Digital Commons Network^™

Estrogen-Related Receptor Signaling In Skeletal Muscle Fitness, Danesh Sopariwala, Hao Nguyen, Vihang Narkar

Faculty, Staff and Student Publications

Skeletal muscle is a highly plastic tissue that can alter its metabolic and contractile features, as well as regenerative potential in response to exercise and other conditions. Multiple signaling factors including metabolites, kinases, receptors, and transcriptional factors have been studied in the regulation of skeletal muscle plasticity. Recently, estrogen-related receptors (ERRs) have emerged as a critical transcriptional hub in control of skeletal muscle homeostasis. ERRα and ERRγ - the two highly expressed ERR sub-types in the muscle respond to various extracellular cues such as exercise, hypoxia, fasting and dietary factors, in turn regulating gene expression in the skeletal muscle. On …

Plasma Cell Myeloma With Ras/Braf Mutations Is Frequently Associated With A Complex Karyotype, Advanced Stage Disease, And Poorer Prognosis, Nianyi Li, Pei Lin, Zhuang Zuo, M James You, Wen Shuai, Robert Orlowski, Elisabet E Manasanch, Shaoying Li, Jie Xu, Sofia Garces, Fatima Zahra Jelloul, Zhenya Tang, Wei Wang, L Jeffrey Medeiros, C Cameron Yin

Faculty, Staff and Student Publications

BACKGROUND: Mutations in the RAS-MAPK pathway, such as KRAS, NRAS, and BRAF, are known as high-risk factors associated with poor prognosis in patients with various cancers, but studies in myeloma have yielded mixed results.

METHODS: We describe the clinicopathologic, cytogenetic, molecular features, and outcomes of 68 patients with RAS/BRAF-mutated myeloma, and compare with 79 patients without any mutations.

RESULTS: We show that KRAS, NRAS, and BRAF were mutated in 16%, 11%, and 5% of cases, respectively. RAS/BRAF-mutated patients had lower hemoglobin and platelet counts, higher levels of serum lactate dehydrogenase and calcium, higher percentage of bone marrow plasma cells, and …

Characterization Of The Oral Microbiota Among Middle-Aged Men With And Without Human Papillomavirus Infection, Kristina R Dahlstrom, Andrew G Sikora, Yanhong Liu, Chia-Chi Chang, Peng Wei, Erich M Sturgis, Guojun Li

Faculty, Staff and Student Publications

OBJECTIVES: To characterize the oral microbiota among middle-aged men and identify differences between men with a prevalent oral high-risk (oncogenic) HPV infection and those without.

MATERIALS AND METHODS: This was a case-control study nested within a prospective screening study for HPV-related cancers among middle-aged men. 16S rRNA sequencing was used to characterize the oral microbiota and the cobas HPV Test was used to detect presence of oral high-risk HPV types. We determined the overall composition of the oral microbiota and assessed differences in relative abundance of bacterial taxa as well as alpha and beta diversity among men with a prevalent …

Pontocerebellar Hypoplasia Associated With Parg183trp Homozygous Variant In Exosc1 Gene: A Case Report, Nadirah S Damseh, Ali N Obeidat, Khondakar Sayef Ahammed, Motee Al-Ashhab, Motee Abu Awad, Ambro Van Hoof

Faculty, Staff and Student Publications

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare neurodegenerative disorders characterized by a wide phenotypic range including severe motor and cognitive impairments, microcephaly, distinctive facial features, and other features according to the type. Several classes of PCH1 have been linked to mutations in the evolutionarily conserved RNA exosome complex that consists of nine subunits (EXOSC1 to EXOSC9) and facilitates the degradation and processing of cytoplasmic and nuclear RNA from the 3' end. Only a single individual with an EXOSC1 mutation was reported with clinical features of PCH type 1 (PCH1F). Here, we report a 3-month-old female with PCH and …

Emerging Signaling Regulation Of Sinoatrial Node Dysfunction, Mingjie Zheng, Shannon Erhardt, Yuhan Cao, Jun Wang

Faculty, Staff and Student Publications

PURPOSE OF REVIEW: The sinoatrial node (SAN), the natural pacemaker of the heart, is responsible for generating electrical impulses and initiating each heartbeat. Sinoatrial node dysfunction (SND) causes various arrhythmias such as sinus arrest, SAN block, and tachycardia/bradycardia syndrome. Unraveling the underlying mechanisms of SND is of paramount importance in the pursuit of developing effective therapeutic strategies for patients with SND. This review provides a concise summary of the most recent progress in the signaling regulation of SND.

RECENT FINDINGS: Recent studies indicate that SND can be caused by abnormal intercellular and intracellular signaling, various forms of heart failure (HF), …

Evidence Of Novel Susceptibility Variants For Prostate Cancer And A Multiancestry Polygenic Risk Score Associated With Aggressive Disease In Men Of African Ancestry, Fei Chen, Ravi K Madduri, Alex A Rodriguez, Burcu F Darst, Alisha Chou, Xin Sheng, Anqi Wang, Jiayi Shen, Edward J Saunders, Suhn K Rhie, Jeannette T Bensen, Sue A Ingles, Rick A Kittles, Sara S Strom, Benjamin A Rybicki, Barbara Nemesure, William B Isaacs, Janet L Stanford, Wei Zheng, Maureen Sanderson, Esther M John, Jong Y Park, Jianfeng Xu, Ying Wang, Sonja I Berndt, Chad D Huff, Edward D Yeboah, Yao Tettey, Joseph Lachance, Wei Tang, Christopher T Rentsch, Kelly Cho, Benjamin H Mcmahon, Richard B Biritwum, Andrew A Adjei, Evelyn Tay, Ann Truelove, Shelley Niwa, Thomas A Sellers, Kosj Yamoah, Adam B Murphy, Dana C Crawford, Alpa V Patel, William S Bush, Melinda C Aldrich, Olivier Cussenot, Gyorgy Petrovics, Jennifer Cullen, Christine M Neslund-Dudas, Mariana C Stern, Zsofia Kote-Jarai, Koveela Govindasami, Michael B Cook, Anand P Chokkalingam, Ann W Hsing, Phyllis J Goodman, Thomas J Hoffmann, Bettina F Drake, Jennifer J Hu, Jacob M Keaton, Jacklyn N Hellwege, Peter E Clark, Mohamed Jalloh, Serigne M Gueye, Lamine Niang, Olufemi Ogunbiyi, Michael O Idowu, Olufemi Popoola, Akindele O Adebiyi, Oseremen I Aisuodionoe-Shadrach, Hafees O Ajibola, Mustapha A Jamda, Olabode P Oluwole, Maxwell Nwegbu, Ben Adusei, Sunny Mante, Afua Darkwa-Abrahams, James E Mensah, Halimatou Diop, Stephen K Van Den Eeden, Pascal Blanchet, Jay H Fowke, Graham Casey, Anselm J Hennis, Alexander Lubwama, Ian M Thompson, Robin Leach, Douglas F Easton, Michael H Preuss, Ruth J Loos, Susan M Gundell, Peggy Wan, James L Mohler, Elizabeth T Fontham, Gary J Smith, Jack A Taylor, Shiv Srivastava, Rosaline A Eeles, John D Carpten, Adam S Kibel, Luc Multigner, Marie-Élise Parent, Florence Menegaux, Geraldine Cancel-Tassin, Eric A Klein, Caroline Andrews, Timothy R Rebbeck, Laurent Brureau, Stefan Ambs, Todd L Edwards, Stephen Watya, Stephen J Chanock, John S Witte, William J Blot, J Michael Gaziano, Amy C Justice, David V Conti, Christopher A Haiman

Faculty, Staff and Student Publications

BACKGROUND: Genetic factors play an important role in prostate cancer (PCa) susceptibility.

OBJECTIVE: To discover common genetic variants contributing to the risk of PCa in men of African ancestry.

DESIGN, SETTING, AND PARTICIPANTS: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness.

RESULTS AND LIMITATIONS: Nine …

A Radiomics Model Based On Synthetic Mri Acquisition For Predicting Neoadjuvant Systemic Treatment Response In Triple-Negative Breast Cancer, Ken-Pin Hwang, Nabil A Elshafeey, Aikaterini Kotrotsou, Huiqin Chen, Jong Bum Son, Medine Boge, Rania M Mohamed, Abeer H Abdelhafez, Beatriz E Adrada, Bikash Panthi, Jia Sun, Benjamin C Musall, Shu Zhang, Rosalind P Candelaria, Jason B White, Elizabeth E Ravenberg, Debu Tripathy, Clinton Yam, Jennifer K Litton, Lei Huo, Alastair M Thompson, Peng Wei, Wei T Yang, Mark D Pagel, Jingfei Ma, Gaiane M Rauch

Faculty, Staff and Student Publications

Purpose

To determine if a radiomics model based on quantitative maps acquired with synthetic MRI (SyMRI) is useful for predicting neoadjuvant systemic therapy (NAST) response in triple-negative breast cancer (TNBC).

Materials and Methods

In this prospective study, 181 women diagnosed with stage I–III TNBC were scanned with a SyMRI sequence at baseline and at midtreatment (after four cycles of NAST), producing T1, T2, and proton density (PD) maps. Histopathologic analysis at surgery was used to determine pathologic complete response (pCR) or non-pCR status. From three-dimensional tumor contours drawn on the three maps, 310 histogram and textural features were extracted, resulting …

Identification Of Unique Α4 Chain Structure And Conserved Antiangiogenic Activity Of Α3nc1 Type Iv Collagen In Zebrafish, Valerie S Lebleu, Jianli Dai, Susan Tsutakawa, Brian A Macdonald, Joseph L Alge, Malin Sund, Liang Xie, Hikaru Sugimoto, John Tainer, Leonard I Zon, Raghu Kalluri

Faculty, Staff and Student Publications

BACKGROUND: Type IV collagen is an abundant component of basement membranes in all multicellular species and is essential for the extracellular scaffold supporting tissue architecture and function. Lower organisms typically have two type IV collagen genes, encoding α1 and α2 chains, in contrast with the six genes in humans, encoding α1-α6 chains. The α chains assemble into trimeric protomers, the building blocks of the type IV collagen network. The detailed evolutionary conservation of type IV collagen network remains to be studied.

RESULTS: We report on the molecular evolution of type IV collagen genes. The zebrafish α4 non-collagenous (NC1) domain, in …

Monte Carlo-Derived 99m Tc Uptake Quantification With Commercial Planar Mbi: Tumor And Breast Activity Concentrations, Benjamin P Lopez, S Cheenu Kappadath

Faculty, Staff and Student Publications

BACKGROUND: Current molecular breast imaging (MBI) images are limited to qualitative evaluation, not absolute measurement, of

PURPOSE: This work assesses the accuracy of previously-published and newly-proposed tumor and normal breast tissue

METHODS: Quantification techniques were tested in over 4000 simulated acquisitions of spherical and ellipsoid tumors with clinically relevant uptake conditions using a validated Monte Carlo application of the GE Discovery NM750b system. The evaluated techniques consisted of four tumor total activity methodologies (two single-detector-based and two geometric-mean-based), two tumor MBI volume methodologies (diameter-based and ROI-based), and two normal tissue activity concentration methodologies (single-detector-based and geometric-mean-based). The most accurate of …

Cisplatin Decreases Voluntary Wheel-Running Activity But Does Not Impair Food-Motivated Behavior In Mice, Kiersten S Scott, Brandon Chelette, Chinenye Chidomere, A Phillip West, Robert Dantzer

Faculty, Staff and Student Publications

Cisplatin is a chemotherapeutic agent that is still commonly used to treat solid tumors. However, it has several toxic side effects due in large part to the mitochondrial damage that it induces. As this mitochondrial damage is likely to result in a decrease in the amount of metabolic energy that is available for behavioral activities, it is not surprising that fatigue develops in cancer patients treated with cisplatin. The present preclinical study was initiated to determine whether the detrimental effects of cisplatin were more pronounced on physical effort requiring a lot of energy versus effort that not only requires less …

Interferon Signaling Promotes Tolerance To Chromosomal Instability During Metastatic Evolution In Renal Cancer, Luigi Perelli, Federica Carbone, Li Zhang, Justin K Huang, Courtney Le, Hania Khan, Francesca Citron, Edoardo Del Poggetto, Tony Gutschner, Hideo Tomihara, Melinda Soeung, Rosalba Minelli, Sanjana Srinivasan, Michael Peoples, Truong Nguyen Anh Lam, Sebastian Lundgren, Ruohan Xia, Cihui Zhu, Alaa M T Mohamed, Jianhua Zhang, Kanishka Sircar, Alessandro Sgambato, Jianjun Gao, Eric Jonasch, Giulio F Draetta, Andrew Futreal, Ziad Bakouny, Eliezer M Van Allen, Toni Choueiri, Sabina Signoretti, Pavlos Msaouel, Kevin Litchfield, Samra Turajlic, Linghua Wang, Ying Bei Chen, Renzo G Di Natale, A Ari Hakimi, Virginia Giuliani, Timothy P Heffernan, Andrea Viale, Christopher A Bristow, Nizar M Tannir, Alessandro Carugo, Giannicola Genovese

Faculty, Staff and Student Publications

Molecular routes to metastatic dissemination are critical determinants of aggressive cancers. Through in vivo CRISPR-Cas9 genome editing, we generated somatic mosaic genetically engineered models that faithfully recapitulate metastatic renal tumors. Disruption of 9p21 locus is an evolutionary driver to systemic disease through the rapid acquisition of complex karyotypes in cancer cells. Cross-species analysis revealed that recurrent patterns of copy number variations, including 21q loss and dysregulation of the interferon pathway, are major drivers of metastatic potential. In vitro and in vivo genomic engineering, leveraging loss-of-function studies, along with a model of partial trisomy of chromosome 21q, demonstrated a dosage-dependent effect …

Examining Mechanisms For Voltage-Sensitive Calcium Channel-Mediated Secretion Events In Bone Cells, Perla C Reyes Fernandez, Christian S Wright, Mary C Farach-Carson, William R Thompson

Faculty, Staff and Student Publications

In addition to their well-described functions in cell excitability, voltage-sensitive calcium channels (VSCCs) serve a critical role in calcium (Ca2+)-mediated secretion of pleiotropic paracrine and endocrine factors, including those produced in bone. Influx of Ca2+ through VSCCs activates intracellular signaling pathways to modulate a variety of cellular processes that include cell proliferation, differentiation, and bone adaptation in response to mechanical stimuli. Less well understood is the role of VSCCs in the control of bone and calcium homeostasis mediated through secreted factors. In this review, we discuss the various functions of VSCCs in skeletal cells as regulators of Ca2+ dynamics and …

Screening Hydrogels For Antifibrotic Properties By Implanting Cellularly Barcoded Alginates In Mice And A Non-Human Primate, Sudip Mukherjee, Boram Kim, Lauren Y Cheng, Michael David Doerfert, Jiaming Li, Andrea Hernandez, Lily Liang, Maria I Jarvis, Peter D Rios, Sofia Ghani, Ira Joshi, Douglas Isa, Trisha Ray, Tanguy Terlier, Cody Fell, Ping Song, Roberto N Miranda, Jose Oberholzer, David Yu Zhang, Omid Veiseh

Faculty, Staff and Student Publications

Screening implantable biomaterials for antifibrotic properties is constrained by the need for in vivo testing. Here we show that the throughput of in vivo screening can be increased by cellularly barcoding a chemically modified combinatorial library of hydrogel formulations. The method involves the implantation of a mixture of alginate formulations, each barcoded with human umbilical vein endothelial cells from different donors, and the association of the identity and performance of each formulation by genotyping single nucleotide polymorphisms of the cells via next-generation sequencing. We used the method to screen 20 alginate formulations in a single mouse and 100 alginate formulations …

Intensity Modulated Proton Arc Therapy Via Geometry-Based Energy Selection For Ependymoma, Wenhua Cao, Yupeng Li, Xiaodong Zhang, Falk Poenisch, Pablo Yepes, Narayan Sahoo, David Grosshans, Susan Mcgovern, G Brandon Gunn, Steven J Frank, Xiaorong R Zhu

Faculty, Staff and Student Publications

PURPOSE: We developed and tested a novel method of creating intensity modulated proton arc therapy (IMPAT) plans that uses computing resources similar to those for regular intensity-modulated proton therapy (IMPT) plans and may offer a dosimetric benefit for patients with ependymoma or similar tumor geometries.

METHODS: Our IMPAT planning method consists of a geometry-based energy selection step with major scanning spot contributions as inputs computed using ray-tracing and single-Gaussian approximation of lateral spot profiles. Based on the geometric relation of scanning spots and dose voxels, our energy selection module selects a minimum set of energy layers at each gantry angle …

Nivolumab And Ipilimumab With Concurrent Stereotactic Radiosurgery For Intracranial Metastases From Non-Small Cell Lung Cancer: Analysis Of The Safety Cohort For Non-Randomized, Open-Label, Phase I/Ii Trial, Mehmet Altan, Yan Wang, Juhee Song, James Welsh, Chad Tang, Nandita Guha-Thakurta, George R Blumenschein, Brett W Carter, Jeffrey S Wefel, Amol J Ghia, Debra N Yeboa, Mary Frances Mcaleer, Caroline Chung, Kristina D Woodhouse, Susan L Mcgovern, Chenyang Wang, Betty Y S Kim, Jeffrey S Weinberg, Tina M Briere, Yasir Y Elamin, Xiuning Le, Tina Cascone, Marcelo V Negrao, Ferdinandos Skoulidis, Renata Ferrarotto, John V Heymach, Jing Li

Faculty, Staff and Student Publications

BACKGROUND: Up to 20% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), for which the current standard of care is radiation therapy with or without surgery. There are no prospective data on the safety of stereotactic radiosurgery (SRS) concurrent with immune checkpoint inhibitor therapy for BM. This is the safety cohort of the phase I/II investigator-initiated trial of SRS with nivolumab and ipilimumab for patients with BM from NSCLC.

PATIENTS AND METHODS: This single-institution study included patients with NSCLC with active BM amenable to SRS. Brain SRS and systemic therapy with nivolumab and ipilimumab were delivered …

Immunotherapy-Related Pneumonitis And The Synergic Impact Of Thoracic Radiation And Preexisting Interstitial Lung Disease, Maria Azhar, Rodeo Abrencillo, Saumil Gandhi, Mehmet Altan, Ajay Sheshadri

Faculty, Staff and Student Publications

PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICIs) are the frontline of therapy for most cancers. Although ICIs are sometimes considered to be less harmful than systemic chemotherapies, ICIs may cause immune-related adverse events, which are cases of off-target inflammation in healthy tissues. Pneumonitis, an immune-related adverse event, is the leading cause of therapy-related mortality with ICIs. The aim of this review is to discuss how preexisting interstitial lung disease (ILD) and thoracic radiation increase the risk for ICI-pneumonitis. We discuss potential mechanisms of lung injury and how pneumonitis may impact cancer treatments.

RECENT FINDINGS: Preexisting ILD and thoracic radiation are …

A Retrospective Study Of Cerebrolysin In Patients With Moderate To Severe Traumatic Brain Injury: Cognitive And Functional Outcomes, Claudio Soto, Pablo Salinas, Daniel Muñoz, Sandra Olivares, Javiera González, Virginia Sáez, Violeta Romero

Faculty, Staff and Student Publications

In this retrospective study, we aimed to evaluate the effects of the neurotrophic compound Cerebrolysin on executive, cognitive, and functional performance in patients with traumatic brain injury (TBI) with a highly severe disability level. A total of 44 patients were included in the study, with 33 patients in the control group and 11 patients in the interventional group who received intravenous infusions of 30 mL Cerebrolysin. Both groups received standard rehabilitation therapy following the rehabilitation protocol for patients with TBI at Hospital Clínico Mutual de Seguridad. Functional and cognitive scales were evaluated at baseline, at four months, and at the …

Src Stimulates Abl-Dependent Phosphorylation Of The Guanine Exchange Factor Net1a To Promote Its Cytosolic Localization And Cell Motility, Ashabari Sprenger, Heather S Carr, Arzu Ulu, Jeffrey A Frost

Faculty, Staff and Student Publications

The neuroepithelial cell transforming gene 1 (Net1) is a guanine nucleotide exchange factor for the small GTPase RhoA that promotes cancer cell motility and metastasis. Two isoforms of Net1 exist, Net1 and Net1A, both of which are sequestered in the nucleus in quiescent cells to prevent aberrant RhoA activation. Many cell motility stimuli drive cytosolic relocalization of Net1A, but mechanisms controlling this event are not fully understood. Here, we demonstrate that epithelial growth factor stimulates protein kinase Src- and Abl1-dependent phosphorylation of Net1A to promote its cytosolic localization. We show that Abl1 efficiently phosphorylates Net1A on Y373, and that phenylalanine …

Comparison Of Different Reconstruction Flap For Maxillofacial Region: An Original Research, Pallavi Khan Chakraborty, Smit Patel, Misbah Farheen Mulla, Manisha Mangesh Kulkarni, Rummaan Ahmed Sheikh, Anuj Kishor Shukla

Faculty, Staff and Student Publications

INTRODUCTION: Large chunks of the tissue are sacrificed during the surgical procedures for the treatment if oral cancers. Our goal was to assess the viability of "

MATERIAL AND METHODS: Sixty subjects were included in this investigation, and they were divided into 3 groups. The follow-up as accompanied for six months. Comparisons were made for the time for the operations, reduction in the width of the mouth opening and the survival rates of the flaps. The data that was collected for the above two parameters and compared for the significance using the

RESULTS: In the subjects with the PM, the …

Development Of Cancer Surveillance Guidelines In Ataxia Telangiectasia: A Delphi-Based Consensus Survey Of International Experts, Renata Neves, Blanca De Dios Perez, Rafal Panek, Sumit Jagani, Sophie Wilne, Jayesh M Bhatt, Caterina Caputi, Emilia Cirillo, David J Coman, Gregor Dückers, Donald L Gilbert, Mary Kay Koenig, Lobna Mansour, Elizabeth Mcdermott, Micaela Pauni, Claudio Pignata, Susan L Perlman, Oscar Porras, Mariela Betina Porto, Katherine Schon, Pere Soler-Palacin, Sam Nick Russo, Masatoshi Takagi, Marc Tischkowitz, Claire Wainwright, Madhumita Dandapani, Cristine Glazebrook, Mohnish Suri, William P Whitehouse, Robert A Dineen

Faculty, Staff and Student Publications

BACKGROUND/OBJECTIVES: Ataxia telangiectasia (A-T) is a multiorgan disorder with increased vulnerability to cancer. Despite this increased cancer risk, there are no widely accepted guidelines for cancer surveillance in people affected by A-T. We aimed to understand the current international practice regarding cancer surveillance in A-T and agreed-upon approaches to develop cancer surveillance in A-T.

DESIGN/METHODS: We used a consensus development method, the e-Delphi technique, comprising three rounds. Round 1 consisted of a Delphi questionnaire and a survey that collected the details of respondents' professional background, experience, and current practice of cancer surveillance in A-T. Rounds 2 and 3 were designed …

Genome-Wide Association Study Of Thoracic Aortic Aneurysm And Dissection In The Million Veteran Program, Derek Klarin, Poornima Devineni, Anoop K Sendamarai, Anthony R Angueira, Sarah E Graham, Ying H Shen, Michael G Levin, James P Pirruccello, Ida Surakka, Purushotham R Karnam, Tanmoy Roychowdhury, Yanming Li, Minxian Wang, Krishna G Aragam, Kaavya Paruchuri, Verena Zuber, Gabrielle E Shakt, Noah L Tsao, Renae L Judy, Ha My T Vy, Shefali S Verma, Daniel J Rader, Ron Do, Joseph E Bavaria, Girish N Nadkarni, Marylyn D Ritchie, Stephen Burgess, Dong-Chuan Guo, Patrick T Ellinor, Scott A Lemaire, Dianna M Milewicz, Cristen J Willer, Pradeep Natarajan, Philip S Tsao, Saiju Pyarajan, Scott M Damrauer

Faculty, Staff and Student Publications

The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and …

Stress Responses And Ammonia Nitrogen Removal Efficiency Of Oocystis Lacustris In Saline Ammonium-Contaminated Wastewater Treatment, Linda Ewing-Cobbs, Christina V Danna, Tammy D Tolar, Douglas Granger, Charles S Cox, Mary R Prasad

Faculty, Staff and Student Publications

Traumatic injury is linked increasingly to alterations in both stress response systems and psychological health. We investigated reactivity of salivary analytes of the hypothalamic-pituitary-adrenal axis (cortisol) and autonomic nervous system (salivary alpha amylase, sAA) during a psychosocial stress procedure in relation to psychological health outcomes. In a prospective cohort design, stress reactivity of children ages 8 to 15 years hospitalized for traumatic brain injury (TBI; n = 74) or extracranial injury (EI; n = 35) was compared with healthy controls (n = 51) 7 months after injury. Area under the curve increase (AUCinc) assessed pre-stressor to post-stressor cortisol and …

Are There Sex Differences In Interactive Associations Of Environmental Exposure To Lead (Pb), Mercury (Hg), And Manganese (Mn) With Gst Genes (Gstp1, Gstt1, And Gstm1) In Relation To Asd In Jamaican Children?, Hiba T Zwiya, Maureen Samms-Vaughan, Jan Bressler, Minjae Lee, Courtney Byrd-Williams, Manouchehr Hessabi, Megan L Grove, Sydonnie Shakespeare-Pellington, Katherine A Loveland, Mohammad H Rahbar

Faculty, Staff and Student Publications

Background: Male preponderance is well-established in children with autism spectrum disorder (ASD). Glutathione S-transferase (GST) genes play a crucial role in suppressing oxidative stress triggered by environmental stressors.

Objective: To determine whether the association between metals and ASD differs by sex and by GST genes.

Methods: Using data from 344 pairs of sex-and age-matched cases and controls, we assessed the association of each metal with ASD or ASD severity, by applying conditional logistic regression (CLR) or general linear models (GLM). Sex was assessed as an effect modifier in separate GST genetic models.

Results: For Pb exposure, using a recessive model …

Non-Canonical Wnt Signaling In The Eye, Ruchi Shah, Cynthia Amador, Steven T Chun, Sean Ghiam, Mehrnoosh Saghizadeh, Andrei A Kramerov, Alexander V Ljubimov

Faculty, Staff and Student Publications

Wnt signaling comprises a group of complex signal transduction pathways that play critical roles in cell proliferation, differentiation, and apoptosis during development, as well as in stem cell maintenance and adult tissue homeostasis. Wnt pathways are classified into two major groups, canonical (β-catenin-dependent) or non-canonical (β-catenin-independent). Most previous studies in the eye have focused on canonical Wnt signaling, and the role of non-canonical signaling remains poorly understood. Additionally, the crosstalk between canonical and non-canonical Wnt signaling in the eye has hardly been explored. In this review, we present an overview of available data on ocular non-canonical Wnt signaling, including developmental …

Mird Pamphlet No 28, Part 1: Mirdcalc—A Software Tool For Medical Internal Radiation Dosimetry, Adam L Kesner, Lukas M Carter, Juan C Ocampo Ramos, Daniel Lafontaine, Edmond A Olguin, Justin L Brown, Bonnie President, Derek W Jokisch, Darrell R Fisher, Wesley E Bolch

Faculty, Staff and Student Publications

Medical internal radiation dosimetry constitutes a fundamental aspect of diagnosis, treatment, optimization, and safety in nuclear medicine. The MIRD committee of the Society of Nuclear Medicine and Medical Imaging developed a new computational tool to support organ-level and suborgan tissue dosimetry (MIRDcalc, version 1). Based on a standard Excel spreadsheet platform, MIRDcalc provides enhanced capabilities to facilitate radiopharmaceutical internal dosimetry. This new computational tool implements the well-established MIRD schema for internal dosimetry. The spreadsheet incorporates a significantly enhanced database comprising details for 333 radionuclides, 12 phantom reference models (International Commission on Radiological Protection), 81 source regions, and 48 target regions, …

Association Of Trauma Molecular Endotypes With Differential Response To Transfusion Resuscitation Strategies, Matthew R Thau, Ted Liu, Neha A Sathe, Grant E O'Keefe, Bryce R H Robinson, Eileen Bulger, Charles E Wade, Erin E Fox, John B Holcomb, W Conrad Liles, Ian B Stanaway, Carmen Mikacenic, Mark M Wurfel, Pavan K Bhatraju, Eric D Morrell

Faculty, Staff and Student Publications

IMPORTANCE: It is not clear which severely injured patients with hemorrhagic shock may benefit most from a 1:1:1 vs 1:1:2 (plasma:platelets:red blood cells) resuscitation strategy. Identification of trauma molecular endotypes may reveal subgroups of patients with differential treatment response to various resuscitation strategies.

OBJECTIVE: To derive trauma endotypes (TEs) from molecular data and determine whether these endotypes are associated with mortality and differential treatment response to 1:1:1 vs 1:1:2 resuscitation strategies.

DESIGN, SETTING, AND PARTICIPANTS: This was a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized clinical trial. The study cohort included individuals with severe …

The Genetics Of Primary Ciliary Dyskinesia In Puerto Rico, Paolo Zanoni, Katharina Steindl, Heinrich Sticht, Beatrice Oneda, Pascal Joset, Ivan Ivanovski, Anselm H C Horn, Elena M Cabello, Julia Laube, Markus Zweier, Alessandra Baumer, Anita Rauch, Nadia Khan

Faculty, Staff and Student Publications

Pediatric Moyamoya Angiopathy (MMA) is a progressive intracranial occlusive arteriopathy that represents a leading cause of transient ischemic attacks and strokes in childhood. Despite this, up to now no large, exclusively pediatric MMA cohort has been subjected to systematic genetic investigation. In this study, we performed molecular karyotyping, exome sequencing and automated structural assessment of missense variants on a series of 88 pediatric MMA patients and correlated genetic, angiographic and clinical (stroke burden) findings. The two largest subgroups in our cohort consisted of RNF213 and neurofibromatosis type 1 (NF1) patients. While deleterious RNF213 variants were associated with a severe MMA …

Genome-Wide Association Analysis Identifies Ancestry-Specific Genetic Variation Associated With Acute Response To Metformin And Glipizide In Sugar-Mgh, Josephine H Li, Laura N Brenner, Varinderpal Kaur, Katherine Figueroa, Philip Schroeder, Alicia Huerta-Chagoya, Miriam S Udler, Aaron Leong, Josep M Mercader, Jose C Florez

Faculty, Staff and Student Publications

AIMS/HYPOTHESIS: Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) examined the acute response to metformin and glipizide in order to identify new pharmacogenetic associations for the response to common glucose-lowering medications in individuals at risk of type 2 diabetes.

METHODS: One thousand participants at risk for type 2 diabetes from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping …

Therapeutic Potential Of Salicylamide Derivatives For Combating Viral Infections, Jimin Xu, Yu Xue, Andrew A Bolinger, Jun Li, Mingxiang Zhou, Haiying Chen, Hongmin Li, Jia Zhou

Faculty, Staff and Student Publications

Since time immemorial human beings have constantly been fighting against viral infections. The ongoing and devastating coronavirus disease 2019 pandemic represents one of the most severe and most significant public health emergencies in human history, highlighting an urgent need to develop broad-spectrum antiviral agents. Salicylamide (2-hydroxybenzamide) derivatives, represented by niclosamide and nitazoxanide, inhibit the replication of a broad range of RNA and DNA viruses such as flavivirus, influenza A virus, and coronavirus. Moreover, nitazoxanide was effective in clinical trials against different viral infections including diarrhea caused by rotavirus and norovirus, uncomplicated influenza A and B, hepatitis B, and hepatitis C. …

A Direct Fiber Approach To Model Sclera Collagen Architecture And Biomechanics, Fengting Ji, Manik Bansal, Bingrui Wang, Yi Hua, Mohammad R. Islam, Felix Matuschke, Markus Axer, Ian A. Sigal

Mechanical Engineering Faculty Publications

Sclera collagen fiber microstructure and mechanical behavior are central to eye physiology and pathology. They are also complex, and are therefore often studied using modeling. Most models of sclera, however, have been built within a conventional continuum framework. In this framework, collagen fibers are incorporated as statistical distributions of fiber characteristics such as the orientation of a family of fibers. The conventional continuum approach, while proven successful for describing the macroscale behavior of the sclera, does not account for the sclera fibers are long, interwoven and interact with one another. Hence, by not considering these potentially crucial characteristics, …