Medical Specialties Commons^™

Predicting Severity Of Radiation Induced Lymphopenia In Individual Proton Therapy Patients For Varying Dose Rate And Fractionation Using Dynamic 4-Dimensional Blood Flow Simulations, Lucas Mccullum, Jungwook Shin, Stella Xing, Chris Beekman, Jan Schuemann, Theodore Hong, Dan Duda, Radhe Mohan, Steven H Lin, Camilo M Correa-Alfonso, Sean Domal, Julia Withrow, Wesley Bolch, Harald Paganetti, Clemens Grassberger

Faculty, Staff and Student Publications

PURPOSE: Radiation-induced lymphopenia has gained attention recently as the result of its correlation with survival in a range of indications, particularly when combining radiation therapy (RT) with immunotherapy. The purpose of this study is to use a dynamic blood circulation model combined with observed lymphocyte depletion in patients to derive the in vivo radiosensitivity of circulating lymphocytes and study the effect of RT delivery parameters.

METHODS AND MATERIALS: We assembled a cohort of 17 patients with hepatocellular carcinoma treated with proton RT alone in 15 fractions (fx) using conventional dose rates (beam-on time [BOT], 120 seconds) for whom weekly absolute …

Tp53 Gain-Of-Function Mutation Modulates The Immunosuppressive Microenvironment In Non-Hpv-Associated Oral Squamous Cell Carcinoma, Yewen Shi, Xiaoyong Ren, Shaolong Cao, Xi Chen, Bo Yuan, Fabio Henrique Brasil Da Costa, Alanis E Rodriguez Rosario, Arnoldo Corona, Chieko Michikawa, Ratna Veeramachaneni, Abdullah A Osman, Tongxin Xie, Wenyi Wang, Andrew G Sikora, Jeffrey N Myers, Roberto Rangel

Faculty, Staff and Student Publications

BACKGROUND: TP53, the most mutated gene in solid cancers, has a profound impact on most hallmarks of cancer. Somatic TP53 mutations occur in high frequencies in head and neck cancers, including oral squamous cell carcinoma (OSCC). Our study aims to understand the role of TP53 gain-of-function mutation in modulating the tumor immune microenvironment (TIME) in OSCC.

METHODS: Short hairpin RNA knockdown of mutant p53R172H in syngeneic oral tumors demonstrated changes in tumor growth between immunocompetent and immunodeficient mice. HTG EdgeSeq targeted messenger RNA sequencing was used to analyze cytokine and immune cell markers in tumors with inactivated mutant p53R172H …

Maternal Provisioning Interacts With Incubation Temperature To Affect Hatchling Mercury Exposure In An Oviparous Reptile, Josiah M Johnson, Christopher R Smaga, Samantha L Bock, Benjamin B Parrott

Faculty, Staff and Student Publications

The thermal environment experienced by developing embryos can influence the utilization of maternally provisioned resources. Despite being particularly consequential for oviparous ectotherms, these dynamics are largely unexplored within ecotoxicological frameworks. Here, we test if incubation temperature interacts with maternally transferred mercury to affect subsequent body burdens and tissue distributions of mercury in hatchling American alligators (

Blastoid And Pleomorphic Mantle Cell Lymphoma Demonstrate Distinct Clinicopathologic And Genetic Features, Mahsa Khanlari, Huan Mo, Do Hwan Kim, Ali Sakhdari, Ken H Young, Preetesh Jain, Michael Wang, Shaoying Li, Rashmi Kanagal-Shamanna, Roberto N Miranda, Francisco Vega, L Jeffrey Medeiros, Chi Young Ok

Faculty, Staff and Student Publications

The blastoid (B) and pleomorphic (P) variants of mantle cell lymphoma (MCL) are associated with aggressive clinical behavior. In this study, we collected 102 cases of B-MCL and P-MCL from untreated patients. We reviewed clinical data, analyzed morphologic features using an image analysis tool (ImageJ) and we assessed mutational and gene expression profiles. The chromatin pattern of lymphoma cells was assessed quantitatively by the pixel value. Cases of B-MCL showed a greater median pixel value with lower variation compared with P-MCL, indicating a homogeneously euchromatin-rich pattern in B-MCL. In addition, the Feret diameter of the nuclei was significantly smaller (median …

Single-Cell Transcriptomic Analysis Uncovers Intratumoral Heterogeneity And Drug-Tolerant Persister In Alk-Rearranged Lung Adenocarcinoma, Hoi-Hin Kwok, Huiyu Li, Jiashuang Yang, Junyang Deng, Nerissa Chui-Mei Lee, Timmy Wing-Kuk Au, Alva Ko-Yung Sit, Michael Kuan-Yew Hsin, Stephanie Kwai-Yee Ma, Lydia Wai-Ting Cheung, Luc Girard, Junya Fujimoto, Ignacio Ivan Wistuba, Boning Gao, John Dorrance Minna, David Chi-Leung Lam

Faculty, Staff and Student Publications

No abstract provided.

The Collaborative National Quality And Efficacy Registry For Scleroderma: Association Of Medication Use On Gastrointestinal Tract Symptoms In Early Disease And The Importance Of Tobacco Cessation, Sarah Luebker, Tracy M Frech, Shervin Assassi, Jessica K Gordon, Elana J Bernstein, Virginia D Steen, Ami A Shah, Laura K Hummers, Carrie Richardson, Dinesh Khanna, Flavia V Castelino, Lorinda Chung, Faye N Hant, Victoria K Shanmugam, John M Vanburen, Jessica Alvey, Monica Harding, Nora Sandorfi

Faculty, Staff and Student Publications

Objectives: Systemic Sclerosis (SSc) is frequently associated with gastrointestinal tract (GIT) involvement. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative study collecting longitudinal follow up data on SSc patients with less than 5-years disease duration enrolled at Scleroderma centres of excellence. This manuscript presents the GIT natural history and outcomes in relation to other scleroderma manifestations and medication exposures.

Methods: CONQUER participants that had completed a minimum of two serial Scleroderma Clinical Trials Consortium GIT Questionnaires (GIT 2.0) were included in this analysis. Patients were categorised by total GIT 2.0 severity at baseline, and by category …

Interpersonal Stress And Proinflammatory Activity In Emerging Adults With A History Of Suicide Risk: A Pilot Study, Annamarie B Defayette, Christianne Esposito-Smythers, Ian Cero, Katherine M Harris, Emma D Whitmyre, Roberto López

Faculty, Staff and Student Publications

Interpersonal stress during adolescence and young adulthood can threaten healthy developmental trajectories. A “primed” proinflammatory response to acute stress may serve as an underlying process that results in negative outcomes for youth. The present pilot study examined the relation between interpersonal stress and two proinflammatory cytokines in a sample of 42 university-recruited emerging adults with recent suicidal thoughts and behaviors. Participants completed self-report measures of mood, suicidal thoughts and behaviors, recent peer-related stressors, and interpersonal sensitivity. They also participated in an acute laboratory social stress task and provided three saliva samples to measure their proinflammatory responses (IL-6 and TNF-α) to …

Dissemination Of Class A Cephalosporinases And Class D Carbapenemases In Escherichia Coli Isolates From A Tertiary Hospital In Sudan, Khalid E Khalid

Faculty, Staff and Student Publications

Introduction

The high prevalence of urinary tract infections (UTIs) and rising resistance to beta-lactam antibiotics, which is a global therapeutic concern, are caused by Escherichia coli (E. coli) extended-spectrum beta-lactamases (ESBLs) producers. It is unclear how E. coli that produces ESBLs spreads throughout Gezira state, Sudan. The study aimed to evaluate the dissemination of class A and class D resistance genes among E. coli and to recognize the antibacterial activity of the locally used cephalosporins and carbapenems.

Methods

One hundred and fifteen isolates of uropathogenic E. coli were collected from patients who attended a tertiary hospital. The isolates …

The Association Of Intensive Blood Pressure Treatment And Non-Fatal Cardiovascular Or Serious Adverse Events In Older Adults With Mortality: Mediation Analysis In Sprint, Adil A Ali, Khalid E Khalid, Hajir M Hussien, Somaya E Mohammed, Osman K Saeed

Faculty, Staff and Student Publications

INTRODUCTION: Human leukocyte antigens (HLA) account for up to one-half of the total genetic contribution to rheumatoid arthritis (RA) risk. The study investigated the association of HLA class II genotyping with RA susceptibility in Sudanese ethnic groups.

METHODS: The DRB1 and DQB1 alleles and haplotypes were determined in 122 RA patients (i.e., Gaalia = 54, Johayna = 24, Baggara = 17, Nile Nubian = 12, and others = 15) and 120 healthy controls of ethnic groups (i.e., Gaalia = 44, Johayna = 11, Baggara = 15, Nile Nubian = 9, and others = 21) using a polymerase chain reaction with …

Effect Of Intravenous Golimumab On Fatigue And The Relationship With Clinical Response In Adults With Active Ankylosing Spondylitis In The Phase 3 Go-Alive Study, Atul Deodhar, Natalie J Shiff, Cinty Gong, Eric K H Chan, Elizabeth C Hsia, Kim Hung Lo, Alianu Akawung, Lilianne Kim, Stephen Xu, John D Reveille

Faculty, Staff and Student Publications

INTRODUCTION: We studied the effect of intravenous (IV)-golimumab on fatigue and the association of fatigue improvement with clinical response post hoc in adults with active ankylosing spondylitis (AS) in the GO-ALIVE trial.

METHODS: Patients were randomized to IV-golimumab 2 mg/kg (N = 105) at week (W) 0, W4, then every 8 W (Q8W) or placebo (N = 103) at W0, W4, W12, crossover to IV-golimumab 2 mg/kg at W16, W20, then Q8W through W52. Fatigue measures included Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Question #1 (fatigue; 0 [none], 10 [worst]; decrease indicates improvement) and 36-Item Short Form Health Survey …

Reduced-Intensity Anthracycline-Free Chemoimmunotherapy In Elderly Patients With Newly Diagnosed Or Relapsed Diffuse Large B-Cell Lymphoma, Binoy Yohannan, Adan Rios

Faculty, Staff and Student Publications

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL); it has a cure rate of approximately 50% with standard anthracycline-based chemoimmunotherapy. However, the clinical outcomes of elderly unfit/frail DLBCL patients remain suboptimal due to poor tolerance of anthracycline-containing regimens. Herein, we report a series of seven elderly unfit patients with DLBCL who were treated with a reduced-intensity anthracycline-free chemoimmunotherapy (rituximab, cyclophosphamide, vincristine, and prednisone) regimen combined with lenalidomide (R

Psoriasiform Mycosis Fungoides–Cutaneous T-Cell Lymphoma In An African American, Austinn C Miller, Alexzandra Mattia, Anthony Thompson, Laurie A Temiz, Susuana Adjei, Stephen K Tyring

Faculty, Staff and Student Publications

No abstract provided.

A Case Of Combined Pulmonary Vein Isolation (Pvi) And Watchman Implant Through Hepatic Vein In A Patient With Interrupted Inferior Vena Cava (Ivc), Sameh Girgis, Negar Niknam, Zabeer Bhatti, Jalal Mohsin, Ahmed Kamel Abdel Aal, Ramesh Hariharan, Khashayar Hematpour

Faculty, Staff and Student Publications

This case report describes a successful procedure involving pulmonary vein isolation (PVI) and left atrial appendage (LAA) closure with a watchman device in a 78-year-old male with atrial fibrillation and an interrupted inferior vena cava. Due to the vascular anomaly, a transhepatic approach was used, which proved successful.

Mosaic Chromosomal Alterations Are Associated With Increased Lung Cancer Risk: Insight From The Integral-Ilcco Cohort Analysis, Chao Cheng, Wei Hong, Yafang Li, Xiangjun Xiao, James Mckay, Younghun Han, Jinyoung Byun, Bo Peng, Demetrios Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Stig E Bojesen, Maria T Landi, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, David C Christiani, Gad Rennert, Susanne Arnold, Gary Goodman, John K Field, Michael P A Davies, Sanjay S Shete, Loic Le Marchand, Geoffrey Liu, Rayjean J Hung, Angeline S Andrew, Lambertus A Kiemeney, Meng Zhu, Hongbing Shen, Shan Zienolddiny, Kjell Grankvist, Mikael Johansson, Angela Cox, Yun-Chul Hong, Jian-Min Yuan, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Paul Brennan, Yong Li, Olga Gorlova, Ivan Gorlov, Christopher I Amos, Integral-Ilcco Lung Cancer Consortium

Faculty, Staff and Student Publications

INTRODUCTION: Mosaic chromosomal alterations (mCAs) detected in white blood cells represent a type of clonal hematopoiesis (CH) that is understudied compared with CH-related somatic mutations. A few recent studies indicated their potential link with nonhematological cancers, especially lung cancer.

METHODS: In this study, we investigated the association between mCAs and lung cancer using the high-density genotyping data from the OncoArray study of INTEGRAL-ILCCO, the largest single genetic study of lung cancer with 18,221 lung cancer cases and 14,825 cancer-free controls.

RESULTS: We identified a comprehensive list of autosomal mCAs, ChrX mCAs, and mosaic ChrY (mChrY) losses from these samples. Autosomal …

Biochemical And Structural Characterization Of The First-Discovered Metazoan Dna Cytosine-N4 Methyltransferase From The Bdelloid Rotifer Adineta Vaga, Jujun Zhou, John R Horton, Gundeep Kaur, Qin Chen, Xuwen Li, Fabian Mendoza, Tao Wu, Robert M Blumenthal, Xing Zhang, Xiaodong Cheng

Faculty, Staff and Student Publications

Much is known about the generation, removal, and roles of 5-methylcytosine (5mC) in eukaryote DNA, and there is a growing body of evidence regarding N6-methyladenine, but very little is known about N4-methylcytosine (4mC) in the DNA of eukaryotes. The gene for the first metazoan DNA methyltransferase generating 4mC (N4CMT) was reported and characterized recently by others, in tiny freshwater invertebrates called bdelloid rotifers. Bdelloid rotifers are ancient, apparently asexual animals, and lack canonical 5mC DNA methyltransferases. Here, we characterize the kinetic properties and structural features of the catalytic domain of the N4CMT protein from the bdelloid rotifer Adineta vaga. We …

Missense Genetic Variation Of Icam1 And Incident Heart Failure, Pedro Giro, Jonathan W Cunningham, Laura Rasmussen-Torvik, Suzette J Bielinski, Nicholas B Larson, Laura A Colangelo, David R Jacobs, Myron Gross, Alex P Reiner, Donald M Lloyd-Jones, Xiuqing Guo, Kent Taylor, Muthiah Vaduganathan, Wendy S Post, Alain Bertoni, Christie Ballantyne, Amil Shah, Brian Claggett, Eric Boerwinkle, Bing Yu, Scott D Solomon, Sanjiv J Shah, Ravi B Patel

Faculty, Staff and Student Publications

BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) is a cell surface protein that participates in endothelial activation and is hypothesized to play a central role in heart failure (HF). We evaluated associations of ICAM1 missense genetic variants with circulating ICAM-1 levels and with incident HF.

METHODS AND RESULTS: We identified 3 missense variants within ICAM1 (rs5491, rs5498 and rs1799969) and evaluated their associations with ICAM-1 levels in the Coronary Artery Risk Development in Young Adults Study and the Multi-Ethnic Study of Atherosclerosis (MESA). We determined the association among these 3 variants and incident HF in MESA. We separately evaluated significant associations in …

Chromatin Architectural Factor Ctcf Is Essential For Progesterone-Dependent Uterine Maturation, Sylvia C Hewitt, Artiom Gruzdev, Cynthia J Willson, San-Pin Wu, John P Lydon, Niels Galjart, Francesco J Demayo

Faculty, Staff and Students Publications

Receptors for estrogen and progesterone frequently interact, via Cohesin/CTCF loop extrusion, at enhancers distal from regulated genes. Loss-of-function CTCF mutation in >20% of human endometrial tumors indicates its importance in uterine homeostasis. To better understand how CTCF-mediated enhancer-gene interactions impact endometrial development and function, the Ctcf gene was selectively deleted in female reproductive tissues of mice. Prepubertal Ctcf

Why Animal Experiments Are Still Indispensable In Bone Research: A Statement By The European Calcified Tissue Society, Merle Stein, Florent Elefteriou, Björn Busse, Imke Ak Fiedler, Ronald Young Kwon, Eric Farrell, Mubashir Ahmad, Anita Ignatius, Liam Grover, Liesbet Geris, Jan Tuckermann

Faculty, Staff and Students Publications

Major achievements in bone research have always relied on animal models and in vitro systems derived from patient and animal material. However, the use of animals in research has drawn intense ethical debate and the complete abolition of animal experimentation is demanded by fractions of the population. This phenomenon is enhanced by the reproducibility crisis in science and the advance of in vitro and in silico techniques. 3D culture, organ-on-a-chip, and computer models have improved enormously over the last years. Nevertheless, the overall complexity of bone tissue-cross talk and the systemic and local regulation of bone physiology can often only …

Prdm16 Deletion Is Associated With Sex-Dependent Cardiomyopathy And Cardiac Mortality: A Translational, Multi-Institutional Cohort Study, Ryan J Kramer, Amir Nima Fatahian, Alice Chan, Jeffery Mortenson, Jennifer Osher, Bo Sun, Lauren E Parker, Michael B Rosamilia, Kyra B Potter, Kaila Moore, Sage L Atkins, Jill A Rosenfeld, Alona Birjiniuk, Edward Jones, Taylor S Howard, Jeffrey J Kim, Daryl A Scott, Seema Lalani, Omid M T Rouzbehani, Samantha Kaplan, Marissa A Hathaway, Jennifer L Cohen, S Yukiko Asaki, Hugo R Martinez, Sihem Boudina, Andrew P Landstrom

Faculty, Staff and Students Publications

BACKGROUND: 1p36 deletion syndrome can predispose to pediatric-onset cardiomyopathy. Deletion breakpoints are variable and may delete the transcription factor

METHODS: This retrospective cohort included subjects with 1p36 deletion syndrome from 4 hospitals. Prevalence of cardiomyopathy and freedom from death, cardiac transplantation, or ventricular assist device were analyzed. A systematic review cohort was derived for further analysis. A cardiac-specific

RESULTS: The retrospective cohort included 71 patients. Among individuals with

CONCLUSIONS:

The Clinical And Genetic Spectrum Of Autosomal-Recessive Tor1a-Related Disorders, Afshin Saffari, Tracy Lau, Homa Tajsharghi, Ehsan Ghayoor Karimiani, Ariana Kariminejad, Stephanie Efthymiou, Giovanni Zifarelli, Tipu Sultan, Mehran Beiraghi Toosi, Sahar Sedighzadeh, Victoria Mok Siu, Juan Darío Ortigoza-Escobar, Aisha M Alshamsi, Shahnaz Ibrahim, Nouriya Abbas Al-Sannaa, Walla Al-Hertani, Whalen Sandra, Mark Tarnopolsky, Shahryar Alavi, Chumei Li, Debra-Lynn Day-Salvatore, Maria Jesús Martínez-González, Kristin M Levandoski, Emma Bedoukian, Suneeta Madan-Khetarpal, Michaela J Idleburg, Minal Juliet Menezes, Aishwarya Siddharth, Konrad Platzer, Henry Oppermann, Martin Smitka, Felicity Collins, Monkol Lek, Mohmmad Shahrooei, Maryam Ghavideldarestani, Isabella Herman, John Rendu, Julien Faure, Janice Baker, Vikas Bhambhani, Laurel Calderwood, Javad Akhondian, Shima Imannezhad, Hanieh Sadat Mirzadeh, Narges Hashemi, Mohammad Doosti, Mojtaba Safi, Najmeh Ahangari, Paria Najarzadeh Torbati, Soheila Abedini, Vincenzo Salpietro, Elif Yilmaz Gulec, Safieh Eshaghian, Mohammadreza Ghazavi, Michael T Pascher, Marina Vogel, Angela Abicht, Sébastien Moutton, Ange-Line Bruel, Claudine Rieubland, Sabina Gallati, Tim M Strom, Hanns Lochmüller, Mohammad Hasan Mohammadi, Javeria Raza Alvi, Elaine H Zackai, Beth A Keena, Cara M Skraban, Seth I Berger, Erin H Andrew, Elham Rahimian, Michelle M Morrow, Ingrid M Wentzensen, Francisca Millan, Lindsay B Henderson, Hormos Salimi Dafsari, Heinz Jungbluth, Natalia Gomez-Ospina, Anne Mcrae, Merlene Peter, Danai Veltra, Nikolaos M Marinakis, Christalena Sofocleous, Farah Ashrafzadeh, Davut Pehlivan, Johannes R Lemke, Judith Melki, Audrey Benezit, Peter Bauer, Denisa Weis, James R Lupski, Jan Senderek, John Christodoulou, Wendy K Chung, Rose Goodchild, Amaka C Offiah, Andres Moreno-De-Luca, Mohnish Suri, Darius Ebrahimi-Fakhari, Henry Houlden, Reza Maroofian

Faculty, Staff and Students Publications

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of …

Clinical And Functional Heterogeneity Associated With The Disruption Of Retinoic Acid Receptor Beta, Véronique Caron, Nicolas Chassaing, Nicola Ragge, Felix Boschann, Angelina My-Hoa Ngu, Elisabeth Meloche, Sarah Chorfi, Saquib A Lakhani, Weizhen Ji, Laurie Steiner, Julien Marcadier, Philip R Jansen, Laura A Van De Pol, Johanna M Van Hagen, Alvaro Serrano Russi, Gwenaël Le Guyader, Magnus Nordenskjöld, Ann Nordgren, Britt-Marie Anderlid, Julie Plaisancié, Corinna Stoltenburg, Denise Horn, Anne Drenckhahn, Fadi F Hamdan, Mathilde Lefebvre, Tania Attie-Bitach, Peggy Forey, Vasily Smirnov, Françoise Ernould, Marie-Line Jacquemont, Sarah Grotto, Alberto Alcantud, Alicia Coret, Rosario Ferrer-Avargues, Siddharth Srivastava, Catherine Vincent-Delorme, Shelby Romoser, Nicole Safina, Dimah Saade, James R Lupski, Daniel G Calame, David Geneviève, Nicolas Chatron, Caroline Schluth-Bolard, Kenneth A Myers, William B Dobyns, Patrick Calvas, Ddd Study, Caroline Salmon, Richard Holt, Frances Elmslie, Marc Allaire, Daniil M Prigozhin, André Tremblay, Jacques L Michaud

Faculty, Staff and Students Publications

PURPOSE: Dominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12.

METHODS: We used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids.

RESULTS: We found that …

Broadening The Phenotypic And Molecular Spectrum Of Finca Syndrome: Biallelic Nhlrc2 Variants In 15 Novel Individuals, Henrike L Sczakiel, Max Zhao, Brigitte Wollert-Wulf, Magdalena Danyel, Nadja Ehmke, Corinna Stoltenburg, Nadirah Damseh, Motee Al-Ashhab, Tugce B Balci, Matthew Osmond, Andrea Andrade, Jens Schallner, Joseph Porrmann, Kimberly Mcdonald, Mingjuan Liao, Henry Oppermann, Konrad Platzer, Nadine Dierksen, Majid Mojarrad, Atieh Eslahi, Behnaz Bakaeean, Daniel G Calame, James R Lupski, Zahra Firoozfar, Seyed Mohammad Seyedhassani, Seyed Ahmad Mohammadi, Najwa Anwaar, Fatima Rahman, Dominik Seelow, Martin Janz, Denise Horn, Reza Maroofian, Felix Boschann

Faculty, Staff and Students Publications

FINCA syndrome [MIM: 618278] is an autosomal recessive multisystem disorder characterized by fibrosis, neurodegeneration and cerebral angiomatosis. To date, 13 patients from nine families with biallelic NHLRC2 variants have been published. In all of them, the recurrent missense variant p.(Asp148Tyr) was detected on at least one allele. Common manifestations included lung or muscle fibrosis, respiratory distress, developmental delay, neuromuscular symptoms and seizures often followed by early death due to rapid disease progression.

Here, we present 15 individuals from 12 families with an overlapping phenotype associated with nine novel NHLRC2 variants identified by exome analysis. All patients described here presented with …

Dental Pulp Stem Cells And Current In Vivo Approaches To Study Dental Pulp Stem Cells In Pulp Injury And Regeneration, Dongwook Yang, Jea Giezl Niedo Solidum, Dongsu Park

Faculty, Staff and Students Publications

Dental pulp stem cells (DPSCs) have garnered significant interest in dental research for their unique characteristics and potential in tooth development and regeneration. While there were many studies to define their stem cell-like characteristics and osteogenic differentiation functions that are considered ideal candidates for regenerating damaged dental pulp tissue, how endogenous DPSCs respond to dental pulp injury and supply new dentin-forming cells has not been extensively investigated in vivo. Here, we review the recent progress in identity, function, and regulation of endogenous DPSCs and their clinical potential for pulp injury and regeneration. In addition, we discuss current advances in new …

Sculpting Astrocyte Diversity Through Circuits And Transcription, Yi-Ting Cheng, Junsung Woo, Benjamin Deneen

Faculty, Staff and Students Publications

Astrocytes are the most abundant glial cell in the central nervous system and occupy a wide range of roles that are essential for brain function. Over the past few years, evidence has emerged that astrocytes exhibit cellular and molecular heterogeneity, raising the possibility that subsets of astrocytes are functionally distinct and that transcriptional mechanisms are involved in encoding this prospective diversity. In this review, we focus on three emerging areas of astrocyte biology: region-specific circuit regulation, molecular diversity, and transcriptional regulation. This review highlights our nascent understanding of how molecular diversity is converted to functional diversity of astrocytes through the …

Effects Of Cathepsin S Inhibition In The Age-Related Dry Eye Phenotype, Jeremias G Galletti, Kaitlin K Scholand, Claudia M Trujillo-Vargas, Wolfgang Haap, Tiago Santos-Ferreira, Christoph Ullmer, Zhiyuan Yu, Cintia S De Paiva

Faculty, Staff and Students Publications

PURPOSE: Aged C57BL/6J (B6) mice have increased levels of cathepsin S, and aged cathepsin S (Ctss-/-) knockout mice are resistant to age-related dry eye. This study investigated the effects of cathepsin S inhibition on age-related dry eye disease.

METHODS: Female B6 mice aged 15.5 to 17 months were randomized to receive a medicated diet formulated by mixing the RO5461111 cathepsin S inhibitor or a standard diet for at least 12 weeks. Cornea mechanosensitivity was measured with a Cochet-Bonnet esthesiometer. Ocular draining lymph nodes and lacrimal glands (LGs) were excised and prepared for histology or assayed by flow cytometry to quantify …

Genetic Testing In Children With Nephrolithiasis And Nephrocalcinosis, Ashley M Gefen, Christine B Sethna, Onur Cil, Farzana Perwad, Megan Schoettler, Mini Michael, Joseph R Angelo, Adnan Safdar, Louise Amlie-Wolf, Tracy E Hunley, Jonathan S Ellison, Daniel Feig, Joshua Zaritsky

Faculty, Staff and Students Publications

BACKGROUND: Diagnosing genetic kidney disease has become more accessible with low-cost, rapid genetic testing. The study objectives were to determine genetic testing diagnostic yield and examine predictors of genetic diagnosis in children with nephrolithiasis/nephrocalcinosis (NL/NC).

METHODS: This retrospective multicenter cross-sectional study was conducted on children ≤ 21 years old with NL/NC from pediatric nephrology/urology centers that underwent the Invitae Nephrolithiasis Panel 1/1/2019-9/30/2021. The diagnostic yield of the genetic panel was calculated. Bivariate and multiple logistic regression were performed to assess for predictors of positive genetic testing.

RESULTS: One hundred and thirteen children (83 NL, 30 NC) from 7 centers were …

Machine Learning Driven Index Of Tumor Multinucleation Correlates With Survival And Suppressed Anti-Tumor Immunity In Head And Neck Squamous Cell Carcinoma Patients, Can F Koyuncu, Mitchell J Frederick, Lester D R Thompson, Germán Corredor, Sirvan Khalighi, Zelin Zhang, Bolin Song, Cheng Lu, Reetoja Nag, Vidya Sankar Viswanathan, Michael Gilkey, Kailin Yang, Shlomo A Koyfman, Deborah J Chute, Patricia Castro, James S Lewis, Anant Madabhushi, Vlad C Sandulache

Faculty, Staff and Students Publications

OBJECTIVES: Matching treatment intensity to tumor biology is critical to precision oncology for head and neck squamous cell carcinoma (HNSCC) patients. We sought to identify biological features of tumor cell multinucleation, previously shown by us to correlate with survival in oropharyngeal (OP) SCC using a machine learning approach.

MATERIALS AND METHODS: Hematoxylin and eosin images from an institutional OPSCC cohort formed the training set (D

RESULTS: MuNI correlated with overall survival. A multivariable nomogram that included MuNI, age, race, sex, T/N stage, and smoking status yielded a C-index of 0.65, and MuNI was prognostic of overall survival (2.25, 1.07-4.71, 0.03), …

Food For Thought: Remission Of Perianal Pediatric Crohn's Disease On Specific Carbohydrate Diet Monotherapy, David Simon, Kalyani Patel, Prakash Masand, Richard Kellermayer

Faculty, Staff and Students Publications

There is growing interest among patients about the specific carbohydrate diet (SCD) as a treatment for Crohn's disease. In the meantime, deep remission in patients using SCD as their sole treatment has not been documented. We report a case with perianal and ileocolonic Crohn's disease in whom SCD monotherapy successfully induced and maintained not only clinical, but also endoscopic, radiographic and histologic (ie, deep mucosal remission) remission as well.

Pediatric Acute Liver Failure Secondary To Autoimmune Hepatitis In An Infant With Thrombocytopenia-Absent Radius (Tar) Syndrome: A Case Report, Rebecca Mercedes, Kalyani Patel, Henry Shiau, Krupa R Mysore, Wenly Ruan, Daniel H Leung, Mary Elizabeth M Tessier, Dana Cerminara, Sarah Nicholas, Kelby Fuller, Marielle Faraone, N Thao N Galvan, John Goss, Anna M Banc-Husu

Faculty, Staff and Students Publications

Thrombocytopenia absent radius (TAR) syndrome is a rare genetic disorder that has been associated with food protein-induced allergic proctocolitis and transient leukemoid reactions, among other manifestations. There has been no prior reports of its association with autoimmune disease, more specifically, autoimmune hepatitis (AIH) or the development of pediatric acute liver failure (PALF). We present a case of an 8-month-old infant with TAR syndrome who presented with PALF, secondary to AIH with elevated liver-kidney microsomal antibody (>1:2560). She received a liver transplant and had a very complicated postoperative course including severe T-cell-mediated rejection, infection, biliary stricture, persistently elevated liver-kidney microsomal …

Interim Results From An Ongoing, Open-Label, Single-Arm Trial Of Odevixibat In Progressive Familial Intrahepatic Cholestasis, Richard J Thompson, Reha Artan, Ulrich Baumann, Pier Luigi Calvo, Piotr Czubkowski, Buket Dalgic, Lorenzo D'Antiga, Angelo Di Giorgio, Özlem Durmaz, Emmanuel Gonzalès, Tassos Grammatikopoulos, Girish Gupte, Winita Hardikar, Roderick H J Houwen, Binita M Kamath, Saul J Karpen, Florence Lacaille, Alain Lachaux, Elke Lainka, Kathleen M Loomes, Cara L Mack, Jan P Mattsson, Patrick Mckiernan, Quanhong Ni, Hasan Özen, Sanjay R Rajwal, Bertrand Roquelaure, Eyal Shteyer, Etienne Sokal, Ronald J Sokol, Nisreen Soufi, Ekkehard Sturm, Mary Elizabeth Tessier, Wendy L Van Der Woerd, Henkjan J Verkade, Jennifer M Vittorio, Terese Wallefors, Natalie Warholic, Qifeng Yu, Patrick Horn, Lise Kjems

Faculty, Staff and Students Publications

BACKGROUND & AIMS: PEDFIC 2, an ongoing, open-label, 72-week study, evaluates odevixibat, an ileal bile acid transporter inhibitor, in patients with progressive familial intrahepatic cholestasis.

METHODS: PEDFIC 2 enrolled and dosed 69 patients across two cohorts; all received odevixibat 120 μg/kg per day. Cohort 1 comprised children from PEDFIC 1, and cohort 2 comprised new patients (any age). We report data through 15 July 2020, with Week 24 of PEDFIC 2 the main time point analysed. This represents up to 48 weeks of cumulative exposure for patients treated with odevixibat from the 24-week PEDFIC 1 study (cohort 1A) and up …