Digital Commons Network^™

Association Of Baseline Characteristics With Insulin Sensitivity And Β-Cell Function In The Glycemia Reduction Approaches In Diabetes: A Comparative Effectiveness (Grade) Study Cohort, Neda Rasouli, Naji Younes, Kristina M Utzschneider, Silvio E Inzucchi, Ashok Balasubramanyam, Andrea L Cherrington, Faramarz Ismail-Beigi, Robert M Cohen, Darin E Olson, Ralph A Defronzo, William H Herman, John M Lachin, Steven E Kahn, Grade Research Group

Faculty, Staff and Students Publications

OBJECTIVE: We investigated sex and racial differences in insulin sensitivity, β-cell function, and glycated hemoglobin (HbA

RESEARCH DESIGN AND METHODS: This is a cross-sectional analysis of baseline data from 3,108 GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) participants. All had type 2 diabetes diagnosedβ-cell function were evaluated using the HOMA of insulin sensitivity and estimates from oral glucose tolerance tests, including the Matsuda Index, insulinogenic index, C-peptide index, and oral disposition index (DI).

RESULTS: The cohort was 56.6 ± 10 years of age (mean ± SD), 63.8% male, with BMI 34.2 ± 6.7 kg/m

CONCLUSIONS: In the …

Polygenic Burden Has Broader Impact On Health, Cognition, And Socioeconomic Outcomes Than Most Rare And High-Risk Copy Number Variants, Elmo Christian Saarentaus, Lei Chen, Ira M Hall, Et Al

Open Access Publications

Copy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on …

Flortaucipir (Tau) Pet In Lgi1 Antibody Encephalitis, Gregory S Day, Brian A Gordon, Austin Mccullough, Robert C Bucelli, Richard J Perrin, Tammie L S Benzinger, Beau M Ances

Open Access Publications

The contributors to persistent cognitive impairment and hippocampal atrophy in leucine-rich glioma-inactivated 1 antibody encephalitis (LGI1) patients are unknown. We evaluated whether tau neuropathology measured with [

A Timely Call To Arms: Covid-19, The Circadian Clock, And Critical Care, Jeffrey Haspel, Minjee Kim, Phyllis Zee, Tanja Schwarzmeier, Sara Montagnese, Satchidananda Panda, Adriana Albani, Martha Merrow

2020-Current year OA Pubs

We currently find ourselves in the midst of a global coronavirus disease 2019 (COVID-19) pandemic, caused by the highly infectious novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we discuss aspects of SARS-CoV-2 biology and pathology and how these might interact with the circadian clock of the host. We further focus on the severe manifestation of the illness, leading to hospitalization in an intensive care unit. The most common severe complications of COVID-19 relate to clock-regulated human physiology. We speculate on how the pandemic might be used to gain insights on the circadian clock but, more importantly, on …

Decoding Visual Information From High-Density Diffuse Optical Tomography Neuroimaging Data, Kalyan Tripathy, Zachary E Markow, Andrew K Fishell, Arefeh Sherafati, Tracy M Burns-Yocum, Mariel L Schroeder, Alexandra M Svoboda, Adam T Eggebrecht, Mark A Anastasio, Bradley L Schlaggar, Joseph P Culver

2020-Current year OA Pubs

BACKGROUND: Neural decoding could be useful in many ways, from serving as a neuroscience research tool to providing a means of augmented communication for patients with neurological conditions. However, applications of decoding are currently constrained by the limitations of traditional neuroimaging modalities. Electrocorticography requires invasive neurosurgery, magnetic resonance imaging (MRI) is too cumbersome for uses like daily communication, and alternatives like functional near-infrared spectroscopy (fNIRS) offer poor image quality. High-density diffuse optical tomography (HD-DOT) is an emerging modality that uses denser optode arrays than fNIRS to combine logistical advantages of optical neuroimaging with enhanced image quality. Despite the resulting promise …

X-Aptamers Targeting Thy-1 Membrane Glycoprotein In Pancreatic Ductal Adenocarcinoma, Hongyu Wang, Xin Li, Lisa A Lai, Teresa A Brentnall, David W Dawson, Kimberly A Kelly, Ru Chen, Sheng Pan

Faculty, Staff and Students Publications

Modified DNA aptamers incorporated with amino-acid like side chains or drug-like ligands can offer unique advantages and enhance specificity as affinity ligands. Thy-1 membrane glycoprotein (THY1 or CD90) was previously identified as a biomarker candidate of neovasculature in pancreatic ductal adenocarcinoma (PDAC). The current study developed and evaluated modified DNA X-aptamers targeting THY1 in PDAC. The expression and glycosylation of THY1 in PDAC tumor tissues were assessed using immunohistochemistry and quantitative proteomics. Bead-based X-aptamer library that contains 108 different sequences was used to screen for high affinity THY1 X-aptamers. The sequences of the X-aptamers were analyzed with the next-generation sequencing. …

Intestinal Stem Cell-Derived Enteroids From Morbidly Obese Patients Preserve Obesity-Related Phenotypes: Elevated Glucose Absorption And Gluconeogenesis, Nesrin M Hasan, Kelli F Johnson, Jianyi Yin, Nicholas W Baetz, Lea Fayad, Vadim Sherman, Sarah E Blutt, Mary K Estes, Vivek Kumbhari, Nicholas C Zachos, Olga Kovbasnjuk

Faculty, Staff and Students Publications

OBJECTIVE: The mechanisms behind the efficacy of bariatric surgery (BS) for treating obesity and type 2 diabetes, particularly with respect to the influence of the small bowel, remain poorly understood. In vitro and animal models are suboptimal with respect to their ability to replicate the human intestinal epithelium under conditions induced by obesity. Human enteroids have the potential to accelerate the development of less invasive anti-obesity therapeutics if they can recapitulate the pathophysiology of obesity. Our aim was to determine whether adult stem cell-derived enteroids preserve obesity-characteristic patient-specific abnormalities in carbohydrate absorption and metabolism.

METHODS: We established 24 enteroid lines …

Clinical Validation Of Combinatorial Pharmacogenomic Testing And Single-Gene Guidelines In Predicting Psychotropic Medication Blood Levels And Clinical Outcomes In Patients With Depression, Anthony J Rothschild, Charles R Conway, Et Al.

2020-Current year OA Pubs

We evaluated the clinical validity of a combinatorial pharmacogenomic test and single-gene Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines against patient outcomes and medication blood levels to assess their ability to inform prescribing in major depressive disorder (MDD). This is a secondary analysis of the Genomics Used to Improve DEpression Decisions (GUIDED) randomized-controlled trial, which included patients with a diagnosis of MDD, and ≥1 prior medication failure. The ability to predict increased/decreased medication metabolism was validated against blood levels at screening (adjusted for age, sex, smoking status). The ability of predicted gene-drug interactions (pharmacogenomic test) or therapeutic recommendations (single-gene guidelines) to …

Fronto-Cerebellar Connectivity Mediating Cognitive Processing Speed, Clive H Y Wong, Jiao Liu, Tatia M C Lee, Jing Tao, Alex W K Wong, Bolton K H Chau, Lidian Chen, Chetwyn C H Chan

2020-Current year OA Pubs

Processing speed is an important construct in understanding cognition. This study was aimed to control task specificity for understanding the neural mechanisms underlying cognitive processing speed. Forty young adult subjects performed attention tasks of two modalities (auditory and visual) and two levels of task rules (compatible and incompatible). Block-design fMRI captured BOLD signals during the tasks. Thirteen regions of interest were defined with reference to publicly available activation maps for processing speed tasks. Cognitive speed was derived from task reaction times, which yielded six sets of connectivity measures. Mixed-effect LASSO regression revealed six significant paths suggestive of a cerebello-frontal network …

Prevalence Of Gastric Intestinal Metaplasia In A Multiethnic Us Veterans Population, Theresa H Nguyen, Mimi C Tan, Yan Liu, Massimo Rugge, Aaron P Thrift, Hashem B El-Serag

Faculty, Staff and Students Publications

BACKGROUND & AIMS: There is a need to identify individuals with gastric intestinal metaplasia, a precursor to gastric cancer, so they can be offered screening and surveillance. We examined the prevalence of gastric intestinal metaplasia, detected by upper endoscopy biopsy analysis, in different race and ethnic subgroups. We also investigated the extent to which Helicobacter pylori infection, with or without acute and chronic gastritis, accounts for observed associations between race or ethnicity and risk of gastric intestinal metaplasia.

METHODS: We used data from a cross-sectional study of consecutively recruited patients at the Michael E. DeBakey Veterans Affairs Medical Center in …

Links Between Thrombosis And Inflammation In Traumatic Brain Injury, W Brad Hubbard, Jing-Fei Dong, Miguel A Cruz, Rolando E Rumbaut

Faculty, Staff and Students Publications

Traumatic brain injury (TBI) continues to be a major healthcare problem and there is much to be explored regarding the secondary pathobiology to identify early predictive markers and new therapeutic targets. While documented changes in thrombosis and inflammation in major trauma have been well described, growing evidence suggests that isolated TBI also results in systemic alterations in these mechanisms. Here, we review recent experimental and clinical findings that demonstrate how blood-brain barrier dysfunction, systemic immune response, inflammation, platelet activation, and thrombosis contribute significantly to the pathogenesis of TBI. Despite advances in the links between thrombosis and inflammation, there is a …

Prevalence Of Barrett’S Esophagus And Performance Of Societal Screening Guidelines In An Unreferred Primary Care Population Of Us Veterans, Theresa H Nguyen, Aaron P Thrift, Massimo Rugge, Hashem B El-Serag

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: Less than 10% of patients diagnosed with esophageal adenocarcinoma have a pre-existing Barrett's esophagus (BE) diagnosis, possibly because of suboptimal performance of guidelines. We examined the prevalence of BE in a previously unscreened primary care population and the potential yield of practice BE screening guidelines.

METHODS: This was a retrospective analysis of a prospective cross-sectional study of consecutively recruited unreferred patients from primary care clinics who underwent study upper endoscopy. We examined the performance of BE screening guidelines of the European Society of Gastrointestinal Endoscopy (ESGE), British Society of Gastroenterology (BSG), American Society for Gastrointestinal Endoscopy (ASGE), …

Prevalence Of Functional Limitation In Covid-19 Recovered Patients Using The Post Covid-19 Functional Status Scale, Pankaj Pant, Aishana Joshi, Babin Basnet, Bibek Man Shrestha, Navindra Raj Bista, Niraj Bam, Santa Kumar Das

Faculty, Staff and Student Publications

INTRODUCTION: COVID-19 is an emerging global health pandemic causing tremendous morbidity and mortality worldwide. Chronic symptoms progressing to poor functional status have been reported in a substantial proportion of COVID-19 patients worldwide. This study aimed to determine the prevalence of functional limitation in COVID-19 recovered patients using the post-COVID-19 functional status scale.

METHODS: A descriptive cross-sectional study was conducted at Tribhuvan University Teaching Hospital. COVID-19 recovered patients with reverse transcription-polymerase chain reaction negative status were included and assessed using the post-COVID-19 functional status scale. Data entry and analysis was done in Statistical Package for the Social Sciences version 20.0. Descriptive …

Social Distancing During The Covid-19 Pandemic: Quantifying The Practice In Michigan - A "Hotspot State" Early In The Pandemic - Using A Volunteer-Based Online Survey, Andrea E. Cassidy-Bushrow, Mohammed Baseer, Karen E. Klippen, Albert M. Levin, Jia Li, Ian Loveless, Laila M. Poisson, Lonni Schultz, Ganesa Wegienka, Yueren Zhou, Christine C. Johnson

Public Health Sciences Articles

BACKGROUND: Public Health policies related to social distancing efforts during the COVID-19 pandemic helped slow the infection rate. However, individual-level factors associated with social distancing are largely unknown. We sought to examine social distancing during the COVID-19 pandemic in Michigan, an infection "hotspot" state in the United States early in the pandemic.

METHODS: Two surveys were distributed to Michigan residents via email lists and social media following COVID-19 related state mandates in March; 45,691 adults responded to the first survey and 8512 to the second. Staying home ≥ 3 out of 5 previous days defined having more social distancing. Logistic …

Genome-Wide Meta-Analysis Of Muscle Weakness Identifies 15 Susceptibility Loci In Older Men And Women, Garan Jones, Katerina Trajanoska, Adam J Santanasto, Najada Stringa, Chia-Ling Kuo, Janice L Atkins, Joshua R Lewis, Thuyvy Duong, Shengjun Hong, Mary L Biggs, Jian'an Luan, Chloe Sarnowski, Kathryn L Lunetta, Toshiko Tanaka, Mary K Wojczynski, Ryan Cvejkus, Maria Nethander, Sahar Ghasemi, Jingyun Yang, M Carola Zillikens, Stefan Walter, Kamil Sicinski, Erika Kague, Cheryl L Ackert-Bicknell, Dan E Arking, B Gwen Windham, Eric Boerwinkle, Megan L Grove, Misa Graff, Dominik Spira, Ilja Demuth, Nathalie Van Der Velde, Lisette C P G M De Groot, Bruce M Psaty, Michelle C Odden, Alison E Fohner, Claudia Langenberg, Nicholas J Wareham, Stefania Bandinelli, Natasja M Van Schoor, Martijn Huisman, Qihua Tan, Joseph Zmuda, Dan Mellström, Magnus Karlsson, David A Bennett, Aron S Buchman, Philip L De Jager, Andre G Uitterlinden, Uwe Völker, Thomas Kocher, Alexander Teumer, Leocadio Rodriguéz-Mañas, Francisco J García, José A Carnicero, Pamela Herd, Lars Bertram, Claes Ohlsson, Joanne M Murabito, David Melzer, George A Kuchel, Luigi Ferrucci, David Karasik, Fernando Rivadeneira, Douglas P Kiel, Luke C Pilling

Faculty, Staff and Student Publications

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10

Absent B Cells, Agammaglobulinemia, And Hypertrophic Cardiomyopathy In Folliculin-Interacting Protein 1 Deficiency, Francesco Saettini, Cecilia Poli, Jaime Vengoechea, Sonia Bonanomi, Julio C Orellana, Grazia Fazio, Fred H Rodriguez, Loreani P Noguera, Claire Booth, Valentina Jarur-Chamy, Marissa Shams, Maria Iascone, Maja Vukic, Serena Gasperini, Manuel Quadri, Amairelys Barroeta Seijas, Elizabeth Rivers, Mario Mauri, Raffaele Badolato, Gianni Cazzaniga, Cristina Bugarin, Giuseppe Gaipa, Wilma G M Kroes, Daniele Moratto, Monique M Van Oostaijen-Ten Dam, Frank Baas, Silvère Van Der Maarel, Rocco Piazza, Zeynep H Coban-Akdemir, James R Lupski, Bo Yuan, Ivan K Chinn, Lucia Daxinger, Andrea Biondi

Faculty, Staff and Student Publications

Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model. Moreover, we identified either uniparental disomy …

Conformation-Dependent Blockage Of Activated Vwf Improves Outcomes Of Traumatic Brain Injury In Mice, Xin Xu, Chenyu Wang, Yingang Wu, Katie Houck, Tristan Hilton, Ashley Zhou, Xiaoping Wu, Cha Han, Mengchen Yang, Wei Yang, Fu-Dong Shi, Moritz Stolla, Miguel A Cruz, Min Li, Jianning Zhang, Jing-Fei Dong

Faculty, Staff and Students Publications

Traumatic brain injury-induced coagulopathy (TBI-IC) causes life-threatening secondary intracranial bleeding. Its pathogenesis differs mechanistically from that of coagulopathy arising from extracranial injuries and hemorrhagic shock, but it remains poorly understood. We report results of a study designed to test the hypothesis that von Willebrand factor (VWF) released during acute TBI is intrinsically hyperadhesive because its platelet-binding A1-domain is exposed and contributes to TBI-induced vascular leakage and consumptive coagulopathy. This hyperadhesive VWF can be selectively blocked by a VWF A2-domain protein to prevent TBI-IC and to improve neurological function with a minimal risk of bleeding. We demonstrated that A2 given through …

"It's Way More Than Just Writing A Prescription": A Qualitative Study Of Preferences For Integrated Versus Non-Integrated Treatment Models Among Individuals With Opioid Use Disorder, Elizabeth C Saunders, Sarah K Moore, Olivia Walsh, Stephen A Metcalf, Alan J Budney, Patricia Cavazos-Rehg, Emily Scherer, Lisa A Marsch

Open Access Publications

BACKGROUND: Increasingly, treatment for opioid use disorder (OUD) is offered in integrated treatment models addressing both substance use and other health conditions within the same system. This often includes offering medications for OUD in general medical settings. It remains uncertain whether integrated OUD treatment models are preferred to non-integrated models, where treatment is provided within a distinct treatment system. This study aimed to explore preferences for integrated versus non-integrated treatment models among people with OUD and examine what factors may influence preferences.

METHODS: This qualitative study recruited participants (n = 40) through Craigslist advertisements and flyers posted in treatment programs …

Mapping The Immune Environment In Clear Cell Renal Carcinoma By Single-Cell Genomics, Nicholas Borcherding, Ajaykumar Vishwakarma, Andrew P Voigt, Andrew Bellizzi, Jacob Kaplan, Kenneth Nepple, Aliasger K Salem, Russell W Jenkins, Yousef Zakharia, Weizhou Zhang

Open Access Publications

Clear cell renal cell carcinoma (ccRCC) is one of the most immunologically distinct tumor types due to high response rate to immunotherapies, despite low tumor mutational burden. To characterize the tumor immune microenvironment of ccRCC, we applied single-cell-RNA sequencing (SCRS) along with T-cell-receptor (TCR) sequencing to map the transcriptomic heterogeneity of 25,688 individual CD45

New Insights And Enhanced Human Norovirus Cultivation In Human Intestinal Enteroids, Khalil Ettayebi, Victoria R Tenge, Nicolas W Cortes-Penfield, Sue E Crawford, Frederick H Neill, Xi-Lei Zeng, Xiaomin Yu, B Vijayalakshmi Ayyar, Douglas Burrin, Sasirekha Ramani, Robert L Atmar, Mary K Estes

Faculty, Staff and Students Publications

Human noroviruses (HuNoVs) are the leading cause of epidemic and sporadic acute gastroenteritis worldwide. We previously demonstrated human intestinal stem cell-derived enteroids (HIEs) support cultivation of several HuNoV strains. However, HIEs did not support virus replication from every HuNoV-positive stool sample, which led us to test and optimize new medium conditions, identify characteristics of stool samples that allow replication, and evaluate consistency of replication over time. Optimization of our HIE-HuNoV culture system has shown the following: (i) a new HIE culture medium made with conditioned medium from a single cell line and commercial media promotes robust replication of HuNoV strains …

Metabolic Compensation Activates Pro-Survival Mtorc1 Signaling Upon 3-Phosphoglycerate Dehydrogenase Inhibition In Osteosarcoma, Richa Rathore, Katharine E Caldwell, Charles Schutt, Caitlyn B Brashears, Bethany C Prudner, William R Ehrhardt, Cheuk Hong Leung, Heather Lin, Najat C Daw, Hannah C Beird, Abigail Giles, Wei-Lien Wang, Alexander J Lazar, John S A Chrisinger, J Andrew Livingston, Brian A Van Tine

Open Access Publications

Osteosarcoma is the most common pediatric and adult primary malignant bone cancer. Curative regimens target the folate pathway, downstream of serine metabolism, with high-dose methotrexate. Here, the rate-limiting enzyme in the biosynthesis of serine from glucose, 3-phosphoglycerate dehydrogenase (PHGDH), is examined, and an inverse correlation between PHGDH expression and relapse-free and overall survival in osteosarcoma patients is found. PHGDH inhibition in osteosarcoma cell lines attenuated cellular proliferation without causing cell death, prompting a robust metabolic analysis to characterize pro-survival compensation. Using metabolomic and lipidomic profiling, cellular response to PHGDH inhibition is identified as accumulation of unsaturated lipids, branched chain amino …

Polyclonal Epitope Mapping Reveals Temporal Dynamics And Diversity Of Human Antibody Responses To H5n1 Vaccination, Julianna Han, Aaron J Schmitz, Sara T Richey, Ya-Nan Dai, Hannah L Turner, Bassem M Mohammed, Daved H Fremont, Ali H Ellebedy, Andrew B Ward

Open Access Publications

Novel influenza A virus (IAV) strains elicit recall immune responses to conserved epitopes, making them favorable antigenic choices for universal influenza virus vaccines. Evaluating these immunogens requires a thorough understanding of the antigenic sites targeted by the polyclonal antibody (pAb) response, which single-particle electron microscopy (EM) can sensitively detect. In this study, we employ EM polyclonal epitope mapping (EMPEM) to extensively characterize the pAb response to hemagglutinin (HA) after H5N1 immunization in humans. Cross-reactive pAbs originating from memory B cells immediately bound the stem of HA and persisted for more than a year after vaccination. In contrast, de novo pAb …

An Analytical Expression For R50% Dependent On Ptv Surface Area And Volume: A Cranial Srs Comparison, Dharmin D. Desai, Ellis Lee Johnson, Ivan L. Cordrey

Radiation Medicine Faculty Publications

The intermediate dose spill for a stereotactic radiosurgery (SRS) plan can be quantified with the metric R50%, defined as the 50% isodose cloud volume (V_IDC50%) divided by the volume of the planning target volume (PTV). By coupling sound physical principles with the basic definition of R50%, we derive an analytical expression for R50% for a spherical PTV. Our analytical expression depends on three quantities: the surface area of PTV (SA_PTV), the volume of PTV (V_PTV), and the distance of dose drop-off to 50% (Δr). The value of ∆r was obtained from a simple set …

Structural Insights Into The Disruption Of Tnf-Tnfr1 Signalling By Small Molecules Stabilising A Distorted Tnf, David Mcmillan, Carlos Martinez-Fleites, John Porter, David Fox, Rachel E. Davis, Prashant Mori, Tom Ceska, Bruce Carrington, Alastair Lawson, Tim Bourne, James O'Connell

Faculty Publications

Tumour necrosis factor (TNF) is a trimeric protein which signals through two membrane receptors, TNFR1 and TNFR2. Previously, we identified small molecules that inhibit human TNF by stabilising a distorted trimer and reduce the number of receptors bound to TNF from three to two. Here we present a biochemical and structural characterisation of the small molecule-stabilised TNF-TNFR1 complex, providing insights into how a distorted TNF trimer can alter signalling function. We demonstrate that the inhibitors reduce the binding affinity of TNF to the third TNFR1 molecule. In support of this, we show by X-ray crystallography that the inhibitor-bound, distorted, TNF …

Investigating Rare Pathogenic/Likely Pathogenic Exonic Variation In Bipolar Disorder, Xiaoming Jia, Fernando S Goes, Adam E Locke, Duncan Palmer, Weiqing Wang, Et Al

Open Access Publications

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes …

Clinical Performance Of The Point-Of-Care Cobas Liat For Detection Of Sars-Cov-2 In 20 Minutes: A Multicenter Study., Glen Hansen, Jamie Marino, Zi-Xuan Wang, Kathleen G Beavis, John Rodrigo, Kylie Labog, Lars F Westblade, Run Jin, Nedra Love, Karen Ding, Sachin Garg, Alan Huang, Joanna Sickler, Nam K Tran

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Highly accurate testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the point of care (POC) is an unmet diagnostic need in emergency care and time-sensitive outpatient care settings. Reverse transcription-PCR (RT-PCR) technology is the gold standard for SARS-CoV-2 diagnostics. We performed a multisite U.S. study comparing the clinical performance of the first U.S. Food and Drug Administration (FDA)-authorized POC RT-PCR for detection of SARS-CoV-2 in 20 min, the cobas Liat SARS-CoV-2 and influenza A/B nucleic acid test, to the most widely used RT-PCR laboratory test, the cobas 68/8800 SARS-CoV-2 test. Clinical nasopharyngeal swab specimens from 444 patients with …

Nanoparticle T-Cell Engagers As A Modular Platform For Cancer Immunotherapy, Kinan Alhallak, Jennifer Sun, Katherine Wasden, Nicole Guenthner, Julie O'Neal, Barbara Muz, Justin King, Daniel Kohnen, Ravi Vij, Samuel Achilefu, John F Dipersio, Abdel Kareem Azab

Open Access Publications

T-cell-based immunotherapy, such as CAR-T cells and bispecific T-cell engagers (BiTEs), has shown promising clinical outcomes in many cancers; however, these therapies have significant limitations, such as poor pharmacokinetics and the ability to target only one antigen on the cancer cells. In multiclonal diseases, these therapies confer the development of antigen-less clones, causing tumor escape and relapse. In this study, we developed nanoparticle-based bispecific T-cell engagers (nanoBiTEs), which are liposomes decorated with anti-CD3 monoclonal antibodies (mAbs) targeting T cells, and mAbs targeting the cancer antigen. We also developed a nanoparticle that targets multiple cancer antigens by conjugating multiple mAbs against …

Spliceosome-Targeted Therapies Trigger An Antiviral Immune Response In Triple-Negative Breast Cancer, Elizabeth A Bowling, Jarey H Wang, Fade Gong, William Wu, Nicholas J Neill, Ik Sun Kim, Siddhartha Tyagi, Mayra Orellana, Sarah J Kurley, Rocio Dominguez-Vidaña, Hsiang-Ching Chung, Tiffany Y-T Hsu, Julien Dubrulle, Alexander B Saltzman, Heyuan Li, Jitendra K Meena, Gino M Canlas, Srinivas Chamakuri, Swarnima Singh, Lukas M Simon, Calla M Olson, Lacey E Dobrolecki, Michael T Lewis, Bing Zhang, Ido Golding, Jeffrey M Rosen, Damian W Young, Anna Malovannaya, Fabio Stossi, George Miles, Matthew J Ellis, Lihua Yu, Silvia Buonamici, Charles Y Lin, Kristen L Karlin, Xiang H-F Zhang, Thomas F Westbrook

Faculty, Staff and Students Publications

Many oncogenic insults deregulate RNA splicing, often leading to hypersensitivity of tumors to spliceosome-targeted therapies (STTs). However, the mechanisms by which STTs selectively kill cancers remain largely unknown. Herein, we discover that mis-spliced RNA itself is a molecular trigger for tumor killing through viral mimicry. In MYC-driven triple-negative breast cancer, STTs cause widespread cytoplasmic accumulation of mis-spliced mRNAs, many of which form double-stranded structures. Double-stranded RNA (dsRNA)-binding proteins recognize these endogenous dsRNAs, triggering antiviral signaling and extrinsic apoptosis. In immune-competent models of breast cancer, STTs cause tumor cell-intrinsic antiviral signaling, downstream adaptive immune signaling, and tumor cell death. Furthermore, RNA …

Distinct Mechanisms Control Genome Recognition By P53 At Its Target Genes Linked To Different Cell Fates., Marina Farkas, Hideharu Hashimoto, Yingtao Bi, Ramana V Davuluri, Lois Resnick-Silverman, James J. Manfredi, Erik W. Debler, Steven B. Mcmahon

Department of Biochemistry and Molecular Biology Faculty Papers

The tumor suppressor p53 integrates stress response pathways by selectively engaging one of several potential transcriptomes, thereby triggering cell fate decisions (e.g., cell cycle arrest, apoptosis). Foundational to this process is the binding of tetrameric p53 to 20-bp response elements (REs) in the genome (RRRCWWGYYYN_0-13RRRCWWGYYY). In general, REs at cell cycle arrest targets (e.g. p21) are of higher affinity than those at apoptosis targets (e.g., BAX). However, the RE sequence code underlying selectivity remains undeciphered. Here, we identify molecular mechanisms mediating p53 binding to high- and low-affinity REs by showing that key determinants of the code are embedded …

Identification Of 3-Chymotrypsin Like Protease (3clpro) Inhibitors As Potential Anti-Sars-Cov-2 Agents., Vicky Mody, Joanna Ho, Savannah Wills, Ahmed Mawri, Latasha Lawson, Maximilian C C J C Ebert, Guillaume M Fortin, Srujana Rayalam, Shashidharamurthy Taval

PCOM Scholarly Works

Emerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARS-CoV-2 specific drugs. Herein, we have identified potential drugs that target the 3-chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 …