Digital Commons Network^™

Comparative Tumor Microenvironment Analysis Of Primary And Recurrent Ovarian Granulosa Cell Tumors, Eleonora Khlebus, Veena K Vuttaradhi, Thomas Welte, Namrata Khurana, Joseph Celestino, Hannah C Beird, Curtis Gumbs, Latasha Little, Alejandra Flores Legarreta, Bryan M Fellman, Tri Nguyen, Barrett Lawson, Sammy Ferri-Borgogno, Samuel C Mok, Russell R Broaddus, David M Gershenson, P Andrew Futreal, R Tyler Hillman

Faculty, Staff and Student Publications

Adult-type granulosa cell tumors (aGCT) are rare ovarian sex cord tumors with few effective treatments for recurrent disease. The objective of this study was to characterize the tumor microenvironment (TME) of primary and recurrent aGCTs and to identify correlates of disease recurrence. Total RNA sequencing (RNA-seq) was performed on 24 pathologically confirmed, cryopreserved aGCT samples, including 8 primary and 16 recurrent tumors. After read alignment and quality-control filtering, DESeq2 was used to identify differentially expressed genes (DEG) between primary and recurrent tumors. Functional enrichment pathway analysis and gene set enrichment analysis was performed using “clusterProfiler” and “GSVA” R packages. TME …

A Model For Gastrointestinal Tract Motility In A 4d Imaging Phantom Of Human Anatomy, Ergys Subashi, Paul Segars, Harini Veeraraghavan, Joseph Deasy, Neelam Tyagi

Faculty, Staff and Student Publications

BACKGROUND: Gastrointestinal (GI) tract motility is one of the main sources for intra/inter-fraction variability and uncertainty in radiation therapy for abdominal targets. Models for GI motility can improve the assessment of delivered dose and contribute to the development, testing, and validation of deformable image registration (DIR) and dose-accumulation algorithms.

PURPOSE: To implement GI tract motion in the 4D extended cardiac-torso (XCAT) digital phantom of human anatomy.

MATERIALS AND METHODS: Motility modes that exhibit large amplitude changes in the diameter of the GI tract and may persist over timescales comparable to online adaptive planning and radiotherapy delivery were identified based on …

Understanding Cardiac Senescence One Cell Type At A Time, Payel Sen, Priyatansh Gurha

Faculty, Staff and Student Publications

No abstract provided.

Molecular Identity Changes Of Tumor-Associated Macrophages And Microglia After Magnetic Resonance Imaging-Guided Focused Ultrasound-Induced Blood-Brain Barrier Opening In A Mouse Glioblastoma Model, Yanrong Zhang, Jing Wang, Sara Natasha Ghobadi, Haiyan Zhou, Ai Huang, Marco Gerosa, Qingyi Hou, Olivier Keunen, Anna Golebiewska, Frezghi G Habte, Gerald A Grant, Ramasamy Paulmurugan, Kevin S Lee, Max Wintermark

Faculty, Staff and Student Publications

An orthotopically allografted mouse GL26 glioma model (Ccr2^RFP/wt-Cx3cr1^GFP/wt) was used to evaluate the effect of transient, focal opening of the Blood Brain Barrier (BBB) on the composition of tumor-associated macrophages and microglia (TAMs). BBB Opening was induced by Magnetic Resonance Imaging (MRI)-guided focused ultrasound (MRgFUS) combined with microbubbles. CX3CR1-GFP cells and CCR2-RFP cells in brain tumors were quantified in microscopic images. Tumors in animals treated with a single session of MRgFUS did not show significant changes in cell numbers when compared to tumors in animals not receiving FUS. However, tumors that received two or three sessions …

Towards A Better Mucolytic, Burton F Dickey, Christopher M Evans

Faculty, Staff and Student Publications

No abstract provided.

Reconstructive Surgery For The Neglected Tropical Diseases: Global Gaps And Future Directions, Kala T Pham, Peter J Hotez, Kristy L Hamilton

Faculty, Staff and Students Publications

BACKGROUND: Several neglected tropical diseases (NTDs) are highly disfiguring, particularly those in resource-poor countries that lack access to basic surgery. There has been a push to integrate surgery into treatment programs for NTDs. In this article, we provide an overview of the major disfiguring NTDs and discuss the processes and barriers that impede access to reconstructive surgical treatments or their integration into health systems.

METHODS: A review of the literature was conducted using the online database PubMed, from 2008 to 2021 with the specific diseases listed as NTDs either on the World Health Organization or the

RESULT: Success in the …

Surgical Reconstruction Of Stage 3 And 4 Pressure Injuries: A Literature Review And Proposed Algorithm From An Interprofessional Working Group, Samir S Awad, James D Stern, Cathy T Milne, Shane G Dowling, Ron Sotomayor, Elizabeth A Ayello, Leandro J Feo Aguirre, Basil Z Khalaf, Lisa J Gould, Michael N Desvigne, Abigail E Chaffin

Faculty, Staff and Students Publications

OBJECTIVE: Stage 3 and 4 pressure injuries (PIs) present an enormous societal burden with no clearly defined interventions for surgical reconstruction. The authors sought to assess, via literature review and a reflection/evaluation of their own clinical practice experience (where applicable), the current limitations to the surgical intervention of stage 3 or 4 PIs and propose an algorithm for surgical reconstruction.

METHODS: An interprofessional working group convened to review and assess the scientific literature and propose an algorithm for clinical practice. Data compiled from the literature and a comparison of institutional management were used to develop an algorithm for the surgical …

The Ratio Of Intratumour To Stromal Infiltrating Lymphocytes Better Predicts Prognosis In Breast Cancer, Baoyi Zhang, Xiang Wang, Chao Cheng

Faculty, Staff and Students Publications

No abstract provided.

Advances In The Management Of Menopausal Symptoms, Fertility Preservation, And Bone Health For Women With Breast Cancer On Endocrine Therapy, Matteo Lambertini, Luca Arecco, Terri Lynn Woodard, Audrey Messelt, Kristin E Rojas

Faculty, Staff and Students Publications

In patients with hormone receptor-positive early-stage breast cancer, adjuvant endocrine treatment administered for up to 5-10 years after diagnosis significantly reduces the risk of recurrence and death. However, this benefit comes with the cost of short- and long-term side effects that may negatively affect patients' quality of life (QoL) and treatment adherence. Among them, the prolonged estrogen suppression associated with the use of adjuvant endocrine therapy in both premenopausal and postmenopausal women can induce life-altering menopausal symptoms, including sexual dysfunction. Moreover, a decrease in bone mineral density and an increased risk of fractures should be carefully considered and prevented whenever …

Immune Profiling Of Adeno-Associated Virus Response Identifies B Cell-Specific Targets That Enable Vector Re-Administration In Mice, Maria Chen, Boram Kim, Maria I Jarvis, Samantha Fleury, Shuyun Deng, Shirin Nouraein, Susan Butler, Sangsin Lee, Courtney Chambers, H Courtney Hodges, Jerzy O Szablowski, Junghae Suh, Omid Veiseh

Faculty, Staff and Students Publications

Adeno-associated virus (AAV) vector-based gene therapies can be applied to a wide range of diseases. AAV expression can last for months to years, but vector re-administration may be necessary to achieve life-long treatment. Unfortunately, immune responses against these vectors are potentiated after the first administration, preventing the clinical use of repeated administration of AAVs. Reducing the immune response against AAVs while minimizing broad immunosuppression would improve gene delivery efficiency and long-term safety. In this study, we quantified the contributions of multiple immune system components of the anti-AAV response in mice. We identified B-cell-mediated immunity as a critical component preventing vector …

A Novel Approach To Diagnostic Left And Right Heart Catheterization In A Patient With A Mechanical Prosthetic Tricuspid Valve, Seulgi E Kim, Dhaval Parekh, Wilson Lam

Faculty, Staff and Students Publications

A 47-year-old patient was experiencing dyspnea and fatigue concerning for right ventricular hypertension and new heart failure. Because of the risks associated with catheter entrapment, prosthetic valve leaflet damage, and valve thrombosis associated with crossing a mechanical valve, a novel technique was used for diagnostic left and right heart catheterization in a patient with mechanical tricuspid valve replacement and tortuous pulmonary arteries. Using a percutaneous subxiphoid approach to avoid traversing the mechanical valve without discontinuing anticoagulation, a Volcano fractional flow reserve pressure wire (Philips Volcano) was advanced for distal measurements of pressures and saturations.

Adad2 Functions In Spermiogenesis And Pirna Biogenesis In Mice, Yonggang Lu, Ippei Nagamori, Hisato Kobayashi, Kanako Kojima-Kita, Kenjiro Shirane, Hsin-Yi Chang, Toru Nishimura, Takayuki Koyano, Zhifeng Yu, Julio M Castañeda, Makoto Matsuyama, Satomi Kuramochi-Miyagawa, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

BACKGROUND: Adenosine deaminase domain containing 2 (ADAD2) is a testis-specific protein composed of a double-stranded RNA binding domain and a non-catalytic adenosine deaminase domain. A recent study showed that ADAD2 is indispensable for the male reproduction in mice. However, the detailed functions of ADAD2 remain elusive.

OBJECTIVES: This study aimed to investigate the cause of male sterility in Adad2 mutant mice and to understand the molecular functions of ADAD2.

MATERIALS AND METHODS: Adad2 homozygous mutant mouse lines, Adad2

RESULTS: Adad2–/– and Adad2Δ/Δ mice exhibit male-specific sterility due to abnormal spermiogenesis. ADAD2 interacts with multiple RNA-binding proteins involved in …

Interaction Modules That Impart Specificity To Disordered Protein, Katerina Cermakova, H Courtney Hodges

Faculty, Staff and Students Publications

Intrinsically disordered regions (IDRs) are especially enriched among proteins that regulate chromatin and transcription. As a result, mechanisms that influence specificity of IDR-driven interactions have emerged as exciting unresolved issues for understanding gene regulation. We review the molecular elements frequently found within IDRs that confer regulatory specificity. In particular, we summarize the differing roles of disordered low-complexity regions (LCRs) and short linear motifs (SLiMs) towards selective nuclear regulation. Examination of IDR-driven interactions highlights SLiMs as organizers of selectivity, with widespread roles in gene regulation and integration of cellular signals. Analysis of recurrent interactions between SLiMs and folded domains suggests diverse …

A Weakly Structured Stem For Human Origins In Africa, Aaron P Ragsdale, Timothy D Weaver, Elizabeth G Atkinson, Eileen G Hoal, Marlo Möller, Brenna M Henn, Simon Gravel

Faculty, Staff and Students Publications

Despite broad agreement that Homo sapiens originated in Africa, considerable uncertainty surrounds specific models of divergence and migration across the continent1. Progress is hampered by a shortage of fossil and genomic data, as well as variability in previous estimates of divergence times1. Here we seek to discriminate among such models by considering linkage disequilibrium and diversity-based statistics, optimized for rapid, complex demographic inference2. We infer detailed demographic models for populations across Africa, including eastern and western representatives, and newly sequenced whole genomes from 44 Nama (Khoe-San) individuals from southern Africa. We infer a reticulated …

Functional Screening Of Lysosomal Storage Disorder Genes Identifies Modifiers Of Alpha-Synuclein Neurotoxicity, Meigen Yu, Hui Ye, Ruth B De-Paula, Carl Grant Mangleburg, Timothy Wu, Tom V Lee, Yarong Li, Duc Duong, Bridget Phillips, Carlos Cruchaga, Genevera I Allen, Nicholas T Seyfried, Ismael Al-Ramahi, Juan Botas, Joshua M Shulman

Faculty, Staff and Students Publications

Heterozygous variants in the glucocerebrosidase (GBA) gene are common and potent risk factors for Parkinson's disease (PD). GBA also causes the autosomal recessive lysosomal storage disorder (LSD), Gaucher disease, and emerging evidence from human genetics implicates many other LSD genes in PD susceptibility. We have systemically tested 86 conserved fly homologs of 37 human LSD genes for requirements in the aging adult Drosophila brain and for potential genetic interactions with neurodegeneration caused by α-synuclein (αSyn), which forms Lewy body pathology in PD. Our screen identifies 15 genetic enhancers of αSyn-induced progressive locomotor dysfunction, including knockdown of fly homologs of GBA …

Pathway-Driven Rare Germline Variants Associated With Transplant-Associated Thrombotic Microangiopathy (Ta-Tma), Zhihui Zhang, Wei Hong, Qian Wu, Spiridon Tsavachidis, Jian-Rong Li, Christopher I Amos, Chao Cheng, Sarah E Sartain, Vahid Afshar-Kharghan, Jing-Fei Dong, Pavan Bhatraju, Paul J Martin, Robert S Makar, Pavan K Bendapudi, Ang Li

Faculty, Staff and Student Publications

The significance of rare germline mutations in transplant-associated thrombotic microangiopathy (TA-TMA) is not well studied. We performed a genetic association study in 100 adult TA-TMA patients vs. 98 post-transplant controls after matching by race, sex, and year. We focused on 5 pathways in complement, von Willebrand factor (VWF) function and related proteins, VWF clearance, ADAMTS13 function and related proteins, and endothelial activation (3641variants in 52 genes). In the primary analysis focused on 189 functional rare variants, no differential variant enrichment was observed in any of the pathways; specifically, 29 % TA-TMA and 33 % controls had at least 1 rare …

Bladder Mucosal Cystitis Cystica Lesions Are Tertiary Lymphoid Tissues That Correlate With Recurrent Urinary Tract Infection Frequency In Postmenopausal Women, Marianne M Ligon, Brooke Liang, Stacy M Lenger, Priyanka Parameswaran, Siobhan Sutcliffe, Jerry L Lowder, Indira U Mysorekar

Faculty, Staff and Students Publications

PURPOSE: We identify correlates and clinical outcomes of cystitis cystica, a poorly understood chronic inflammatory bladder change, in women with recurrent urinary tract infections.

MATERIALS AND METHODS: A retrospective, observational cohort of women with recurrent urinary tract infections who underwent cystoscopy (n=138) from 2015 to 2018 were identified using electronic medical records. Cystitis cystica status was abstracted from cystoscopy reports and correlations were identified by logistic regression. Urinary tract infection-free survival time associated with cystitis cystica was evaluated by Cox proportional hazards regression. Exact logistic regression was used to identify factors associated with changes to cystitis cystica lesions on repeat …

Harmonizing Ptsd Severity Scales Across Instruments And Sites, Eamonn Kennedy, Emily L Dennis, Hannah M Lindsey, Terri Deroon-Cassini, Stefan Du Plessis, Negar Fani, Milissa L Kaufman, Nastassja Koen, Christine L Larson, Sarah Laskowitz, Lauren A M Lebois, Rajendra A Morey, Mary R Newsome, Cori Palermo, Nicholas J Pastorek, Abigail Powers, Randall Scheibel, Soraya Seedat, Antonia Seligowski, Dan J Stein, Jennifer Stevens, Delin Sun, Paul Thompson, Maya Troyanskaya, Sanne J H Van Rooij, Amanda A Watts, Carissa W Tomas, Wright Williams, Frank G Hillary, Mary Jo Pugh, Elisabeth A Wilde, David F Tate

Faculty, Staff and Students Publications

Objective: The variety of instruments used to assess posttraumatic stress disorder (PTSD) allows for flexibility, but also creates challenges for data synthesis. The objective of this work was to use a multisite mega analysis to derive quantitative recommendations for equating scores across measures of PTSD severity.

Method: Empirical Bayes harmonization and linear models were used to describe and mitigate site and covariate effects. Quadratic models for converting scores across PTSD assessments were constructed using bootstrapping and tested on hold out data.

Results: We aggregated 17 data sources and compiled an n = 5,634 sample of individuals who were assessed for …

Margetuximab In Her2-Positive Metastatic Breast Cancer, William J Gradishar, Ruth O'Regan, Mothaffar F Rimawi, Jeffrey L Nordstrom, Minori K Rosales, Hope S Rugo

Faculty, Staff and Students Publications

Several anti-HER2 agents are approved for third-line treatment and beyond (after first-line and second-line); however, no specific treatment strategy is recommended for third-line and beyond. Although these agents improve disease outcomes, HER2-positive metastatic breast cancer remains incurable and there is an unmet need for effective therapies in the later line setting. This review focuses on the development of margetuximab-cmkb, a novel, Fc-engineered, anti-HER2 monoclonal antibody, and its role in the systemic treatment of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease.

Investigating Gene-Diet Interactions Impacting The Association Between Macronutrient Intake And Glycemic Traits, Kenneth E Westerman, Maura E Walker, Sheila M Gaynor, Jennifer Wessel, Daniel Dicorpo, Jiantao Ma, Alvaro Alonso, Stella Aslibekyan, Abigail S Baldridge, Alain G Bertoni, Mary L Biggs, Jennifer A Brody, Yii-Der Ida Chen, Joseé Dupuis, Mark O Goodarzi, Xiuqing Guo, Natalie R Hasbani, Adam Heath, Bertha Hidalgo, Marguerite R Irvin, W Craig Johnson, Rita R Kalyani, Leslie Lange, Rozenn N Lemaitre, Ching-Ti Liu, Simin Liu, Jee-Young Moon, Rami Nassir, James S Pankow, Mary Pettinger, Laura M Raffield, Laura J Rasmussen-Torvik, Elizabeth Selvin, Mackenzie K Senn, Aladdin H Shadyab, Albert V Smith, Nicholas L Smith, Lyn Steffen, Sameera Talegakwar, Kent D Taylor, Paul S De Vries, James G Wilson, Alexis C Wood, Lisa R Yanek, Jie Yao, Yinan Zheng, Eric Boerwinkle, Alanna C Morrison, Miriam Fornage, Tracy P Russell, Bruce M Psaty, Daniel Levy, Nancy L Heard-Costa, Vasan S Ramachandran, Rasika A Mathias, Donna K Arnett, Robert Kaplan, Kari E North, Adolfo Correa, April Carson, Jerome I Rotter, Stephen S Rich, Joann E Manson, Alexander P Reiner, Charles Kooperberg, Jose C Florez, James B Meigs, Jordi Merino, Deirdre K Tobias, Han Chen, Alisa K Manning

Faculty, Staff and Student Publications

Few studies have demonstrated reproducible gene-diet interactions (GDIs) impacting metabolic disease risk factors, likely due in part to measurement error in dietary intake estimation and insufficient capture of rare genetic variation. We aimed to identify GDIs across the genetic frequency spectrum impacting the macronutrient-glycemia relationship in genetically and culturally diverse cohorts. We analyzed 33,187 participants free of diabetes from 10 National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program cohorts with whole-genome sequencing, self-reported diet, and glycemic trait data. We fit cohort-specific, multivariable-adjusted linear mixed models for the effect of diet, modeled as an isocaloric substitution of carbohydrate …

Identification Of Dietary Supplements Associated With Blood Metabolites In The Hispanic Community Health Study/Study Of Latinos Cohort Study, Robert C Kaplan, Jessica S Williams-Nguyen, Yuhan Huang, Yasmin Mossavar-Rahmani, Bing Yu, Eric Boerwinkle, Marc D Gellman, Martha Daviglus, Aisha Chilcoat, Linda Van Horn, Kim Faurot, Qibin Qi, Heather Greenlee

Faculty, Staff and Student Publications

BACKGROUND: Metabolomics approaches have been widely used to define the consumption of foods but have less often been used to study exposure to dietary supplements.

OBJECTIVES: This study aimed to identify dietary supplements associated with metabolite levels and to examine whether these metabolites predicted incident diabetes risk.

METHODS: We studied 3972 participants from a prospective cohort study of 18-74-y-old Hispanic/Latino adults. At a baseline examination, we ascertained use of dietary supplements using recall methods and concurrently, a serum metabolomic panel. After adjustment for potential confounders, we identified dietary supplements associated with metabolites. We then examined the association of these metabolites …

Effect Of Quality Of Life On Radiation Adherence For Patients With Cervical Cancer In An Urban Safety Net Health System, Alison K Yoder, Elizabeth Dong, Xiaoman Yu, Alfredo Echeverria, Shelly Sharma, Jane Montealegre, Michelle S Ludwig

Faculty, Staff and Students Publications

PURPOSE: Outcomes for patients undergoing chemoradiation for cervical cancer are dependent on adherence to radiation therapy (RT). In other diseases, quality of life (QoL) is associated with treatment adherence, but the association between QoL and RT adherence for patients with cervical cancer remains unclear.

METHODS AND MATERIALS: This prospective study included patients undergoing RT for cervical cancer from 2017 to 2021 at an urban safety net hospital. The Functional Assessment of Cancer Therapy-Cervical Cancer Version 4 was used to assess QoL based on 5 subscales (physical, functional, social and emotional, and cervical-cancer specific). The survey was administered at radiation consult, …

Genetic Associations Between Modifiable Risk Factors And Alzheimer Disease, Jiao Luo, Jesper Qvist Thomassen, Céline Bellenguez, Benjamin Grenier-Boley, Itziar De Rojas, Atahualpa Castillo, Kayenat Parveen, Fahri Küçükali, Aude Nicolas, Oliver Peters, Anja Schneider, Martin Dichgans, Dan Rujescu, Norbert Scherbaum, Deckert Jürgen, Steffi Riedel-Heller, Lucrezia Hausner, Laura Molina Porcel, Emrah Düzel, Timo Grimmer, Jens Wiltfang, Stefanie Heilmann-Heimbach, Susanne Moebus, Thomas Tegos, Nikolaos Scarmeas, Jordi Clarimon, Fermin Moreno, Jordi Pérez-Tur, María J Bullido, Pau Pastor, Raquel Sánchez-Valle, Victoria Álvarez, Mercè Boada, Pablo García-González, Raquel Puerta, Pablo Mir, Luis M Real, Gerard Piñol-Ripoll, Jose María García-Alberca, Jose Luís Royo, Eloy Rodriguez-Rodriguez, Hilkka Soininen, Teemu Kuulasmaa, Alexandre De Mendonça, Shima Mehrabian, Jakub Hort, Martin Vyhnalek, Sven Van Der Lee, Caroline Graff, Goran Papenberg, Vilmantas Giedraitis, Anne Boland, Delphine Bacq-Daian, Jean-François Deleuze, Gael Nicolas, Carole Dufouil, Florence Pasquier, Olivier Hanon, Stéphanie Debette, Edna Grünblatt, Julius Popp, Luisa Benussi, Daniela Galimberti, Beatrice Arosio, Patrizia Mecocci, Vincenzo Solfrizzi, Lucilla Parnetti, Alessio Squassina, Lucio Tremolizzo, Barbara Borroni, Benedetta Nacmias, Sandro Sorbi, Paolo Caffarra, Davide Seripa, Innocenzo Rainero, Antonio Daniele, Carlo Masullo, Gianfranco Spalletta, Julie Williams, Philippe Amouyel, Frank Jessen, Patrick Kehoe, Magda Tsolaki, Giacomina Rossi, Pascual Sánchez-Juan, Kristel Sleegers, Martin Ingelsson, Ole A Andreassen, Mikko Hiltunen, Cornelia Van Duijn, Rebecca Sims, Wiesje Van Der Flier, Agustín Ruiz, Alfredo Ramirez, Jean-Charles Lambert, Ruth Frikke-Schmidt

Faculty, Staff and Students Publications

IMPORTANCE: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia.

OBJECTIVE: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention.

DESIGN, SETTING, AND PARTICIPANTS: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for …

Meta-Analysis Of The Association Between Atrial Fibrillation, Hypertension, Sleep-Disordered Breathing, And Wake-Up Stroke, Jin Zhou, Jing Xu, Aijuan Cheng, Yimiti Kadier, Xiaoli Liang, Maimaitijiang Mutailipu, Shan Sun

The Texas Heart Institute Journal

BACKGROUND: The occurrence of atrial fibrillation, circadian fluctuation in blood pressure, and oxygen desaturation at night is likely associated with the pathophysiology of wake-up stroke. Whether patients who experience wake-up strokes are candidates for thrombolysis treatment is a serious dilemma. The aim is to investigate the association between risk factors and wake-up stroke and to determine variations that are associated with the pathophysiology of wake-up stroke.

METHODS: Five major electronic databases were searched using a fitted search strategy to identify relevant studies. Odds ratios with 95% CIs were used to calculate estimates, and the Quality Assessment for Diagnostic Accuracy Studies-2 …

Neddylation Inhibition Sensitises Renal Medullary Carcinoma Tumours To Platinum Chemotherapy, Daniel D Shapiro, Niki Millward Zacharias, Durga N Tripathi, Menuka Karki, Jean-Philippe Bertocchio, Melinda Soeung, Rong He, Mary E Westerman, Jianjun Gao, Priya Rao, Truong N A Lam, Eric Jonasch, Luigi Perelli, Emily H Cheng, Alessandro Carugo, Timothy P Heffernan, Cheryl L Walker, Giannicola Genovese, Nizar M Tannir, Jose A Karam, Pavlos Msaouel

Faculty, Staff and Student Publications

BACKGROUND: Renal medullary carcinoma (RMC) is a highly aggressive cancer in need of new therapeutic strategies. The neddylation pathway can protect cells from DNA damage induced by the platinum-based chemotherapy used in RMC. We investigated if neddylation inhibition with pevonedistat will synergistically enhance antitumour effects of platinum-based chemotherapy in RMC.

METHODS: We evaluated the IC50 concentrations of the neddylation‐activating enzyme inhibitor pevonedistat in vitro in RMC cell lines. Bliss synergy scores were calculated using growth inhibition assays following treatment with varying concentrations of pevonedistat and carboplatin. Protein expression was assessed by western blot and immunofluorescence assays. The efficacy of pevonedistat …

Defining The Genetic Landscape Of Idiopathic Pulmonary Fibrosis: Role Of Common And Rare Variants, Benjamin J Moss, Ivan O Rosas

Faculty, Staff and Students Publications

No abstract provided.

Genome-Wide Analysis Of Structural Variants In Parkinson Disease, Kimberley J Billingsley, Jinhui Ding, Pilar Alvarez Jerez, Anastasia Illarionova, Kristin Levine, Francis P Grenn, Mary B Makarious, Anni Moore, Daniel Vitale, Xylena Reed, Dena Hernandez, Ali Torkamani, Mina Ryten, John Hardy, Uk Brain Expression Consortium (Ukbec), Ruth Chia, Sonja W Scholz, Bryan J Traynor, Clifton L Dalgard, Debra J Ehrlich, Toshiko Tanaka, Luigi Ferrucci, Thomas G Beach, Geidy E Serrano, John P Quinn, Vivien J Bubb, Ryan L Collins, Xuefang Zhao, Mark Walker, Emma Pierce-Hoffman, Harrison Brand, Michael E Talkowski, Bradford Casey, Mark R Cookson, Androo Markham, Mike A Nalls, Medhat Mahmoud, Fritz J Sedlazeck, Cornelis Blauwendraat, J Raphael Gibbs, Andrew B Singleton

Faculty, Staff and Students Publications

OBJECTIVE: Identification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large-scale characterization of SVs in PD.

METHODS: We leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 …

Alveolar Rhabdomyosarcoma Has Superior Response Rates To Vinorelbine Compared To Embryonal Rhabdomyosarcoma In Patients With Relapsed/Refractory Disease: A Meta-Analysis, Wendy Allen-Rhoades, Philip J Lupo, Michael E Scheurer, Yueh-Yun Chi, John F Kuttesch, Rajkumar Venkatramani, William H Meyer, Leo Mascarenhas

Faculty, Staff and Students Publications

BACKGROUND: Patients with alveolar rhabdomyosarcoma (ARMS) have inferior outcomes compared to patients with embryonal rhabdomyosarcoma (ERMS) and more effective chemotherapy options are needed for these patients. Vinorelbine is a semisynthetic vinca alkaloid that has clinical activity in relapsed rhabdomyosarcoma (RMS) when used alone or in combination with cyclophosphamide.

AIMS: The goal of our study was to evaluate whether RMS histology subtype influences response rate to vinorelbine alone or in combination.

MATERIALS & METHODS: Five Phase 2 trials that enrolled RMS patients were included in the meta-analysis. Two studies evaluated vinorelbine alone, two studies evaluated vinorelbine in combination with low dose …

The Impact Of Initial Specimen Diversion Systems On Blood Culture Contamination, Mayar Al Mohajer, Todd Lasco

Faculty, Staff and Students Publications

Blood culture contamination is associated with increased antimicrobial use, length of stay, and hospital cost. To address this problem, blood culture diversion has been developed as an additional measure to reduce contamination to targeted goals. Three different versions were proposed, including an open technique and 2 commercially available devices. This study aims to review the existing literature and analyze evidence for these 3 techniques.

Cascade Testing After Exome Sequencing: Retrospective Analysis Of Linked Family Data At 2 Us Laboratories, Julie Stefka, Haley Streff, Pengfei Liu, Meghan Towne, Hadley Stevens Smith

Faculty, Staff and Students Publications

Purpose: Cascade testing, the process of testing a proband's at-risk relatives, is integral to realizing the full value of genomic sequencing. However, there is little empirical evidence on the uptake of cascade testing after a positive exome sequencing (ES) result in a population of probands with diverse clinical indications.

Methods: We retrospectively reviewed administrative data from 2 US clinical laboratories that perform ES. For each proband with a positive ES result, we used linked family data to describe the frequency of relatives' cascade testing performed at the same laboratory, variant detection yield of cascade tests, and characteristics of probands and …