Medical Genetics Commons^™

A Phase 1 Trial Of 8-Chloro-Adenosine In Relapsed/Refractory Acute Myeloid Leukemia: An Evaluation Of Safety And Pharmacokinetics, Vinod Pullarkat, Lisa S Chen, Joycelynne Palmer, Jianying Zhang, Timothy W Synold, Ralf Buettner, Le Xuan Truong Nguyen, Guido Marcucci, Ni-Chun Tsai, Yan Wang, James O'Hearn, Varsha Gandhi, Steven T Rosen

Faculty, Staff and Student Publications

Background: This study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 8-chloro-adenosine (8-Cl-Ado) in patients with relapsed/refractory acute myeloid leukemia (AML).

Methods: 8-Cl-Ado was administered daily for 5 days; the starting dose was 100 mg/m2 , the highest dose tested was 800 mg/m2 . The end points were toxicity, disease response, and PK/PD measurements.

Results: The predominant nonhematologic toxicity was cardiac with grade ≥3 toxicity. Plasma PK in all patients suggested heterogeneity among patients, yet, some dose-dependency for the accumulation of 8-Cl-Ado. Two 8-Cl-Ado metabolites accumulated at similar levels to 8-Cl-Ado. Cellular PK in eight patients indicated accumulation of …

Outcomes In 14 Live Births Resulting From Pegvaliase-Treated Pregnancies In Pku-Affected Females, Caide Bier, Kaelin Dickey, Brittan Bibb, Angela Crutcher, Rebecca Sponberg, Richard Chang, Monica Boyer, Laura Davis-Keppen, Cindy Matthes, Michelle Tharp, Danielle Vice, Erin Cooney, Megan Morand, Joseph Ray, Melissa Lah, Markey Mcnutt, Hans C Andersson

Faculty, Staff and Student Publications

Background: Adults with PKU have difficulty maintaining plasma phenylalanine (Phe) in the range that is safe for neurologic function. Elevated plasma Phe is a risk factor for congenital anomalies and developmental delay in offspring resulting from pregnancies with poor Phe control in women with PKU. Enzyme supplementation with pegvaliase allows adults with PKU to eat an unrestricted diet and have plasma Phe levels in a safe range for pregnancy but pegvaliase has not been approved for use in pregnant females with PKU. We report the results of chart review of 14 living offspring of females affected with PKU who were …

Empirically Derived Principles For Research Funding Success: A Primer For Early Career Academic Investigators, Kareem A Wahid, Michael K Rooney, Jillian R Gunther, Amy C Moreno, Chelsea C Pinnix, Charles R Thomas, Clifton D Fuller

Faculty, Staff and Student Publications

No abstract provided.

Clinical And Dosimetric Results Of Proton Or Photon Radiation Therapy For Large (>5 Cm) Hepatocellular Carcinoma: A Retrospective Analysis, Rodney Cheng-En Hsieh, Ching-Hsin Lee, Hsiao-Chieh Huang, Shu-Wei Wu, Chen-Yu Chou, Sheng-Ping Hung, Chao-Wei Lee, Sunil Krishnan, Bhanu Prasad Venkatesulu, Jin-Chiao Lee, Yung-Chih Chou, Kun-Ming Chan, Po-Ting Lin, Wei-Chen Lee, Chen-Chun Lin, Shen-Yen Lin, Ji-Hong Hong

Faculty, Staff and Student Publications

Purpose: Our purpose was to report the clinical and dosimetric attributes of patients with large unresectable hepatocellular carcinoma (HCC) undergoing proton or photon radiation therapy.

Methods and materials: We retrospectively analyzed the outcomes and dosimetric indices of 159 patients with >5 cm nonmetastatic HCC who underwent definitive radiation therapy using either protons (N = 105) or photons (N = 54) between 2014 and 2018. Additional photon plans were performed in the 105 proton-treated patients using the same dose prescription criteria for intragroup dosimetric comparison.

Results: After a median follow-up of 47 months, patients with biologically effective dose (BED10) ≥ 75 …

Polygenic Risk Scores, Radiation Treatment Exposures And Subsequent Cancer Risk In Childhood Cancer Survivors, Todd M Gibson, Danielle M Karyadi, Stephen W Hartley, Michael A Arnold, Amy Berrington De Gonzalez, Miriam R Conces, Rebecca M Howell, Vidushi Kapoor, Wendy M Leisenring, Joseph P Neglia, Joshua N Sampson, Lucie M Turcotte, Stephen J Chanock, Gregory T Armstrong, Lindsay M Morton

Faculty, Staff and Student Publications

Survivors of childhood cancer are at increased risk for subsequent cancers attributable to the late effects of radiotherapy and other treatment exposures; thus, further understanding of the impact of genetic predisposition on risk is needed. Combining genotype data for 11,220 5-year survivors from the Childhood Cancer Survivor Study and the St Jude Lifetime Cohort, we found that cancer-specific polygenic risk scores (PRSs) derived from general population, genome-wide association study, cancer loci identified survivors of European ancestry at increased risk of subsequent basal cell carcinoma (odds ratio per s.d. of the PRS: OR = 1.37, 95% confidence interval (CI) = 1.29-1.46), …

Preclinical Efficacy Of Targeting Epigenetic Mechanisms In Aml With 3q26 Lesions And Evi1 Overexpression, Christine E Birdwell, Warren Fiskus, Tapan M Kadia, Christopher P Mill, Koji Sasaki, Naval Daver, Courtney D Dinardo, Naveen Pemmaraju, Gautam Borthakur, John A Davis, Kaberi Das, Sunil Sharma, Stephen Horrigan, Xinjia Ruan, Xiaoping Su, Joseph D Khoury, Hagop Kantarjian, Kapil N Bhalla

Faculty, Staff and Student Publications

AML with chromosomal alterations involving 3q26 overexpresses the transcription factor (TF) EVI1, associated with therapy refractoriness and inferior overall survival in AML. Consistent with a CRISPR screen highlighting BRD4 dependency, treatment with BET inhibitor (BETi) repressed EVI1, LEF1, c-Myc, c-Myb, CDK4/6, and MCL1, and induced apoptosis of AML cells with 3q26 lesions. Tegavivint (TV, BC-2059), known to disrupt the binding of nuclear β-catenin and TCF7L2/LEF1 with TBL1, also inhibited co-localization of EVI1 with TBL1 and dose-dependently induced apoptosis in AML cell lines and patient-derived (PD) AML cells with 3q26.2 lesions. TV treatment repressed EVI1, attenuated enhancer activity at ERG, TCF7L2, …

Targeting Hypoxia-Inducible Factors: Therapeutic Opportunities And Challenges, Xiaoyi Yuan, Wei Ruan, Bentley Bobrow, Peter Carmeliet, Holger K Eltzschig

Faculty, Staff and Student Publications

Hypoxia-inducible factors (HIFs) are highly conserved transcription factors that are crucial for adaptation of metazoans to limited oxygen availability. Recently, HIF activation and inhibition have emerged as therapeutic targets in various human diseases. Pharmacologically desirable effects of HIF activation include erythropoiesis stimulation, cellular metabolism optimization during hypoxia and adaptive responses during ischaemia and inflammation. By contrast, HIF inhibition has been explored as a therapy for various cancers, retinal neovascularization and pulmonary hypertension. This Review discusses the biochemical mechanisms that control HIF stabilization and the molecular strategies that can be exploited pharmacologically to activate or inhibit HIFs. In addition, we examine …

Desirability Of Outcome Ranking For Obstetrical Trials: Illustration And Application To The Arrive Trial, Grecio J Sandoval, William A Grobman, Scott R Evans, Madeline M Rice, Rebecca G Clifton, Suneet P Chauhan, Maged M Costantine, Kelly S Gibson, Monica Longo, Torri D Metz, Emily S Miller, Samuel Parry, Uma M Reddy, Dwight J Rouse, Hyagriv N Simhan, John M Thorp, Alan T N Tita, George R Saade

Faculty, Staff and Student Publications

BACKGROUND: In randomized trials, 1 primary outcome is typically chosen to evaluate the consequences of an intervention, whereas other important outcomes are relegated to secondary outcomes. This issue is amplified for many obstetrical trials in which an intervention may have consequences for both the pregnant person and the child. In contrast, desirability of outcome ranking, a paradigm shift for the design and analysis of clinical trials based on patient-centric evaluation, allows multiple outcomes-including from >1 individual-to be considered concurrently.

OBJECTIVE: This study aimed to describe desirability of outcome ranking methodology tailored to obstetrical trials and to apply the methodology to …

Identifying A Stable And Generalizable Factor Structure Of Major Depressive Disorder Across Three Large Longitudinal Cohorts, Vincent W S Tseng, Jordan A Tharp, Jacob E Reiter, Weston Ferrer, David S Hong, P Murali Doraiswamy, Stefanie Nickels

Faculty, Staff and Student Publications

The Patient Health Questionnaire 9 (PHQ-9) is the current standard outpatient screening tool for measuring and tracking the nine symptoms of major depressive disorder (MDD). While the PHQ-9 was originally conceptualized as a unidimensional measure, it has become clear that MDD is not a monolithic construct, as evidenced by high comorbidities with other theoretically distinct diagnoses and common symptom overlap between depression and other diagnoses. Therefore, identifying reliable and temporally stable subfactors of depressive symptoms could allow research and care to be tailored to different depression phenotypes. This study improved on previous factor analysis studies of the PHQ-9 by leveraging …

Stroke And The Microbiome, Anik Banerjee, Swati Mohapatra, Louise D Mccullough

Faculty, Staff and Student Publications

No abstract provided.

Targeted Inhibition Of Scfskp2 Confers Anti-Tumor Activities Resulting In A Survival Benefit In Osteosarcoma, Jichuan Wang, Alexander Ferrena, Ranxin Zhang, Swapnil Singh, Valentina Viscarret, Waleed Al-Harden, Osama Aldahamsheh, Hasibagan Borjihan, Amit Singla, Simon Yaguare, Janet Tingling, Xiaolin Zi, Yungtai Lo, Richard Gorlick, Edward L Schwartz, Hongling Zhao, Rui Yang, David S Geller, Deyou Zheng, Bang H Hoang

Faculty, Staff and Student Publications

Osteosarcoma(OS) is a highly aggressive bone cancer for which treatment has remained essentially unchanged for decades. Although OS is characterized by extensive genomic heterogeneity and instability, RB1 and TP53 have been shown to be the most commonly inactivated tumor suppressors in OS. We previously generated a mouse model with a double knockout (DKO) of Rb1 and Trp53 within cells of the osteoblastic lineage, which largely recapitulates human OS with nearly complete penetrance. SKP2 is a repression target of pRb and serves as a substrate recruiting subunit of the SCFSKP2 complex. In addition, SKP2 plays a central role in regulating the …

Image-Based Multiplex Immune Profiling Of Cancer Tissues: Translational Implications A Report Of The International Immuno-Oncology Biomarker Working Group On Breast Cancer, Chowdhury Arif Jahangir, David B Page, Glenn Broeckx, Claudia A Gonzalez, Caoimbhe Burke, Clodagh Murphy, Jorge S Reis-Filho, Amy Ly, Paul W Harms, Rajarsi R Gupta, Michael Vieth, Akira I Hida, Mohamed Kahila, Zuzana Kos, Paul J Van Diest, Sara Verbandt, Jeppe Thagaard, Reena Khiroya, Khalid Abduljabbar, Gabriela Acosta Haab, Balazs Acs, Sylvia Adams, Jonas S Almeida, Isabel Alvarado-Cabrero, Farid Azmoudeh-Ardalan, Sunil Badve, Nurkhairul Bariyah Baharun, Enrique R Bellolio, Vydehi Bheemaraju, Kim Rm Blenman, Luciana Botinelly Mendonça Fujimoto, Octavio Burgues, Alexandros Chardas, Maggie Chon U Cheang, Francesco Ciompi, Lee Ad Cooper, An Coosemans, Germán Corredor, Flavio Luis Dantas Portela, Frederik Deman, Sandra Demaria, Sarah N Dudgeon, Mahmoud Elghazawy, Claudio Fernandez-Martín, Susan Fineberg, Stephen B Fox, Jennifer M Giltnane, Sacha Gnjatic, Paula I Gonzalez-Ericsson, Anita Grigoriadis, Niels Halama, Matthew G Hanna, Aparna Harbhajanka, Steven N Hart, Johan Hartman, Stephen Hewitt, Hugo M Horlings, Zaheed Husain, Sheeba Irshad, Emiel Am Janssen, Tatsuki R Kataoka, Kosuke Kawaguchi, Andrey I Khramtsov, Umay Kiraz, Pawan Kirtani, Liudmila L Kodach, Konstanty Korski, Guray Akturk, Ely Scott, Anikó Kovács, Anne-Vibeke Laenkholm, Corinna Lang-Schwarz, Denis Larsimont, Jochen K Lennerz, Marvin Lerousseau, Xiaoxian Li, Anant Madabhushi, Sai K Maley, Vidya Manur Narasimhamurthy, Douglas K Marks, Elizabeth S Mcdonald, Ravi Mehrotra, Stefan Michiels, Durga Kharidehal, Fayyaz Ul Amir Afsar Minhas, Shachi Mittal, David A Moore, Shamim Mushtaq, Hussain Nighat, Thomas Papathomas, Frederique Penault-Llorca, Rashindrie D Perera, Christopher J Pinard, Juan Carlos Pinto-Cardenas, Giancarlo Pruneri, Lajos Pusztai, Nasir Mahmood Rajpoot, Bernardo Leon Rapoport, Tilman T Rau, Joana M Ribeiro, David Rimm, Anne Vincent-Salomon, Joel Saltz, Shahin Sayed, Evangelos Hytopoulos, Sarah Mahon, Kalliopi P Siziopikou, Christos Sotiriou, Albrecht Stenzinger, Maher A Sughayer, Daniel Sur, Fraser Symmans, Sunao Tanaka, Timothy Taxter, Sabine Tejpar, Jonas Teuwen, E Aubrey Thompson, Trine Tramm, William T Tran, Jeroen Van Der Laak, Gregory E Verghese, Giuseppe Viale, Noorul Wahab, Thomas Walter, Yannick Waumans, Hannah Y Wen, Wentao Yang, Yinyin Yuan, John Bartlett, Sibylle Loibl, Carsten Denkert, Peter Savas, Sherene Loi, Elisabeth Specht Stovgaard, Roberto Salgado, William M Gallagher, Arman Rahman

Faculty, Staff and Student Publications

Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour …

The Risk And Burden Of Thromboembolic And Hemorrhagic Events In Patients With Malignant Gliomas Receiving Bevacizumab, Pushan Dasgupta, Alexander Ou, Heather Lin, Timothy Gregory, Kristin D Alfaro-Munoz, Ying Yuan, Vahid Afshar-Khargan, Carlos Kamiya-Matsuoka, Justin F Rousseau, Nazanin K Majd

Faculty, Staff and Student Publications

Purpose: Bevacizumab has evolved as an integral treatment option for patients with high-grade gliomas. Little is known about clinical risk factors that predispose patients with high-grade gliomas receiving bevacizumab to VTE or ICH. We sought to characterize the clinical risk factors associated with risk of either event.

Methods: In this multi-institutional retrospective study, we first evaluated patients with high-grade gliomas who were treated with bevacizumab at University of Texas MD Anderson Cancer Center from 2015-2021. We compared clinical and treatment-related factors among three cohorts: those who developed VTE, ICH, or neither. We further compared survival outcomes of these patients from …

Personalized Accelerated Chemoradiation (Pacer) For Lung Cancer: Protocol For A Bayesian Optimal Phase I/Ii Trial, Caressa Hui, Eleanor Brown, Samantha Wong, Millie Das, Heather Wakelee, Joel Neal, Kavitha Ramchandran, Nathaniel J Myall, Daniel Pham, Lei Xing, Yong Yang, Nataliya Kovalchuk, Ying Yuan, Ying Lu, Michael Xiang, Alex Chin, Maximilian Diehn, Billy W Loo, Lucas K Vitzthum

Faculty, Staff and Student Publications

Introduction: Prior attempts to escalate radiation dose for non-small cell lung cancer (NSCLC) have not improved survival. Given the high risk for cardiopulmonary toxicity with treatment and heterogenous presentation of locally advanced NSCLC, it is unlikely that a single dose regimen is optimal for all patients. This phase I/II trial aims to evaluate a novel treatment approach where the level of accelerated hypofractionation is determined by the predicted toxicity from dose to organs at risk (OARs).

Methods: Patients ≥ 18 years old with lung cancer planned for fractionated radiotherapy to the lung with concurrent chemotherapy will be eligible. Radiation therapy …

A Phase I Study Of Docetaxel Plus Synthetic Lycopene In Metastatic Prostate Cancer Patients, Michael B Lilly, Chunli Wu, Yu Ke, Wen-Pin Chen, Adam C Soloff, Kent Armeson, Noriko N Yokoyama, Xiaotian Li, Liankun Song, Ying Yuan, Christine E Mclaren, Xiaolin Zi

Faculty, Staff and Student Publications

Purpose: Our preclinical studies showed that lycopene enhanced the anti-prostate cancer efficacy of docetaxel in animal models. A phase I trial (NCT0149519) was conducted to identify an optimum dose of synthetic lycopene in combination with docetaxel (and androgen blockade [androgen deprivation therapy, ADT]), and to evaluate its effect on the safety and pharmacokinetics of docetaxel in men with metastatic prostate cancer.

Methods: Subjects were treated with 21-day cycles of 75 mg/m2 docetaxel (and ADT), plus lycopene at 30, 90 or 150 mg/day. A Bayesian model averaging continual reassessment method was used to guide dose escalation. Pharmacokinetics of docetaxel …

Prenatal Vs Postnatal Diagnosis Of 22q112 Deletion Syndrome: Cardiac And Noncardiac Outcomes Through 1 Year Of Age, Lindsay R Freud, Stephanie Galloway, T Blaine Crowley, Julie Moldenhauer, Ann Swillen, Jeroen Breckpot, Antoni Borrell, Neeta L Vora, Bettina Cuneo, Hilary Hoffman, Lisa Gilbert, Beata Nowakowska, Maciej Geremek, Anna Kutkowska-Kaźmierczak, Joris R Vermeesch, Koen Devriendt, Tiffany Busa, Sabine Sigaudy, Trisha Vigneswaran, John M Simpson, Jeffrey Dungan, Nina Gotteiner, Karl-Philipp Gloning, Maria Cristina Digilio, Marta Unolt, Carolina Putotto, Bruno Marino, Gabriela Repetto, Magdalena Fadic, Sixto Garcia-Minaur, Ana Achón Buil, Mary Ann Thomas, Deborah Fruitman, Taylor Beecroft, Pui Wah Hui, Solveig Oskarsdottir, Rachael Bradshaw, Amanda Criebaum, Mary E Norton, Tiffany Lee, Miwa Geiger, Leslie Dunnington, Jacqueline Isaac, Louise Wilkins-Haug, Lindsey Hunter, Claudia Izzi, Marika Toscano, Tullio Ghi, Julie Mcglynn, Francesca Romana Grati, Beverly S Emanuel, Kimberly Gaiser, J William Gaynor, Elizabeth Goldmuntz, Daniel E Mcginn, Erica Schindewolf, Oanh Tran, Elaine H Zackai, Qi Yan, Anne S Bassett, Ronald Wapner, Donna M Mcdonald-Mcginn

Faculty, Staff and Student Publications

Background: The 22q11.2 deletion syndrome is the most common microdeletion syndrome and is frequently associated with congenital heart disease. Prenatal diagnosis of 22q11.2 deletion syndrome is increasingly offered. It is unknown whether there is a clinical benefit to prenatal detection as compared with postnatal diagnosis.

Objective: This study aimed to determine differences in perinatal and infant outcomes between patients with prenatal and postnatal diagnosis of 22q11.2 deletion syndrome.

Study design: This was a retrospective cohort study across multiple international centers (30 sites, 4 continents) from 2006 to 2019. Participants were fetuses, neonates, or infants with a genetic diagnosis of 22q11.2 …

Mechanisms Of Sleep Disturbances In Long-Term Cancer Survivors: A Childhood Cancer Survivor Study Report, Lauren C Daniel, Huiqi Wang, Tara M Brinkman, Kathy Ruble, Eric S Zhou, Oxana Palesh, Robyn Stremler, Rebecca Howell, Daniel A Mulrooney, Valerie M Crabtree, Sogol Mostoufi-Moab, Kevin Oeffinger, Joseph Neglia, Yutaka Yasui, Gregory T Armstrong, Kevin Krull

Faculty, Staff and Student Publications

Background: Sleep problems following childhood cancer treatment may persist into adulthood, exacerbating cancer-related late effects and putting survivors at risk for poor physical and psychosocial functioning. This study examines sleep in long-term survivors and their siblings to identify risk factors and disease correlates.

Methods: Childhood cancer survivors (≥5 years from diagnosis; n = 12 340; 51.5% female; mean [SD] age = 39.4 [9.6] years) and siblings (n = 2395; 57.1% female; age = 44.6 [10.5] years) participating in the Childhood Cancer Survivor Study completed the Pittsburgh Sleep Quality Index (PSQI). Multivariable Poisson-error generalized estimating equation compared prevalence of binary sleep …

Mortality After Major Cardiovascular Events In Survivors Of Childhood Cancer, Wendy Bottinor, Cindy Im, David R Doody, Saro H Armenian, Alexander Arynchyn, Borah Hong, Rebecca M Howell, David R Jacobs, Kirsten K Ness, Kevin C Oeffinger, Alexander P Reiner, Gregory T Armstrong, Yutaka Yasui, Eric J Chow

Faculty, Staff and Student Publications

Background: Adult survivors of childhood cancer are at risk for cardiovascular events.

Objectives: In this study, we sought to determine the risk for mortality after a major cardiovascular event among childhood cancer survivors compared with noncancer populations.

Methods: All-cause and cardiovascular cause-specific mortality risks after heart failure (HF), coronary artery disease (CAD), or stroke were compared among survivors and siblings in the Childhood Cancer Survivor Study (CCSS) and participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Cox proportional hazard regression models were used to estimate HRs and 95% CIs between groups, adjusted for demographic and clinical …

Evidence Review And Considerations For Use Of First Line Genome Sequencing To Diagnose Rare Genetic Disorders, Kristen M Wigby, Deanna Brockman, Gregory Costain, Caitlin Hale, Stacie L Taylor, John Belmont, David Bick, David Dimmock, Susan Fernbach, John Greally, Vaidehi Jobanputra, Shashikant Kulkarni, Elizabeth Spiteri, Ryan J Taft

Center for Medical Ethics and Health Policy Staff Publications

Early use of genome sequencing (GS) in the diagnostic odyssey can reduce suffering and improve care, but questions remain about which patient populations are most amenable to GS as a first-line diagnostic test. To address this, the Medical Genome Initiative conducted a literature review to identify appropriate clinical indications for GS. Studies published from January 2011 to August 2022 that reported on the diagnostic yield (DY) or clinical utility of GS were included. An exploratory meta-analysis using a random effects model evaluated DY based on cohort size and diagnosed cases per cohort. Seventy-one studies met inclusion criteria, comprising over 13,000 …

Comparative Genomics Incorporating Translocation Renal Cell Carcinoma Mouse Model Reveals Molecular Mechanisms Of Tumorigenesis, Gopinath Prakasam, Akhilesh Mishra, Alana Christie, Jeffrey Miyata, Deyssy Carrillo, Vanina T Tcheuyap, Hui Ye, Quyen N Do, Yunguan Wang, Oscar Reig Torras, Ramesh Butti, Hua Zhong, Jeffrey Gagan, Kevin B Jones, Thomas J Carroll, Zora Modrusan, Steffen Durinck, Mai-Carmen Requena-Komuro, Noelle S Williams, Ivan Pedrosa, Tao Wang, Dinesh Rakheja, Payal Kapur, James Brugarolas

Faculty, Staff and Student Publications

Translocation renal cell carcinoma (tRCC) most commonly involves an ASPSCR1-TFE3 fusion, but molecular mechanisms remain elusive and animal models are lacking. Here, we show that human ASPSCR1-TFE3 driven by Pax8-Cre (a credentialed clear cell RCC driver) disrupted nephrogenesis and glomerular development, causing neonatal death, while the clear cell RCC failed driver, Sglt2-Cre, induced aggressive tRCC (as well as alveolar soft part sarcoma) with complete penetrance and short latency. However, in both contexts, ASPSCR1-TFE3 led to characteristic morphological cellular changes, loss of epithelial markers, and an epithelial-mesenchymal transition. Electron microscopy of tRCC tumors showed lysosome expansion, and functional studies revealed simultaneous …

Deep Phenotyping Of Post-Infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Brian Walitt, Komudi Singh, Samuel R. Lamunion, Mark Hallett, Steve Jacobson, Kong Chen, Yoshimi Enose-Akahata, Richard Apps, Jennifer J. Barb, Patrick Bedard, Robert J. Brychta, Ashura Williams Buckley, Peter D. Burbelo, Brice Calco, Brianna Cathay, Li Chen, Snigdha Chigurupati, Jinguo Chen, Foo Cheung, Lisa M.K. Chin, Benjamin W. Coleman, Amber B. Courville, Madeleine S. Deming, Bart Drinkard, Li Rebekah Feng, Luigi Ferrucci, Scott A. Gabel, Angelique Gavin, David S. Goldstein, Shahin Hassanzadeh, Sean C. Horan, Silvina G. Horovitz, Kory R. Johnson, Anita Jones Govan, Kristine M. Knutson, Joy D. Kreskow, Mark Levin, Jonathan J. Lyons, Nicholas Madian, Nasir Malik, Andrew L. Mammen, John A. Mcculloch, Patrick M. Mcgurrin, Joshua D. Milner, Ruin Moaddel, Geoffrey A. Mueller, Amrita Mukherjee, Sandra Muñoz-Braceras, Gina Norato, Katherine Pak, Iago Pinal-Fernandez, Traian Popa, Lauren B. Reoma, Michael N. Sack, Farinaz Safavi, Leorey N. Saligan, Brian A. Sellers, Stephen Sinclair, Bryan Smith, Joseph Snow, Stacey Solin, Barbara J. Stussman, Giorgio Trinchieri, Sara A. Turner, C. Stephenie Vetter, Felipe Vial, Carlotta Vizioli, Ashley Williams, Shanna B. Yang, Avindra Nath

Student Papers, Posters & Projects

Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping. Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning. Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease …

Progestin-Associated Meningiomatosis With Unusual Schwannoma-Like Morphology, Katherine A Krause, Jared K Woods, Alexandra J Golby, Eudocia Q Lee, Shyam Tanguturi, Zachary Spigelman, Azra H Ligon, Umberto De Girolami, Matthew Torre

Duncan NRI Faculty and Staff Publications

No abstract provided.

Bioinformatics Characterization Of Variants Of Uncertain Significance In Pediatric Sensorineural Hearing Loss, Sloane Clay, Adele Evans, Regina Zambrano, David Otohinoyi, Chindo Hicks, Fern Tsien

School of Medicine Faculty Publications

Introduction: Rapid advancements in Next Generation Sequencing (NGS) and bioinformatics tools have allowed physicians to obtain genetic testing results in a more rapid, cost-effective, and comprehensive manner than ever before. Around 50% of pediatric sensorineural hearing loss (SNHL) cases are due to a genetic etiology, thus physicians regularly utilize targeted sequencing panels that identify variants in genes related to SNHL. These panels allow for early detection of pathogenic variants which allows physicians to provide anticipatory guidance to families. Molecular testing does not always reveal a clear etiology due to the presence of multigenic variants with varying classifications, including the presence …

Orbital And Periocular Complications In Patients With Sinonasal Tumours With Orbital Invasion, Jiawei Zhao, Xinyang Jiang, Ehab Hanna, Shirley Y Su, Amy Moreno, Brandon Gunn, Steven Jay Frank, Renata Ferrarotto, Jing Ning, Bita Esmaeli

Faculty, Staff and Student Publications

Aims: The purpose of this study was to determine the frequency and associated risk factors of orbital/periocular complications in patients with sinonasal tumour with orbital invasion managed with eye-sparing treatments.

Methods: A retrospective case series of patients with primary sinonasal tumour with orbital invasion from January 2008 to December 2018. Patient factors were compared between the following groups: (1)patients with orbital/periocular complications versus those who did not and (2) patients who needed secondary oculoplastic surgical procedures versus those who did not.

Results: Out of 80 patients, 48 had eye-sparing surgery, 8 had orbital exenteration and 24 were managed non-surgically. The …

Impact Of Immunopathy And Coagulopathy On Multi-Organ Failure And Mortality In A Lethal Porcine Model Of Controlled And Uncontrolled Hemorrhage, Milomir O Simovic, James Bynum, Bin Liu, Jurandir J Dalle Lucca, Yansong Li

Faculty, Staff and Student Publications

Uncontrolled hemorrhage is a major preventable cause of death in patients with trauma. However, the majority of large animal models of hemorrhage have utilized controlled hemorrhage rather than uncontrolled hemorrhage to investigate the impact of immunopathy and coagulopathy on multi-organ failure (MOF) and mortality. This study evaluates these alterations in a severe porcine controlled and uncontrolled hemorrhagic shock (HS) model. Anesthetized female swine underwent controlled hemorrhage and uncontrolled hemorrhage by partial splenic resection followed with or without lactated Ringer solution (LR) or Voluven® resuscitation. Swine were surveyed 6 h after completion of splenic hemorrhage or until death. Blood chemistry, physiologic …

Multivalent Cytomegalovirus Glycoprotein B Nucleoside Modified Mrna Vaccines Did Not Demonstrate A Greater Antibody Breadth, Hsuan-Yuan Wang, Leike Li, Cody S Nelson, Richard Barfield, Sarah Valencia, Cliburn Chan, Hiromi Muramatsu, Paulo J C Lin, Norbert Pardi, Zhiqiang An, Drew Weissman, Sallie R Permar

Faculty, Staff and Student Publications

Human cytomegalovirus (HCMV) remains the most common congenital infection and infectious complication in immunocompromised patients. The most successful HCMV vaccine to date, an HCMV glycoprotein B (gB) subunit vaccine adjuvanted with MF59, achieved 50% efficacy against primary HCMV infection. A previous study demonstrated that gB/MF59 vaccinees were less frequently infected with HCMV gB genotype strains most similar to the vaccine strain than strains encoding genetically distinct gB genotypes, suggesting strain-specific immunity accounted for the limited efficacy. To determine whether vaccination with multiple HCMV gB genotypes could increase the breadth of anti-HCMV gB humoral and cellular responses, we immunized 18 female …

An Extended Bayesian Semi-Mechanistic Dose-Finding Design For Phase I Oncology Trials Using Pharmacokinetic And Pharmacodynamic Information, Chao Yang, Yisheng Li

Faculty, Staff and Student Publications

We propose a model-based, semi-mechanistic dose-finding (SDF) design for phase I oncology trials that incorporates pharmacokinetic/pharmacodynamic (PK/PD) information when modeling the dose-toxicity relationship. This design is motivated by a phase Ib/II clinical trial of anti-CD20/CD3 T cell therapy in non-Hodgkin lymphoma patients; it extends a recently proposed SDF model framework by incorporating measurements of a PD biomarker relevant to the primary dose-limiting toxicity (DLT). We propose joint Bayesian modeling of the PK, PD, and DLT outcomes. Our extensive simulation studies show that on average the proposed design outperforms some common phase I trial designs, including modified toxicity probability interval (mTPI) …

Circulating Microrna Biomarkers Of Thiazide Response In Hypertension, Lakshmi Manasa S Chekka, Marwa Tantawy, Taimour Langaee, Danxin Wang, Rolf Renne, Arlene B Chapman, John G Gums, Eric Boerwinkle, Rhonda M Cooper-Dehoff, Julie A Johnson

Faculty, Staff and Student Publications

Background: Thiazide diuretics are the second most frequently prescribed class of antihypertensives, but up to 50% of patients with hypertension have minimal antihypertensive response to thiazides. We explored circulating microRNAs (miRNAs) in search of predictive biomarkers of thiazide response.

Methods and results: We profiled 754 miRNAs in baseline plasma samples of 36 hypertensive European American adults treated with hydrochlorothiazide, categorized into responders (n=18) and nonresponders (n=18) on the basis of diastolic blood pressure response to hydrochlorothiazide. miRNAs with ≥2.5-fold differential expression between responders and nonresponders were considered for validation in 3 cohorts (n=50 each): hydrochlorothiazide-treated European Americans, chlorthalidone-treated European Americans, …

Correction: Neural Correlates Of Automatic Emotion Regulation And Their Association With Suicidal Ideation In Adolescents During The First 90-Days Of Residential Care, Matthew Dobbertin, Karina S Blair, Joseph Aloi, Sahil Bajaj, Johannah Bashford-Largo, Avantika Mathur, Ru Zhang, Erin Carollo, Amanda Schwartz, Jaimie Elowsky, J L Ringle, Patrick Tyler, R James Blair

Faculty, Staff and Student Publications

No abstract provided.

Cpsf3 Inhibition Blocks Pancreatic Cancer Cell Proliferation Through Disruption Of Core Histone Mrna Processing, Abdulrahman A Alahmari, Aditi H Chaubey, Venkata S Jonnakuti, Arwen A Tisdale, Carla D Schwarz, Abigail C Cornwell, Kathryn E Maraszek, Emily J Paterson, Minsuh Kim, Swati Venkat, Eduardo Cortes Gomez, Jianmin Wang, Katerina V Gurova, Hari Krishna Yalamanchili, Michael E Feigin

Duncan NRI Faculty and Staff Publications

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target cleavage and polyadenylation specificity factor 3 (CPSF3), the 3′ endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that CPSF3 is highly expressed in PDAC and is associated with poor prognosis. CPSF3 knockdown blocks PDAC cell proliferation and colony formation in vitro and tumor growth in vivo. Chemical inhibition of CPSF3 by the small molecule JTE-607 also attenuates PDAC cell proliferation and colony formation, while it has no effect on cell proliferation …