Medical Specialties Commons^™

A Polygenic Risk Score For Alzheimer’S Disease Constructed Using Apoe-Region Variants Has Stronger Association Than Apoe Alleles With Mild Cognitive Impairment In Hispanic/Latino Adults In The Us, Tamar Sofer, Nuzulul Kurniansyah, Einat Granot-Hershkovitz, Matthew O Goodman, Wassim Tarraf, Iris Broce, Richard B Lipton, Martha Daviglus, Melissa Lamar, Sylvia Wassertheil-Smoller, Jianwen Cai, Charles S Decarli, Hector M Gonzalez, Myriam Fornage

Faculty, Staff and Student Publications

INTRODUCTION: Polygenic Risk Scores (PRSs) are summaries of genetic risk alleles for an outcome.

METHODS: We used summary statistics from five GWASs of AD to construct PRSs in 4,189 diverse Hispanics/Latinos (mean age 63 years) from the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA). We assessed the PRS associations with MCI in the combined set of people and in diverse subgroups, and when including and excluding the APOE gene region. We also assessed PRS associations with MCI in an independent dataset from the Mass General Brigham Biobank.

RESULTS: A simple sum of 5 PRSs ("PRSsum"), each constructed based on a …

Game-Based Intradialytic Non-Weight-Bearing Exercise Training On Gait Speed And Balance In Older Adults With Diabetes: A Single-Blind Randomized Controlled Trial, M G Finco, Bijan Najafi, He Zhou, Abdullah Hamad, Rania Ibrahim, Fadwa Al-Ali

Center on Aging Staff Publications

Older adults with diabetes receiving hemodialysis have impaired gait speed and balance compared to the general population, which have been associated with increased risks of falls and mortality. This study evaluated the effectiveness of a game-based intradialytic exercise training program (iExergame) on improving gait speed and balance. This was a single-blind randomized controlled trial. The intervention group (IG) received iExergame training using real-time audiovisual feedback with wearable inertial sensors. The control group (CG) received conventional training without any technology. Both trainings were intradialytic, non-weight-bearing, and used ankle range of motion. Gait and balance parameters were collected at baseline and 4-week …

One Cluster Per Condition Is Not A Valid Design In Cluster-Randomized Trials Comment On Wang Et Al The Effect Of Different Physical Exercise Programs On Physical Fitness Among Preschool Children: A Cluster-Randomized Controlled Trial Int J Environ Res Public Health 2023, 20, 4254, Yasaman Jamshidi-Naeini, Armando Pena, Abu Bakkar Siddique, Andrew W Brown, David B Allison

Children’s Nutrition Research Center Staff Publications

Wang et al. [...].

Bcl-2 Inhibition Combined With Pparα Activation Synergistically Targets Leukemic Stem Cell-Like Cells In Acute Myeloid Leukemia, Chendi Xie, Hui Zhou, Dongmei Qin, Huijian Zheng, Yuanfang Tang, Wenjuan Li, Jie Zhou, Long Liu, Xinxin Yu, Hongpeng Duan, Yong Zhou, Zhifeng Li, Zhihong Fang, Yiming Luo, Bing Z Carter, Bing Xu, Jie Zha

Faculty, Staff and Student Publications

Persistence of leukemic stem cells (LSCs) is one of the determining factors to acute myeloid leukemia (AML) treatment failure and responsible for the poor prognosis of the disease. Hence, novel therapeutic strategies that target LSCs are crucial for treatment success. We investigated if targeting Bcl-2 and peroxisome proliferator activated receptor α (PPARα), two distinct cell survival regulating mechanisms could eliminate LSCs. This study demonstrate that the Bcl-2 inhibitor venetoclax combined with the PPARα agonist chiglitazar resulted in synergistic killing of LSC-like cell lines and CD34+ primary AML cells while sparing their normal counterparts. Furthermore, the combination regimen significantly suppressed AML …

Aggregated Molecular Phenotype Scores: Enhancing Assessment And Visualization Of Mass Spectrometry Imaging Data For Tissue-Based Diagnostics, Jessie R Chappel, Mary E King, Jonathon Fleming, Livia S Eberlin, David M Reif, Erin S Baker

Faculty, Staff and Students Publications

Mass spectrometry imaging (MSI) has gained increasing popularity for tissue-based diagnostics due to its ability to identify and visualize molecular characteristics unique to different phenotypes within heterogeneous samples. Data from MSI experiments are often assessed and visualized using various supervised and unsupervised statistical approaches. However, these approaches tend to fall short in identifying and concisely visualizing subtle, phenotype-relevant molecular changes. To address these shortcomings, we developed aggregated molecular phenotype (AMP) scores. AMP scores are generated using an ensemble machine learning approach to first select features differentiating phenotypes, weight the features using logistic regression, and combine the weights and feature abundances. …

A Comprehensive Drosophila Resource To Identify Key Functional Interactions Between Sars-Cov-2 Factors And Host Proteins, Annabel Guichard, Shenzhao Lu, Oguz Kanca, Daniel Bressan, Yan Huang, Mengqi Ma, Sara Sanz Juste, Jonathan C Andrews, Kristy L Jay, Marketta Sneider, Ruth Schwartz, Mei-Chu Huang, Danqing Bei, Hongling Pan, Liwen Ma, Wen-Wen Lin, Ankush Auradkar, Pranjali Bhagwat, Soo Park, Kenneth H Wan, Takashi Ohsako, Toshiyuki Takano-Shimizu, Susan E Celniker, Michael F Wangler, Shinya Yamamoto, Hugo J Bellen, Ethan Bier

Faculty, Staff and Students Publications

Development of effective therapies against SARS-CoV-2 infections relies on mechanistic knowledge of virus-host interface. Abundant physical interactions between viral and host proteins have been identified, but few have been functionally characterized. Harnessing the power of fly genetics, we develop a comprehensive Drosophila COVID-19 resource (DCR) consisting of publicly available strains for conditional tissue-specific expression of all SARS-CoV-2 encoded proteins, UAS-human cDNA transgenic lines encoding established host-viral interacting factors, and GAL4 insertion lines disrupting fly homologs of SARS-CoV-2 human interacting proteins. We demonstrate the utility of the DCR to functionally assess SARS-CoV-2 genes and candidate human binding partners. We show that …

Examining The Latent Structure And Correlates Of Sensory Reactivity In Autism: A Multi-Site Integrative Data Analysis By The Autism Sensory Research Consortium, Zachary J. Williams, Roseann Schaaf, Karla K. Ausderau, Grace T. Baranek, D. Jonah Barrett, Carissa J. Cascio, Rachel L. Dumont, Ekomobong E. Eyoh, Michelle D. Failla, Jacob I. Feldman, Jennifer H. Foss-Feig, Heather L. Green, Shulamite A. Green, Jason L. He, Elizabeth A. Kaplan-Kahn, Bahar Keçeli-Kaysılı, Keren Maclennan, Zoe Mailloux, Elysa J. Marco, Lisa E. Mash, Elizabeth P. Mckernan, Sophie Molholm, Stewart H. Mostofsky, Nicolaas A.J. Puts, Caroline E. Robertson, Natalie Russo, Nicole Shea, John Sideris, James S. Sutcliffe, Teresa Tavassoli, Mark T. Wallace, Ericka L. Wodka, Tiffany G. Woynaroski

Department of Occupational Therapy Faculty Papers

BACKGROUND: Differences in responding to sensory stimuli, including sensory hyperreactivity (HYPER), hyporeactivity (HYPO), and sensory seeking (SEEK) have been observed in autistic individuals across sensory modalities, but few studies have examined the structure of these "supra-modal" traits in the autistic population.

METHODS: Leveraging a combined sample of 3868 autistic youth drawn from 12 distinct data sources (ages 3-18 years and representing the full range of cognitive ability), the current study used modern psychometric and meta-analytic techniques to interrogate the latent structure and correlates of caregiver-reported HYPER, HYPO, and SEEK within and across sensory modalities. Bifactor statistical indices were used to …

Impact Of Detectable Monoclonal Protein At Diagnosis On Outcomes In Marginal Zone Lymphoma: A Multicenter Cohort Study, Narendranath Epperla, Qiuhong Zhao, Reem Karmali, Pallawi Torka, Lauren Shea, Timothy S. Oh, Andrea Anampa-Guzmán, Heather Reves, Montreh Tavakkoli, Irl Brian Greenwell, Emily Hansinger, Elvira Umyarova, Kaitlin Annunzio, Yazeed Sawalha, Beth Christian, Colin Thomas, Stefan K. Barta, Praveen Ramakrishnan Geethakumari, Nancy L. Bartlett, Natalie S. Grover, Adam J Olszewski

Department of Medicine Faculty Papers

Given the paucity of data surrounding the prognostic relevance of monoclonal paraprotein (M-protein) in marginal zone lymphoma (MZL), we sought to evaluate the impact of detecting M-protein at diagnosis on outcomes in patients with MZL in a large retrospective cohort. The study included 547 patients receiving first-line therapy for MZL. M-protein was detectable at diagnosis in 173 (32%) patients. There was no significant difference in the time from diagnosis to initiation of any therapy (systemic and local) between the M-protein and no M-protein groups. Patients with M-protein at diagnosis had significantly inferior progression-free survival (PFS) compared with those without M-protein …

Flavonoids Quercetin And Kaempferol Are Nr4a1 Antagonists And Suppress Endometriosis In Female Mice, Lei Zhang, Kumaravel Mohankumar, Gregory Martin, Fuada Mariyam, Yuri Park, Sang Jun Han, Stephen Safe

Faculty, Staff and Students Publications

Nuclear receptor 4A1 (NR4A1) plays an important role in endometriosis progression; levels of NR4A1 in endometriotic lesions are higher than in normal endometrium, and substituted bis-indole analogs (NR4A1) antagonists suppress endometriosis progression in mice with endometriosis. In addition, the flavonoids kaempferol and quercetin are natural products that directly bind NR4A1 and significantly repress the intrinsic NR4A1-dependent transcriptional activity in human endometriotic epithelial and stromal cells and Ishikawa endometrial cancer cells. NR4A1 knockdown and inhibition of NR4A1 by kaempferol and quercetin suppressed proliferation of human endometriotic epithelial cells and Ishikawa cells by inhibiting epidermal growth factor receptor/c-Myc/survivin-mediated growth-promoting and survival pathways, …

Early Treatment With Vigabatrin Does Not Decrease Focal Seizures Or Improve Cognition In Tuberous Sclerosis Complex: The Prevent Trial, Elizabeth Martina Bebin, Jurriaan M Peters, Brenda E Porter, Tarrant O Mcpherson, Sarah O'Kelley, Mustafa Sahin, Katherine S Taub, Rajsekar Rajaraman, Stephanie C Randle, William M Mcclintock, Mary Kay Koenig, Mike D Frost, Hope A Northrup, Klaus Werner, Danielle A Nolan, Michael Wong, Jessica L Krefting, Fred Biasini, Kalyani Peri, Gary Cutter, Darcy A Krueger

Faculty, Staff and Student Publications

Objective: This study was undertaken to test the hypothesis that early vigabatrin treatment in tuberous sclerosis complex (TSC) infants improves neurocognitive outcome at 24 months of age.

Methods: A phase IIb multicenter randomized double-blind placebo-controlled trial was conducted of vigabatrin at first epileptiform electroencephalogram (EEG) versus vigabatrin at seizure onset in infants with TSC. Primary outcome was Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) cognitive assessment score at 24 months. Secondary outcomes were prevalence of drug-resistant epilepsy, additional developmental outcomes, and safety of vigabatrin.

Results: Of 84 infants enrolled, 12 were screen failures, 4 went straight to …

Isolated Cerebral Mucormycosis And Aspergillosis Coinfection In An Immunocompromised Adult, George Sun, Allison Weiss, Joy Zhao, Mitchell Silver, Michael Demaio, Sara Dehbashi

Department of Neurology Faculty Papers

Opportunistic fungal infections are a major cause of mortality in immunosuppressed patients, with mucormycosis and aspergillosis as two of the most commonly identified fungal organisms. Coinfection with mucormycosis and aspergillosis is rare, but cases have been reported in literature, most commonly presenting as disseminated invasive fungal infection with cerebrorhino-orbital involvement in an immunocompromised patient. Infections are most commonly caused by direct implantation of spores with localised angioinvasion. Haematogenous spread is rare, with most cases secondary to haematological malignancies or intravenous drug use. Coinfection with mucormycosis and aspergillosis portends a poor prognosis, with a high mortality rate. Thus, prompt recognition and …

A Non-Coding Insertional Mutation Of Grhl2 Causes Gene Over-Expression And Multiple Structural Anomalies Including Cleft Palate, Spina Bifida And Encephalocele, Zoe Crane-Smith, Sandra C P De Castro, Evanthia Nikolopoulou, Paul Wolujewicz, Damian Smedley, Yunping Lei, Emma Mather, Chloe Santos, Mark Hopkinson, Andrew A Pitsillides, Richard H Finnell, M Elisabeth Ross, Andrew J Copp, Nicholas D E Greene

Faculty, Staff and Students Publications

Orofacial clefts, including cleft lip and palate (CL/P) and neural tube defects (NTDs) are among the most common congenital anomalies, but knowledge of the genetic basis of these conditions remains incomplete. The extent to which genetic risk factors are shared between CL/P, NTDs and related anomalies is also unclear. While identification of causative genes has largely focused on coding and loss of function mutations, it is hypothesized that regulatory mutations account for a portion of the unidentified heritability. We found that excess expression of Grainyhead-like 2 (Grhl2) causes not only spinal NTDs in Axial defects (Axd) mice but also multiple …

Intrinsic Disorder In Prame And Its Role In Uveal Melanoma, Michael Antonietti, David J. Taylor Gonzalez, Mak Djulbegovic, Guy W. Dayhoff, Vladimir N. Uversky, Carol L. Shields, Carol L. Karp

Wills Eye Hospital Papers

Introduction

The PReferentially expressed Antigen in MElanoma (PRAME) protein has been shown to be an independent biomarker for increased risk of metastasis in Class 1 uveal melanomas (UM). Intrinsically disordered proteins and regions of proteins (IDPs/IDPRs) are proteins that do not have a well-defined three-dimensional structure and have been linked to neoplastic development. Our study aimed to evaluate the presence of intrinsic disorder in PRAME and the role these structureless regions have in PRAME( +) Class 1 UM.

Methods

A bioinformatics study to characterize PRAME’s propensity for the intrinsic disorder. We first used the AlphaFold tool to qualitatively assess the …

Immunotherapy Targeting Different Immune Compartments In Combination With Radiation Therapy Induces Regression Of Resistant Tumors, Nils-Petter Rudqvist, Maud Charpentier, Claire Lhuillier, Erik Wennerberg, Sheila Spada, Caroline Sheridan, Xi Kathy Zhou, Tuo Zhang, Silvia C Formenti, Jennifer S Sims, Alicia Alonso, Sandra Demaria

Faculty, Staff and Student Publications

Radiation therapy (RT) increases tumor response to CTLA-4 inhibition (CTLA4i) in mice and in some patients, yet deep responses are rare. To identify rational combinations of immunotherapy to improve responses we use models of triple negative breast cancer highly resistant to immunotherapy in female mice. We find that CTLA4i promotes the expansion of CD4+ T helper cells, whereas RT enhances T cell clonality and enriches for CD8+ T cells with an exhausted phenotype. Combination therapy decreases regulatory CD4+ T cells and increases effector memory, early activation and precursor exhausted CD8+ T cells. A combined gene signature comprising these three CD8+ …

Effect Of Various Types Of Extracellular Dna On V Hyugaensis Biofilm Formation, Carmen Gu Liu, Anthony W Maresso

Faculty, Staff and Students Publications

Marine bacteria face a constant influx of new extracellular DNA (exDNA) due to the massive viral lysis that occurs in the ocean on a daily basis. Generally, biofilms have shown to be induced by self-secreted exDNA. However, the effect of various types of exDNA with varying lengths, self vs non-self, as well as guanine-cytosine content (GC) content on biofilm formation has not been explored, despite being a critical component of the extracellular polymeric substance. To test the effect of such exDNA on biofilms, a marine bioluminescent bacterium (Vibrio hyugaensis) was isolated from the Sippewissett Salt Marsh, USA, and …

Bioaccumulation Of Non-Essential Trace Elements Detected In Women's Follicular Fluid, Urine, And Plasma Is Associated With Poor Reproductive Outcomes Following Single Euploid Embryo Transfer: A Pilot Study, Andrea Palomar, Roberto Gonzalez-Martin, Alicia Quiñonero, Nuria Pellicer, Rocio Fernandez-Saavedra, Isabel Rucandio, Rodolfo Fernandez-Martinez, Estefania Conde-Vilda, Alberto J. Quejido, Caroline Zuckerman, Christine Whitehead, Richard T. Scott, Francisco Dominguez

Department of Obstetrics and Gynecology Faculty Papers

This study aims to determine the association of non-essential trace elements present in follicular fluid, plasma, and urine with reproductive outcomes of women undergoing intracytoplasmic sperm injection (ICSI), preimplantation genetic testing for aneuploidies (PGT-A) and single frozen euploid embryo transfer (SET/FET). This single-center, prospective cohort study included sixty women undergoing ICSI with PGT-A and SET/FET between 2018 and 2019. Urine, plasma and follicular fluid samples were collected on the vaginal oocyte retrieval day to simultaneously quantify ten non-essential trace elements (i.e., Ba, Sr, Rb, Sn, Ti, Pb, Cd, Hg, Sb, and As). We found several associations between the levels of …

Temporal Dynamics Of Genetically Heterogeneous Extended-Spectrum Cephalosporin-Resistant Escherichia Coli Bloodstream Infections, William C Shropshire, Benjamin Strope, Selvalakshmi Selvaraj Anand, Jordan Bremer, Patrick Mcdaneld, Micah M Bhatti, Anthony R Flores, Awdhesh Kalia, Samuel A Shelburne

Faculty, Staff and Student Publications

Extended-spectrum cephalosporin-resistant Escherichia coli (ESC-R-Ec) is an urgent public health threat with sequence type clonal complex 131 (STc131), phylogroup B2 strains being particularly concerning as the dominant cause of ESC-R-Ec infections. To address the paucity of recent ESC-R-Ec molecular epidemiology data in the United States, we used whole-genome sequencing (WGS) to fully characterize a large cohort of invasive ESC-R-Ec at a tertiary care cancer center in Houston, Texas, collected from 2016 to 2020. During the study time frame, there were 1,154 index E. coli bloodstream infections (BSIs) of which 389 (33.7%) were ESC-R-Ec. …

Identifying The Serious Clinical Outcomes Of Adverse Reactions To Drugs By A Multi-Task Deep Learning Framework, Haochen Zhao, Peng Ni, Qichang Zhao, Xiao Liang, Di Ai, Shannon Erhardt, Jun Wang, Yaohang Li, Jianxin Wang

Faculty, Staff and Student Publications

Adverse Drug Reactions (ADRs) have a direct impact on human health. As continuous pharmacovigilance and drug monitoring prove to be costly and time-consuming, computational methods have emerged as promising alternatives. However, most existing computational methods primarily focus on predicting whether or not the drug is associated with an adverse reaction and do not consider the core issue of drug benefit-risk assessment-whether the treatment outcome is serious when adverse drug reactions occur. To this end, we categorize serious clinical outcomes caused by adverse reactions to drugs into seven distinct classes and present a deep learning framework, so-called GCAP, for predicting the …

A Survey Of Microvascular Technique Preferences Among American Head Neck Society Members, Ramez Philips, Keisha A. Best, Aarti Agarwal, Hamad Sagheer, Yamil Selman, Larissa Sweeney, Mark Wax, Howard Krein, Ryan Heffelfinger, Adam Luginbuhl, Joseph Curry

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

OBJECTIVE: To identify practices in microvascular techniques in routine and challenging scenarios.

STUDY DESIGN: Cross-sectional study.

METHODS: A national survey addressing practices related to microvascular free flap reconstruction was distributed to AHNS members between October and November 2021.

RESULTS: The respondents encompassed 95 microvascular surgeons. Median years of practice was 6 (interquartile range, 2-13) and median flaps per year was 35 (22-50). Common practices in arterial anastomosis included limited cleaning of artery (84.2%), use of a double approximating clamp (64.2%), and use of interrupted suture (88.4%). Common practices in venous anastomosis included limited cleaning (89.5%), downsizing the coupler (53.7%), and …

Clinical And Prognostic Biomarker Value Of Blood-Circulating Inflammatory Cytokines In Hepatocellular Carcinoma, Shadi Chamseddine, Yehia I Mohamed, Sunyoung S Lee, James C Yao, Zishuo Ian Hu, Hop S Tran Cao, Lianchun Xiao, Ryan Sun, Jeffrey S Morris, Rikita I Hatia, Manal Hassan, Dan G Duda, Maria Diab, Amr Mohamed, Ahmed Nassar, Saumil Datar, Hesham M Amin, Ahmed Omar Kaseb

Faculty, Staff and Student Publications

INTRODUCTION: Circulating inflammatory cytokines play critical roles in tumor-associated inflammation and immune responses. Recent data have suggested that several interleukins (ILs) mediate carcinogenesis in hepatocellular carcinoma (HCC). However, the predictive and prognostic value of circulating ILs is yet to be validated. Our study aimed to evaluate the association of the serum ILs with overall survival (OS) and clinicopathologic features in a large cohort of HCC patients.

METHODS: We prospectively collected data and serum samples from 767 HCC patients treated at the University of Texas MD Anderson Cancer Center between 2001 and 2014, with a median follow-up of 67.4 months (95% …

Development Of Chimeric Protein As A Multivalent Vaccine For Human Kinetoplastid Infections: Chagas Disease And Leishmaniasis, Marianna De Carvalho Clímaco, Luiza Almeida De Figueiredo, Rayane Cristina Lucas, Guilherme Rafael Gomide Pinheiro, Luísa Mourão Dias Magalhães, Ana Laura Grossi De Oliveira, Raquel Martins Almeida, Fernando Sérgio Barbosa, Daniella Castanheira Bartholomeu, Lilian Lacerda Bueno, Tiago Antonio Mendes, Bin Zhan, Kathryn Marie Jones, Peter Hotez, Maria Elena Bottazzi, Fabrício Marcus Silva Oliveira, Ricardo Toshio Fujiwara

Faculty, Staff and Students Publications

Leishmania spp. and Trypanosoma cruzi are parasitic kinetoplastids of great medical and epidemiological importance since they are responsible for thousands of deaths and disability-adjusted life-years annually, especially in low- and middle-income countries. Despite efforts to minimize their impact, current prevention measures have failed to fully control their spread. There are still no vaccines available. Taking into account the genetic similarity within the Class Kinetoplastida, we selected CD8+ T cell epitopes preserved among Leishmania spp. and T. cruzi to construct a multivalent and broad-spectrum chimeric polyprotein vaccine. In addition to inducing specific IgG production, immunization with the vaccine was able to …

Building A Predictive Model Of Low Birth Weight In Low- And Middle-Income Countries: A Prospective Cohort Study, Jackie K. Patterson, Vanessa R Thorsten, Barry Eggleston, Tracy Nolen, Adrien Lokangaka, Antoinette Tshefu, Shivaprasad S. Goudar, Richard J. Derman, Elwyn Chomba, Waldemar A. Carlo, Manolo Mazariegos, Nancy F. Krebs, Sarah Saleem, Robert L. Goldenberg, Archana Patel, Patricia L. Hibberd, Fabian Esamai, Edward A. Liechty, Rashidul Haque, Bill Petri, Marion Koso-Thomas, Elizabeth M. Mcclure, Carl L. Bose, Melissa Bauserman

Global Health Articles

BACKGROUND: Low birth weight (LBW, < 2500 g) infants are at significant risk for death and disability. Improving outcomes for LBW infants requires access to advanced neonatal care, which is a limited resource in low- and middle-income countries (LMICs). Predictive modeling might be useful in LMICs to identify mothers at high-risk of delivering a LBW infant to facilitate referral to centers capable of treating these infants.

METHODS: We developed predictive models for LBW using the NICHD Global Network for Women's and Children's Health Research Maternal and Newborn Health Registry. This registry enrolled pregnant women from research sites in the Democratic Republic of the Congo, Zambia, Kenya, Guatemala, India (2 sites: Belagavi, Nagpur), Pakistan, and Bangladesh between January 2017 - December 2020. We tested five predictive models: decision tree, random forest, logistic regression, K-nearest neighbor and support vector machine.

RESULTS: We report a rate of LBW of 13.8% among the eight Global Network sites from 2017-2020, with a range of 3.8% (Kenya) …

Easy To Miss Large Left Atrial Myxoma, Art Burgess Kelleher, Tara Ní Dhonnchu, Carl Vaughan, Terence M O'Connor

Children’s Nutrition Research Center Staff Publications

No abstract provided.

Triple-Negative Breast Tumors Are Dependent On Mutant P53 For Growth And Survival, Denada Dibra, Sydney M Moyer, Adel K El-Naggar, Yuan Qi, Xiaoping Su, Guillermina Lozano

Faculty, Staff and Student Publications

The TP53 tumor suppressor gene is mutated early in the majority of patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. We developed an autochthonous somatic K14-Cre driven TNBC mouse model with p53R172H and p53R245W mutations in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53. These mice develop TNBCs with a median latency of 1 y. Deletion of mutant p53R172H or p53R245W in vivo in these tumors blunts their tumor growth and significantly extends survival of mice. Downstream …

Bicuspid Aortic Valve And Thoracic Aortic Disease: Further Evidence Of Clinically Silent But Deadly Risk To Family Members Of Affected Individuals, Siddharth K Prakash, Hector I Michelena, Dianna M Milewicz

Faculty, Staff and Student Publications

No abstract provided.

Exploration Of A Potential Desirability Of Outcome Ranking Endpoint For Complicated Intra-Abdominal Infections Using 9 Registrational Trials For Antibacterial Drugs, Tori Kinamon, Ramya Gopinath, Ursula Waack, Mark Needles, Daniel Rubin, Deborah Collyar, Sarah B Doernberg, Scott Evans, Toshimitsu Hamasaki, Thomas L Holland, Jessica Howard-Anderson, Henry Chambers, Vance G Fowler, Sumati Nambiar, Peter Kim, Helen W Boucher

Faculty, Staff and Student Publications

BACKGROUND: Desirability of outcome ranking (DOOR) is a novel approach to clinical trial design that incorporates safety and efficacy assessments into an ordinal ranking system to evaluate overall outcomes of clinical trial participants. Here, we derived and applied a disease-specific DOOR endpoint to registrational trials for complicated intra-abdominal infection (cIAI).

METHODS: Initially, we applied an a priori DOOR prototype to electronic patient-level data from 9 phase 3 noninferiority trials for cIAI submitted to the US Food and Drug Administration between 2005 and 2019. We derived a cIAI-specific DOOR endpoint based on clinically meaningful events that trial participants experienced. Next, we …

Early Detection Of Lung Cancer Using Artificial Intelligence-Enhanced Optical Nanosensing Of Chromatin Alterations In Field Carcinogenesis, Ali Daneshkhah, Sravya Prabhala, Parvathi Viswanathan, Hariharan Subramanian, Jianan Lin, Andrew S Chang, Ankit Bharat, Hemant Kumar Roy, Vadim Backman

Faculty, Staff and Students Publications

Supranucleosomal chromatin structure, including chromatin domain conformation, is involved in the regulation of gene expression and its dysregulation has been associated with carcinogenesis. Prior studies have shown that cells in the buccal mucosa carry a molecular signature of lung cancer among the cigarette-smoking population, the phenomenon known as field carcinogenesis or field of injury. Thus, we hypothesized that chromatin structural changes in buccal mucosa can be predictive of lung cancer. However, the small size of the chromatin chain (approximately 20 nm) folded into chromatin packing domains, themselves typically below 300 nm in diameter, preclude the detection of alterations in intradomain …

Clinical Predictors And Outcomes After Left Ventricular Assist Device Implantation And Tracheostomy, Harveen K Lamba, Lucy D Hart, Qianzi Zhang, Jackquelin M Loera, Andrew B Civitello, Ajith P Nair, Mourad H Senussi, Gabriel Loor, Kenneth K Liao, Alexis E Shafii, Subhasis Chatterjee

Faculty, Staff and Students Publications

BACKGROUND: Postoperative respiratory failure is a major complication that affects up to 10% of patients who undergo cardiac surgery and has a high in-hospital mortality rate. Few studies have investigated whether patients who require tracheostomy for postoperative respiratory failure after continuous-flow left ventricular assist device (CF-LVAD) implantation have worse survival outcomes than patients who do not.

OBJECTIVE: To identify risk factors for respiratory failure necessitating tracheostomy in CF-LVAD recipients and to compare survival outcomes between those who did and did not require tracheostomy.

METHODS: Consecutive patients who underwent primary CF-LVAD placement at a single institution between August 1, 2002, and …

Identification Of Usp9x As A Leukemia Susceptibility Gene, Saumya Dushyant Sisoudiya, Pamela Mishra, He Li, Jeremy M Schraw, Michael E Scheurer, Sejal Salvi, Harsha Doddapaneni, Donna Muzny, Danielle Mitchell, Olga Taylor, Aniko Sabo, Philip J Lupo, Sharon E Plon

Faculty, Staff and Students Publications

We recently reported that children with multiple birth defects have a significantly higher risk of childhood cancer. We performed whole-genome sequencing on a cohort of probands from this study with birth defects and cancer and their parents. Structural variant analysis identified a novel 5 kb de novo heterozygous inframe deletion overlapping the catalytic domain of USP9X in a female proband with multiple birth defects, developmental delay, and B-cell acute lymphoblastic leukemia (B-ALL). Her phenotype was consistent with female-restricted X-linked syndromic intellectual developmental disorder-99 (MRXS99F). Genotype-phenotype analysis including previously reported female probands (n = 42) demonstrated that MRXS99F probands with B-ALL …

Identifying The Reactive Metabolites Of Tyrosine Kinase Inhibitor Pexidartinib In Vitro Using Lc-Ms-Based Metabolomic Approaches, Xuan Qin, Yong Wang, Kevin R Mackenzie, John M Hakenjos, Si Chen, Saleh M Khalil, Sung Yun Jung, Damian W Young, Lei Guo, Feng Li

Faculty, Staff and Students Publications

Pexidartinib (PEX, TURALIO), a selective and potent inhibitor of the macrophage colony-stimulating factor-1 receptor, has been approved for the treatment of tenosynovial giant cell tumor. However, frequent and severe adverse effects have been reported in the clinic, resulting in a boxed warning on PEX for its risk of liver injury. The mechanisms underlying PEX-related hepatotoxicity, particularly metabolism-related toxicity, remain unknown. In the current study, the metabolic activation of PEX was investigated in human/mouse liver microsomes (HLM/MLM) and primary human hepatocytes (PHH) using glutathione (GSH) and methoxyamine (NH2OMe) as trapping reagents. A total of 11 PEX-GSH and 7 PEX-NH2OMe adducts were …