Medical Specialties Commons^™

Analysis Of Performance And Failure Modes Of The Iroc Proton Liver Phantom, Hunter Mehrens, Paige Taylor, Paola Alvarez, Stephen Kry

Faculty, Staff and Student Publications

Purpose: To analyze trends in institutional performance and failure modes for the Imaging and Radiation Oncology Core’s (IROC’s) proton liver phantom.

Materials and Methods: Results of 66 phantom irradiations from 28 institutions between 2015 and 2020 were retrospectively analyzed. Univariate analysis and random forest models were used to associate irradiation conditions with phantom results. Phantom results included pass/fail classification, average thermoluminescent dosimeter (TLD) ratio of both targets, and percentage of pixels passing gamma of both targets. The following categories were evaluated in terms of how they predicted these outcomes: irradiation year, treatment planning system (TPS), TPS algorithm, treatment machine, number …

Notes From The Field: Multipathogen Respiratory Virus Testing Among Primary And Secondary School Students And Staff Members In A Large Metropolitan School District - Missouri, November 2, 2022-April 19, 2023., Jennifer Goldman, Brian R. Lee, Janelle Porter, Anila Deliu, Shannon Tilsworth, Olivia M. Almendares, Sadia Sleweon, Hannah L. Kirking, Rangaraj Selvarangan, Jennifer E. Schuster

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.

Resistance To Human Immunodeficiency Virus 1 Infection Conferred By A Compound Ccr5Δ32 And Ccr5 C20s Heterozygote, Bashar Alkhatib, Mary Jabari, Shymaa Bilasy, Husni Abdul-Rahman, Kamal Sandhu, Stephen Lai, Ghalib Alkhatib

Faculty, Staff and Student Publications

We analyzed findings in a same-gender couple discordant in their human immunodeficiency virus (HIV) status. The HIV+ partner was homozygous for CCR5 while his receptive HIV- partner was a CCR5Δ32 heterozygote with a C20S missense mutation in his CCR5 allele. The cells from the HIV- partner showed significant resistance to R5 fusion/infection and had no chemotactic response to CCL4 (macrophage inflammatory protein 1β). We demonstrated abundant CCR5-specific RNA in the HIV- partner's cells but no detectable CCR5 protein. CCR5 promoter region cloned from each partner's DNA indicated no significant impact on RNA transcription. The compound effect of CCR5Δ32 and C20S …

Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven By Different P53 Mutants, Dhruv Chachad, Lalit R Patel, Carlos Vera Recio, Rasoul Pourebrahim, Elizabeth M Whitley, Wenyi Wang, Xiaoping Su, An Xu, Dung-Fang Lee, Guillermina Lozano

Faculty, Staff and Student Publications

Missense mutations in the DNA binding domain of p53 are characterized as structural or contact mutations based on their effect on the conformation of the protein. These mutations show gain-of-function (GOF) activities, such as promoting increased metastatic incidence compared with p53 loss, often mediated by the interaction of mutant p53 with a set of transcription factors. These interactions are largely context specific. To understand the mechanisms by which p53 DNA binding domain mutations drive osteosarcoma progression, we created mouse models, in which either the p53 structural mutant p53R172H or the contact mutant p53R245W are expressed specifically in osteoblasts, yielding osteosarcoma …

Bicc1 Drives Pancreatic Cancer Progression By Inducing Vegf-Independent Angiogenesis, Chongbiao Huang, Hui Li, Yang Xu, Chao Xu, Huizhi Sun, Zengxun Li, Yi Ge, Hongwei Wang, Tiansuo Zhao, Song Gao, Xiuchao Wang, Shengyu Yang, Peiqing Sun, Zhe Liu, Jing Liu, Antao Chang, Jihui Hao

Faculty, Staff and Student Publications

VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors. Nevertheless, pancreatic adenocarcinoma (PAAD) cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways, thereby conferring resistance to VEGF inhibitors. Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD. The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth, and worse prognosis. In cells and mice with xenograft tumors, BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent …

Molecular Dissection And Testing Of Prss37 Function Through Lc-Ms/Ms And The Generation Of A Prss37 Humanized Mouse Model, Courtney Sutton, Kaori Nozawa, Katarzyna Kent, Alexander Saltzman, Mei Leng, Sureshbabu Nagarajan, Anna Malovannaya, Masahito Ikawa, Thomas X Garcia, Martin M Matzuk

Faculty, Staff and Students Publications

The quest for a non-hormonal male contraceptive pill for men still exists. Serine protease 37 (PRSS37) is a sperm-specific protein that when ablated in mice renders them sterile. In this study we sought to examine the molecular sequelae of PRSS37 loss to better understand its molecular function, and to determine whether human PRSS37 could rescue the sterility phenotype of knockout (KO) mice, allowing for a more appropriate model for drug molecule testing. To this end, we used CRISPR-EZ to create mice lacking the entire coding region of Prss37, used pronuclear injection to create transgenic mice expressing human PRSS37, intercrossed these …

Relative Burden Of Cancer And Noncancer Mortality Among Long-Term Survivors Of Breast, Prostate, And Colorectal Cancer In The Us, Madhav Kc, Jane Fan, Terry Hyslop, Sirad Hassan, Michael Cecchini, Shi-Yi Wang, Andrea Silber, Michael S. Leapman, Ira Leeds, Stephanie B. Wheeler, Lisa P. Spees, Cary P. Gross, Maryam Lustberg, Rachel A. Greenup, Amy C. Justice, Kevin C. Oeffinger, Michaela A. Dinan

Kimmel Cancer Center Faculty Papers

IMPORTANCE: Improvements in cancer outcomes have led to a need to better understand long-term oncologic and nononcologic outcomes and quantify cancer-specific vs noncancer-specific mortality risks among long-term survivors.

OBJECTIVE: To assess absolute and relative cancer-specific vs noncancer-specific mortality rates among long-term survivors of cancer, as well as associated risk factors.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study included 627 702 patients in the Surveillance, Epidemiology, and End Results cancer registry with breast, prostate, or colorectal cancer who received a diagnosis between January 1, 2003, and December 31, 2014, who received definitive treatment for localized disease and who were alive 5 …

Mettl3-Mediated M6a Modification Of Linc00839 Maintains Glioma Stem Cells And Radiation Resistance By Activating Wnt/Β-Catenin Signaling, Jianxing Yin, Fangshu Ding, Zhangchun Cheng, Xin Ge, Yanhui Li, Ailiang Zeng, Junxia Zhang, Wei Yan, Zhumei Shi, Xu Qian, Yongping You, Zhiliang Ding, Jing Ji, Xiefeng Wang

Faculty, Staff and Student Publications

Long noncoding RNAs (lncRNAs) are involved in glioma initiation and progression. Glioma stem cells (GSCs) are essential for tumor initiation, maintenance, and therapeutic resistance. However, the biological functions and underlying mechanisms of lncRNAs in GSCs remain poorly understood. Here, we identified that LINC00839 was overexpressed in GSCs. A high level of LINC00839 was associated with GBM progression and radiation resistance. METTL3-mediated m6A modification on LINC00839 enhanced its expression in a YTHDF2-dependent manner. Mechanistically, LINC00839 functioned as a scaffold promoting c-Src-mediated phosphorylation of β-catenin, thereby inducing Wnt/β-catenin activation. Combinational use of celecoxib, an inhibitor of Wnt/β-catenin signaling, greatly sensitized GSCs to …

A Global Study For Acute Myeloid Leukemia With Rarg Rearrangement, Hong-Hu Zhu, Ya-Zhen Qin, Zhang-Lin Zhang, Yong-Jing Liu, Li-Jun Wen, M James You, Cheng Zhang, Esperanza Such, Hong Luo, Hong-Jian Yuan, Hong-Sheng Zhou, Hong-Xing Liu, Reng Xu, Ji Li, Jian-Hu Li, Jian-Ping Hao, Jie Jin, Liang Yu, Jing-Ying Zhang, Li-Ping Liu, Le-Ping Zhang, Rui-Bin Huang, Shu-Hong Shen, Su-Jun Gao, Wei Wang, Xiao-Jing Yan, Xin-You Zhang, Xin Du, Xiao-Xia Chu, Yan-Fang Yu, Yi Wang, Ying-Chang Mi, Ying Lu, Zhen Cai, Zhan Su, David Christopher Taussig, Suzanne Macmahon, Edward D Ball, Huan-You Wang, John S Welch, C Cameron Yin, Gautam Borthakur, Miguel A Sanz, Hagop M Kantarjian, Jin-Yan Huang, Jiong Hu, Su-Ning Chen

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) with retinoic acid receptor γ (RARG) rearrangement has clinical, morphologic, and immunophenotypic features similar to classic acute promyelocytic leukemia. However, AML with RARG rearrangement is insensitive to alltrans retinoic acid (ATRA) and arsenic trioxide (ATO) and carries a poor prognosis. We initiated a global cooperative study to define the clinicopathological features, genomic and transcriptomic landscape, and outcomes of AML with RARG rearrangements collected from 29 study groups/institutions worldwide. Thirty-four patients with AML with RARG rearrangements were identified. Bleeding or ecchymosis was present in 18 (54.5%) patients. Morphology diagnosed as M3 and M3v accounted for 73.5% and …

When A Calorie Is Not Just A Calorie: Diet Quality And Timing As Mediators Of Metabolism And Healthy Aging, Maria M Mihaylova, Amandine Chaix, Mirela Delibegovic, Jon J Ramsey, Joseph Bass, Girish Melkani, Rajat Singh, Zheng Chen, William W Ja, Michele Shirasu-Hiza, Mary N Latimer, Julie A Mattison, Anna E Thalacker-Mercer, Vishwa Deep Dixit, Satchidananda Panda, Dudley W Lamming

Faculty, Staff and Student Publications

An epidemic of obesity has affected large portions of the world, increasing the risk of developing many different age-associated diseases, including cancer, cardiovascular disease, and diabetes. In contrast with the prevailing notion that "a calorie is just a calorie," there are clear differences, within and between individuals, in the metabolic response to different macronutrient sources. Recent findings challenge this oversimplification; calories from different macronutrient sources or consumed at different times of day have metabolic effects beyond their value as fuel. Here, we summarize discussions conducted at a recent NIH workshop that brought together experts in calorie restriction, macronutrient composition, and …

Emt Activates Exocytotic Rabs To Coordinate Invasion And Immunosuppression In Lung Cancer, Guan-Yu Xiao, Xiaochao Tan, Bertha L Rodriguez, Don L Gibbons, Shike Wang, Chao Wu, Xin Liu, Jiang Yu, Mayra E Vasquez, Hai T Tran, Jun Xu, William K Russell, Cara Haymaker, Younghee Lee, Jianjun Zhang, Luisa Solis, Ignacio I Wistuba, Jonathan M Kurie

Faculty, Staff and Student Publications

Epithelial-to-mesenchymal transition (EMT) underlies immunosuppression, drug resistance, and metastasis in epithelial malignancies. However, the way in which EMT orchestrates disparate biological processes remains unclear. Here, we identify an EMT-activated vesicular trafficking network that coordinates promigratory focal adhesion dynamics with an immunosuppressive secretory program in lung adenocarcinoma (LUAD). The EMT-activating transcription factor ZEB1 drives exocytotic vesicular trafficking by relieving Rab6A, Rab8A, and guanine nucleotide exchange factors from miR-148a-dependent silencing, thereby facilitating MMP14-dependent focal adhesion turnover in LUAD cells and autotaxin-mediated CD8

Undetectable Measurable Residual Disease Is Associated With Improved Outcomes In Aml Irrespective Of Treatment Intensity, Alexandre Bazinet, Tapan Kadia, Nicholas J Short, Gautam Borthakur, Sa A Wang, Wei Wang, Sanam Loghavi, Jeffrey Jorgensen, Keyur Patel, Courtney Dinardo, Naval Daver, Yesid Alvarado, Fadi G Haddad, Sherry Pierce, Graciela Nogueras Gonzalez, Abhishek Maiti, Koji Sasaki, Musa Yilmaz, Philip Thompson, William Wierda, Guillermo Garcia-Manero, Michael Andreeff, Elias Jabbour, Marina Konopleva, Xuelin Huang, Hagop Kantarjian, Farhad Ravandi

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) can be treated with either high- or low-intensity regimens. Highly sensitive assays for measurable residual disease (MRD) now allow for a more precise assessment of response quality. We hypothesized that treatment (Rx) intensity may not be a key predictor of outcomes, assuming that an optimal response to therapy is achieved. We performed a single-center retrospective study including 635 patients with newly diagnosed AML responding to either intensive cytarabine/anthracycline-based chemotherapy (IA; n = 385) or low-intensity venetoclax-based regimens (LOW + VEN; n = 250) and who had adequate flow cytometry-based MRD testing performed at the time of …

Brentuximab Vedotin After Autologous Transplantation In Pediatric Patients With Relapsed/Refractory Hodgkin Lymphoma, Christopher J Forlenza, Jaclyn Rosenzweig, Audrey Mauguen, Ilia Buhtoiarov, Branko Cuglievan, Hema Dave, Rebecca J Deyell, Jamie E Flerlage, Anna K Franklin, Jennifer Krajewski, Kasey J Leger, Lianna J Marks, Robin E Norris, Martha Pacheco, Faye Willen, Adam Paul Yan, Paul D Harker-Murray, Lisa Giulino-Roth

Faculty, Staff and Student Publications

Outcomes for children and adolescents with relapsed and refractory Hodgkin lymphoma (HL) are poor, with ∼50% of patients experiencing a subsequent relapse. The anti-CD30 antibody-drug conjugate brentuximab vedotin improved progression-free survival (PFS) when used as consolidation after autologous stem cell transplantation (ASCT) in adults with high-risk relapsed/refractory HL. Data on brentuximab vedotin as consolidative therapy after ASCT in pediatric patients with HL are extremely limited, with data of only 11 patients reported in the literature. We performed a retrospective analysis of 67 pediatric patients who received brentuximab vedotin as consolidation therapy after ASCT for the treatment of relapsed/refractory HL to …

High Throughput Single Cell Long-Read Sequencing Analyses Of Same-Cell Genotypes And Phenotypes In Human Tumors, Cheng-Kai Shiau, Lina Lu, Rachel Kieser, Kazutaka Fukumura, Timothy Pan, Hsiao-Yun Lin, Jie Yang, Eric L Tong, Gahyun Lee, Yuanqing Yan, Jason T Huse, Ruli Gao

Faculty, Staff and Student Publications

Single-cell nanopore sequencing of full-length mRNAs transforms single-cell multi-omics studies. However, challenges include high sequencing errors and dependence on short-reads and/or barcode whitelists. To address these, we develop scNanoGPS to calculate same-cell genotypes (mutations) and phenotypes (gene/isoform expressions) without short-read nor whitelist guidance. We apply scNanoGPS onto 23,587 long-read transcriptomes from 4 tumors and 2 cell-lines. Standalone, scNanoGPS deconvolutes error-prone long-reads into single-cells and single-molecules, and simultaneously accesses both phenotypes and genotypes of individual cells. Our analyses reveal that tumor and stroma/immune cells express distinct combination of isoforms (DCIs). In a kidney tumor, we identify 924 DCI genes involved in …

Randomized, Double-Blinded, Placebo-Controlled Trial Of Allogeneic Cord Blood T-Regulatory Cells For Treatment Of Covid-19 Ards, Douglas E Gladstone, Franco D'Alessio, Christopher Howard, Mi-Ae Lyu, Jason R Mock, Kevin W Gibbs, Darryl Abrams, Meixian Huang, Ke Zeng, James P Herlihy, Sergio T Castillo, Roland Bassett, Tara Sadeghi, Simrit Parmar, Christopher R Flowers, Siddhartha Mukherjee, David Schoenfeld, Peter F Thall, Arthur S Slutsky

Faculty, Staff and Students Publications

No abstract provided.

Developing A National-Scale Exposure Index For Combined Environmental Hazards And Social Stressors And Applications To The Environmental Influences On Child Health Outcomes (Echo) Cohort., Sheena E. Martenies, Mingyu Zhang, Anne E. Corrigan, Anton Kvit, Timothy Shields, William Wheaton, Deana Around Him, Judy Aschner, Maria M. Talavera-Barber, Emily S. Barrett, Theresa M. Bastain, Casper Bendixsen, Carrie V. Breton, Nicole R. Bush, Ferdinand Cacho, Carlos A. Camargo, Kecia N. Carroll, Brian S. Carter, Andrea E. Cassidy-Bushrow, Whitney Cowell, Lisa A. Croen, Dana Dabelea, Cristiane S. Duarte, Anne L. Dunlop, Todd M. Everson, Rima Habre, Tina V. Hartert, Jennifer B. Helderman, Alison E. Hipwell, Margaret R. Karagas, Barry M. Lester, Kaja Z. Lewinn, Sheryl Magzamen, Rachel Morello-Frosch, Thomas G. O'Connor, Amy M. Padula, Michael Petriello, Sheela Sathyanarayana, Joseph B. Stanford, Tracey J. Woodruff, Rosalind J. Wright, Amii M. Kress, Program Collaborators For Environmental Influences On Child Health Outcomes

Manuscripts, Articles, Book Chapters and Other Papers

Tools for assessing multiple exposures across several domains (e.g., physical, chemical, and social) are of growing importance in social and environmental epidemiology because of their value in uncovering disparities and their impact on health outcomes. Here we describe work done within the Environmental influences on Child Health Outcomes (ECHO)-wide Cohort Study to build a combined exposure index. Our index considered both environmental hazards and social stressors simultaneously with national coverage for a 10-year period. Our goal was to build this index and demonstrate its utility for assessing differences in exposure for pregnancies enrolled in the ECHO-wide Cohort Study. Our unitless …

Propensity Score Analysis With Local Balance, Yan Li, Liang Li

Faculty, Staff and Student Publications

Most propensity score (PS) analysis methods rely on a correctly specified parametric PS model, which may result in biased estimation of the average treatment effect (ATE) when the model is misspecified. More flexible nonparametric models for treatment assignment alleviate this issue, but they do not always guarantee covariate balance. Methods that force balance in the means of covariates and their transformations between the treatment groups, termed global balance in this article, do not always lead to unbiased estimation of ATE. Their estimated propensity scores only ensure global balance but not the balancing property, which is defined as the conditional independence …

Accumulation Of Chronic Disease Among Survivors Of Childhood Cancer Predicts Early Mortality, Adam J Esbenshade, Lu Lu, Debra L Friedman, Kevin C Oeffinger, Gregory T Armstrong, Kevin R Krull, Joseph P Neglia, Wendy M Leisenring, Rebecca Howell, Robyn Partin, Amy Sketch, Leslie L Robison, Kirsten K Ness

Faculty, Staff and Student Publications

Purpose: Cancer survivors develop cancer and treatment-related morbidities at younger than normal ages and are at risk for early mortality, suggestive of an aging phenotype. The Cumulative Illness Rating Scale for Geriatrics (CIRS-G) is specifically designed to describe the accumulation of comorbidities over time with estimates of severity such as total score (TS) which is a sum of possible conditions weighted by severity. These severity scores can then be used to predict future mortality.

Methods: CIRS-G scores were calculated in cancer survivors and their siblings from Childhood Cancer Survivor Study cohort members from two time points 19 years apart and …

Effect Of Reduced Versus Usual Lipid Emulsion Dosing On Bilirubin Neurotoxicity And Neurodevelopmental Impairment In Extremely Preterm Infants: Study Protocol For A Randomized Controlled Trial, Lindsay F Holzapfel, Cody Arnold, Jon E Tyson, Steven M Shapiro, Eric W Reynolds, Claudia Pedroza, Emily K Stephens, Alan Kleinfeld, Andrew H Huber, Matthew A Rysavy, Maria Del Mar Romero Lopez, Amir M Khan

Faculty, Staff and Student Publications

BACKGROUND: Bilirubin neurotoxicity (BN) occurs in premature infants at lower total serum bilirubin levels than term infants and causes neurodevelopmental impairment. Usual dose lipid infusions in preterm infants may increase free fatty acids sufficiently to cause bilirubin displacement from albumin, increasing passage of unbound bilirubin (UB) into the brain leading to BN and neurodevelopmental impairment not reliably identifiable in infancy. These risks may be influenced by whether cycled or continuous phototherapy is used to control bilirubin levels.

OBJECTIVE: To assess differences in wave V latency measured by brainstem auditory evoked responses (BAER) at 34-36 weeks gestational age in infants born …

Myc Regulates Csf1 Expression Via Microrna 17/20a To Modulate Tumor-Associated Macrophages In Osteosarcoma, Bikesh K Nirala, Tajhal D Patel, Lyazat Kurenbekova, Ryan Shuck, Atreyi Dasgupta, Nino Rainusso, Cristian Coarfa, Jason T Yustein

Faculty, Staff and Students Publications

Osteosarcoma (OS) is the most common primary bone tumor of childhood. Approximately 20%-30% of OSs carry amplification of chromosome 8q24, which harbors the oncogene c-MYC and correlates with a poor prognosis. To understand the mechanisms that underlie the ability of MYC to alter both the tumor and its surrounding tumor microenvironment (TME), we generated and molecularly characterized an osteoblast-specific Cre-Lox-Stop-Lox-c-MycT58A p53fl/+ knockin genetically engineered mouse model (GEMM). Phenotypically, the Myc-knockin GEMM had rapid tumor development with a high incidence of metastasis. MYC-dependent gene signatures in our murine model demonstrated significant homology to the human hyperactivated MYC OS. We established that …

Roving Methyltransferases Generate A Mosaic Epigenetic Landscape And Influence Evolution In Bacteroides Fragilis Group, Michael J Tisza, Derek D N Smith, Andrew E Clark, Jung-Ho Youn, Pavel P Khil, John P Dekker

Faculty, Staff and Students Publications

Three types of DNA methyl modifications have been detected in bacterial genomes, and mechanistic studies have demonstrated roles for DNA methylation in physiological functions ranging from phage defense to transcriptional control of virulence and host-pathogen interactions. Despite the ubiquity of methyltransferases and the immense variety of possible methylation patterns, epigenomic diversity remains unexplored for most bacterial species. Members of the Bacteroides fragilis group (BFG) reside in the human gastrointestinal tract as key players in symbiotic communities but also can establish anaerobic infections that are increasingly multi-drug resistant. In this work, we utilize long-read sequencing technologies to perform pangenomic (n = …

The Neutralization Of The Eosinophil Peroxidase Antibody Accelerates Eosinophilic Mucin Decomposition, Panagiotis Doukas, Jan Paul Frese, Thorsten Eierhoff, Gabriel Hellfritsch, Ben Raude, Michael J Jacobs, Andreas Greiner, Alexander Oberhuber, Alexander Gombert

Faculty, Staff and Student Publications

Acute kidney injury (AKI) is a common complication after complex aortic procedures and it is associated with relevant mortality and morbidity. Biomarkers for early and specific AKI detection are lacking. The aim of this work is to investigate the reliability of the NephroCheck bedside system for diagnosing stage 3 AKI following open aortic surgery. In this prospective, multicenter, observational study,- https://clinicaltrials.gov/ct2/show/NCT04087161 -we included 45 patients undergoing open thoracoabdominal aortic repair. AKI risk (AKIRisk-Index) was calculated from urine samples at 5 timepoints: baseline, immediately postoperatively and at 12, 24, 48, and 72 h post-surgery. AKIs were classified according to the KDIGO …

Self-Administered Intranasal Etripamil Using A Symptom-Prompted, Repeat-Dose Regimen For Atrioventricular-Nodal-Dependent Supraventricular Tachycardia (Rapid): A Multicentre, Randomised Trial, Bruce S Stambler, A John Camm, Marco Alings, Paul Dorian, Hein Heidbuchel, Jaco Houtgraaf, Peter R. Kowey, Jose L Merino, Blandine Mondésert, Jonathan P Piccini, Sean D Pokorney, Philip T Sager, Atul Verma, J Marcus Wharton, David B Bharucha, Francis Plat, Silvia Shardonofsky, Michael Chen, James E Ip

Department of Medicine Faculty Papers

BACKGROUND: Etripamil is a fast-acting, intranasally administered calcium-channel blocker in development for on-demand therapy outside a health-care setting for paroxysmal supraventricular tachycardia. We aimed to evaluate the efficacy and safety of etripamil 70 mg nasal spray using a symptom-prompted, repeat-dose regimen for acute conversion of atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia to sinus rhythm within 30 min.

METHODS: RAPID was a multicentre, randomised, placebo-controlled, event-driven trial, conducted at 160 sites in North America and Europe as part 2 of the NODE-301 study. Eligible patients were aged at least 18 years and had a history of paroxysmal supraventricular tachycardia with sustained, symptomatic episodes …

Overactive Bladder Syndrome Symptoms In Youth With Abdominal Pain-Associated Disorders Of Gut-Brain Interaction., Hunter J. Friesen, Pierce Thompson, Jennifer Verrill Schurman, Jennifer Colombo, Craig A. Friesen

Manuscripts, Articles, Book Chapters and Other Papers

The purpose of the current study was to assess the frequency of overactive bladder syndrome (OBS) symptoms and their relationship to gastrointestinal symptoms in youth with abdominal pain-associated disorders of gut-brain interaction (AP-DGBI). This is a retrospective study of 226 youth diagnosed with an AP-DGBI. As part of standard care, all patients completed a symptom questionnaire regarding gastrointestinal and non-gastrointestinal symptoms including increased urinary frequency, nighttime urination, and urinary urgency. Overall, 54% of patients reported at least one OBS symptom. Increased frequency of urination was reported by 19%, urinary urgency by 34%, and nighttime urination by 36%. Increased frequency of …

A Phase 1/2 Study Of Azacitidine, Venetoclax And Pevonedistat In Newly Diagnosed Secondary Aml And In Mds Or Cmmlafter Failure Of Hypomethylating Agents, Nicholas J Short, Muharrem Muftuoglu, Faustine Ong, Lewis Nasr, Walid Macaron, Guillermo Montalban-Bravo, Yesid Alvarado, Mahesh Basyal, Naval Daver, Courtney D Dinardo, Gautam Borthakur, Nitin Jain, Maro Ohanian, Elias Jabbour, Ghayas C Issa, Wei Qiao, Xuelin Huang, Rashmi Kanagal-Shamanna, Keyur P Patel, Prithviraj Bose, Farhad Ravandi, Ricardo Delumpa, Regina Abramova, Guillermo Garcia-Manero, Michael Andreeff, Jorge Cortes, Hagop Kantarjian

Faculty, Staff and Student Publications

BACKGROUND: Pevonedistat is a first-in-class, small molecular inhibitor of NEDD8-activating enzyme that has clinical activity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Preclinical data suggest synergy of pevonedistat with azacitidine and venetoclax.

METHODS: This single-center, phase 1/2 study evaluated the combination of azacitidine, venetoclax and pevonedistat in older adults with newly diagnosed secondary AML or with MDS or chronic myelomonocytic leukemia (CMML) after failure of hypomethylating agents. Patients received azacitidine 75 mg/m

FINDINGS: Forty patients were enrolled (32 with AML and 8 with MDS/CMML). In the AML cohort, the median age was 74 years (range 61-86 years), and …

Measuring The Effect Of Newborn Screening On Survival After Haematopoietic Cell Transplantation For Severe Combined Immunodeficiency: A 36-Year Longitudinal Study From The Primary Immune Deficiency Treatment Consortium, Monica S Thakar, Brent R Logan, Jennifer M Puck, Elizabeth A Dunn, Rebecca H Buckley, Morton J Cowan, Richard J O'Reilly, Neena Kapoor, Lisa Forbes Satter, Sung-Yun Pai, Jennifer Heimall, Sharat Chandra, Christen L Ebens, Deepak Chellapandian, Olatundun Williams, Lauri M Burroughs, Blachy Davila Saldana, Ahmad Rayes, Lisa M Madden, Shanmuganathan Chandrakasan, Jeffrey J Bednarski, Kenneth B Desantes, Geoffrey D E Cuvelier, Pierre Teira, Alfred P Gillio, Hesham Eissa, Alan P Knutsen, Frederick D Goldman, Victor M Aquino, Evan B Shereck, Theodore B Moore, Emi H Caywood, Mark T Vander Lugt, Jacob Rozmus, Larisa Broglie, Lolie C Yu, Ami J Shah, Jeffrey R Andolina, Xuerong Liu, Roberta E Parrott, Jasmeen Dara, Susan Prockop, Caridad A Martinez, Malika Kapadia, Soma C Jyonouchi, Kathleen E Sullivan, Jack J Bleesing, Sonali Chaudhury, Aleksandra Petrovic, Michael D Keller, Troy C Quigg, Suhag Parikh, Shalini Shenoy, Christine Seroogy, Tamar Rubin, Hélène Decaluwe, John M Routes, Troy R Torgerson, Jennifer W Leiding, Michael A Pulsipher, Donald B Kohn, Linda M Griffith, Elie Haddad, Christopher C Dvorak, Luigi D Notarangelo

Faculty, Staff and Students Publications

Background: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010-18.

Methods: We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982-89, 1990-99, 2000-09, and 2010-18. Categorical variables were compared by χ2 test and continuous outcomes by …

A Phase 1/2 Study Of Azacitidine, Venetoclax And Pevonedistat In Newly Diagnosed Secondary Aml And In Mds Or Cmml After Failure Of Hypomethylating Agents, Nicholas J Short, Muharrem Muftuoglu, Faustine Ong, Lewis Nasr, Walid Macaron, Guillermo Montalban-Bravo, Yesid Alvarado, Mahesh Basyal, Naval Daver, Courtney D Dinardo, Gautam Borthakur, Nitin Jain, Maro Ohanian, Elias Jabbour, Ghayas C Issa, Wei Qiao, Xuelin Huang, Rashmi Kanagal-Shamanna, Keyur P Patel, Prithviraj Bose, Farhad Ravandi, Ricardo Delumpa, Regina Abramova, Guillermo Garcia-Manero, Michael Andreeff, Jorge Cortes, Hagop Kantarjian

Faculty, Staff and Student Publications

BACKGROUND: Pevonedistat is a first-in-class, small molecular inhibitor of NEDD8-activating enzyme that has clinical activity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Preclinical data suggest synergy of pevonedistat with azacitidine and venetoclax.

METHODS: This single-center, phase 1/2 study evaluated the combination of azacitidine, venetoclax and pevonedistat in older adults with newly diagnosed secondary AML or with MDS or chronic myelomonocytic leukemia (CMML) after failure of hypomethylating agents. Patients received azacitidine 75 mg/m

FINDINGS: Forty patients were enrolled (32 with AML and 8 with MDS/CMML). In the AML cohort, the median age was 74 years (range 61-86 years), and …

Opportunistic Detection Of Type 2 Diabetes Using Deep Learning From Frontal Chest Radiographs, Ayis Pyrros, Stephen M. Borstelmann, Ramana Mantravadi, Zachary Zaiman, Kaesha Thomas, Brandon Price, Eugene Greenstein, Nasir Siddiqui, Melinda Willis, Ihar Shulhan, John Hines-Shah, Jeanne M. Horowitz, Paul Nikolaidis, Matthew P. Lungren, Jorge Mario Rodríguez-Fernández, Judy Wawira Gichoya, Sanmi Koyejo, Adam E. Flanders, Nishith Khandwala, Amit Gupta, John W. Garrett, Joseph Paul Cohen, Brian T. Layden, Perry J. Pickhardt, William Galanter

Department of Radiology Faculty Papers

Deep learning (DL) models can harness electronic health records (EHRs) to predict diseases and extract radiologic findings for diagnosis. With ambulatory chest radiographs (CXRs) frequently ordered, we investigated detecting type 2 diabetes (T2D) by combining radiographic and EHR data using a DL model. Our model, developed from 271,065 CXRs and 160,244 patients, was tested on a prospective dataset of 9,943 CXRs. Here we show the model effectively detected T2D with a ROC AUC of 0.84 and a 16% prevalence. The algorithm flagged 1,381 cases (14%) as suspicious for T2D. External validation at a distinct institution yielded a ROC AUC of …

Mitophagy Promotes Resistance To Bh3 Mimetics In Acute Myeloid Leukemia, Christina Glytsou, Xufeng Chen, Emmanouil Zacharioudakis, Wafa Al-Santli, Hua Zhou, Bettina Nadorp, Soobeom Lee, Audrey Lasry, Zhengxi Sun, Dimitrios Papaioannou, Michael Cammer, Kun Wang, Tomasz Zal, Malgorzata Anna Zal, Bing Z Carter, Jo Ishizawa, Raoul Tibes, Aristotelis Tsirigos, Michael Andreeff, Evripidis Gavathiotis, Iannis Aifantis

Faculty, Staff and Student Publications

BH3 mimetics are used as an efficient strategy to induce cell death in several blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL-2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML. Moreover, MCL1 or dual BCL-2/BCL-xL antagonists are under investigation. Yet, resistance to single or combinatorial BH3-mimetic therapies eventually ensues. Integration of multiple genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy modulators sensitizes AML cells to various BH3 mimetics targeting different BCL-2 family members. One such regulator is MFN2, whose protein levels positively correlate with drug resistance in patients with AML. MFN2 …

Using Predictive Validity To Compare Associations Between Brain Damage And Behavior, John F Magnotti, Jaclyn S Patterson, Tatiana T Schnur

Faculty, Staff and Student Publications

Lesion-behavior mapping (LBM) provides a statistical map of the association between voxel-wise brain damage and individual differences in behavior. To understand whether two behaviors are mediated by damage to distinct regions, researchers often compare LBM weight outputs by either the Overlap method or the Correlation method. However, these methods lack statistical criteria to determine whether two LBM are distinct versus the same and are disconnected from a major goal of LBMs: predicting behavior from brain damage. Without such criteria, researchers may draw conclusions from numeric differences between LBMs that are irrelevant to predicting behavior. We developed and validated a predictive …