuclear factor-κB ligand (RANKL), which is mainly supplied by osteoblasts. Additionally, osteocytes embedded within …