Medicine and Health Sciences Commons^™

Reduced Venetoclax Exposure To 7 Days Vs Standard Exposure With Hypomethylating Agents In Newly Diagnosed Aml Patients, Christophe Willekens, Alexandre Bazinet, Samy Chraibi, Alex Bataller, Justine Decroocq, Naszrin Arani, Benjamin Carpentier, Caitlin Rausch, Delphine Lebon, Abhishek Maiti, Nicolas Gauthier, Nicholas Short, Sarah Bonnet, Koji Sasaki, Sabine Khalife-Hachem, Mahesh Swaminathan, Jean-Baptiste Micol, Florence Pasquier, Christophe Marzac, Damien Roos-Weil, Laurent Pascal, Naval Daver, Tapan Kadia, Didier Bouscary, Farhad Ravandi, Arnaud Pages, Hagop Kantarjian, Stéphane De Botton, Courtney Dinardo

Faculty, Staff and Student Publications

Hypomethylating agent (HMA) plus venetoclax (VEN) regimens are standard of care in patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy. While the VEN label recommends continuous 28-day cycles, shortened VEN durations may induce similar response rates and improve tolerability. It is unknown how a VEN exposure reduced to 7 days during cycles compares to standard HMA + VEN. We retrospectively compared newly diagnosed AML patients treated with azacitidine (AZA) x 7 days plus VEN x 7 days ("7 + 7" regimen) from the first cycle (n = 82) vs patients treated with standard dose HMA + VEN (std-HMA/VEN) …

Humanized Saccharomyces Cerevisiae Provides A Facile And Effective Tool To Identify Damaging Human Variants That Cause Exosomopathies, Khondakar Sayef Ahammed, Milo B Fasken, Anita H Corbett, Ambro Van Hoof

Faculty, Staff and Student Publications

The RNA exosome is an evolutionarily conserved, multiprotein complex that is the major RNase in 3' processing and degradation of a wide range of RNAs in eukaryotes. Single amino acid changes in RNA exosome subunits cause rare genetic diseases collectively called exosomopathies. However, distinguishing disease-causing variants from nonpathogenic ones remains challenging, and the mechanism by which these variants cause disease is largely unknown. Previous studies have employed a budding yeast model of RNA exosome-linked diseases that relies on mutating the orthologous yeast genes. Here, we develop a humanized yeast model of exosomopathies that allows us to unambiguously assess damaging effects …

Kras Mutation Detection By Liquid Biopsy For Pancreatic Ductal Adenocarcinoma, Mahmoud Yousef, Abdelrahman Yousef, Mark W Hurd, Ashwathy Pillai, Saikat Chowdhury, Rebecca Snyder, Mark Knafl, Ryan L Lewis, Paul M Roy, Mohammad Fanaeian, Sali Albarouki, Luca F Castelnovo, Jennifer Peterson, Brandon G Smaglo, Robert A Wolff, Shubham Pant, Jason Willis, Ryan Huey, Michael Overman, Ching-Wei Tzeng, Michael P Kim, Naruhiko Ikoma, Jess E Maxwell, Matthew H G Katz, Huamin Wang, Anirban Maitra, Eugene Koay, Ethan B Ludmir, Anthony Chen, Camila Lopez, Haoqiang Ying, John Paul Shen, Dan Zhao

Faculty, Staff and Student Publications

The clinical utility of liquid biopsy (LB) for pancreatic ductal adenocarcinoma (PDAC) remain understudied. Our single-institution cohort of 311 PDAC patients with non-tumor tissues informed LB found 81.2% positivity (N = 186) in metastatic cases and in 52.4% (N = 43) of localized disease. KRAS mutations were detected in 64.6% (N = 148) of metastatic cases and 16% (N = 13) for localized disease. Positive LB, especially KRAS mutation detection, is associated with worse overall survival (OS) in metastatic PDAC (median 14.5 vs. 31.3 months, HR = 2.7, 95%CI = 1.7-4.3, P <  0.0001). The positive concordance rates of KRAS and TP53 mutations were 63% and 68% in metastatic disease but only 7% (KRAS) and 33% (TP53) in localized disease, respectively. Among the 41 patients who underwent serial liquid biopsy testing, 25% tested positive after an initial negative result. LB detects therapeutically targetable mutations in 58.5% of PDAC patients and is associated with OS.

Multimeric Transcription Factor Bcl11a Utilizes Two Zinc-Finger Tandem Arrays To Bind Clustered Short Sequence Motifs, John R Horton, Meigen Yu, Jujun Zhou, Melody Tran, Rithvi R Anakal, Yue Lu, Robert M Blumenthal, Xiaotian Zhang, Yun Huang, Xing Zhang, Xiaodong Cheng

Faculty, Staff and Student Publications

BCL11A, a transcription factor, is vital for hematopoiesis, including B and T cell maturation and the fetal-to-adult hemoglobin switch. Mutations in BCL11A are linked to neurodevelopmental disorders. BCL11A contains two DNA-binding zinc-finger arrays, low-affinity ZF2-3 and high-affinity ZF4-6, separated by a 300-amino-acid linker. ZF2-3 and ZF4-5 share 73% identity, including five out of six DNA base-interacting residues. These arrays bind similar short sequence motifs in clusters, with the linker enabling a broader binding span. Crystallographic structures of ZF4-6, in complex with oligonucleotides from the β-globin locus region, reveal DNA sequence recognition by residues Asn756 (ZF4), Lys784 and Arg787 (ZF5). A …

A Nuclear Rna Degradation Code Is Recognized By Paxt For Eukaryotic Transcriptome Surveillance, Lindsey V Soles, Liang Liu, Xudong Zou, Yoseop Yoon, Shuangyu Li, Lusong Tian, Marielle Valdez, Angela M Yu, Hong Yin, Wei Li, Fangyuan Ding, Georg Seelig, Lei Li, Yongsheng Shi

Faculty, Staff and Students Publications

The RNA exosome plays critical roles in eukaryotic RNA degradation, but how it specifically recognizes its targets remains unclear. The poly(A) tail exosome targeting (PAXT) connection is a nuclear adaptor that recruits the exosome to polyadenylated RNAs, especially transcripts polyadenylated at intronic poly(A) sites. Here, we show that PAXT-mediated RNA degradation is induced by the combination of a 5' splice site (ss) and a poly(A) junction (PAJ) but not by either sequence alone. These sequences are bound by U1 small nuclear ribonucleoprotein particle (snRNP) and cleavage/polyadenylation factors, which, in turn, cooperatively recruit PAXT. As the 5' ss-PAJ combination is typically …

A Deep Learning Strategy To Identify Cell Types Across Species From High-Density Extracellular Recordings, Maxime Beau, David J Herzfeld, Francisco Naveros, Marie E Hemelt, Federico D'Agostino, Marlies Oostland, Alvaro Sánchez-López, Young Yoon Chung, Michael Maibach, Stephen Kyranakis, Hannah N Stabb, M Gabriela Martínez Lopera, Agoston Lajko, Marie Zedler, Shogo Ohmae, Nathan J Hall, Beverley A Clark, Dana Cohen, Stephen G Lisberger, Dimitar Kostadinov, Court Hull, Michael Häusser, Javier F Medina

Faculty, Staff and Students Publications

High-density probes allow electrophysiological recordings from many neurons simultaneously across entire brain circuits but fail to reveal cell type. Here, we develop a strategy to identify cell types from extracellular recordings in awake animals and reveal the computational roles of neurons with distinct functional, molecular, and anatomical properties. We combine optogenetics and pharmacology using the cerebellum as a testbed to generate a curated ground-truth library of electrophysiological properties for Purkinje cells, molecular layer interneurons, Golgi cells, and mossy fibers. We train a semi-supervised deep learning classifier that predicts cell types with greater than 95% accuracy based on the waveform, discharge …

A Qualitative Inquiry Of Exercise Preferences Among Hispanic Adults With Multiple Sclerosis, Stephanie L Silveira, Robert W Motl, Tania Ontiveros, Victoria Flores

Faculty, Staff and Student Publications

This study aimed to identify the components of an ideal exercise training program for Hispanics with multiple sclerosis (MS), cultural adaptations, and avenues for dissemination of information to this population. Online, semi-structured interviews were conducted with 27 adults with MS who identified as Hispanic. A deductive content analysis approach was applied for assessing necessary and desired components of an exercise program. Participants articulated preferences for "what," "when," "where," and "who" of exercise programs. All participants expressed an interest in aerobic training (n = 27) and need for resistance (n = 14), flexibility (n = 8), and neuromotor components (n = …

Using The Healthy Native Youth Implementation Toolbox To Provide Web-Based Adolescent Health Promotion Decision Support To American Indian And Alaska Native Communities: Implementation Study, Amrita Sidhu, Ross Shegog, Stephanie Craig-Rushing, Nicole Trevino, Michelle Singer, Cornelia Jessen, Gwenda Gorman, Sean Simpson, Melissa Peskin, Belinda Hernandez, Christine Markham

Faculty, Staff and Student Publications

Background: American Indian and Alaska Native (AI/AN) youth experience numerous health inequities, including those in sexual, reproductive, and mental health. Implementation of culturally relevant, age-appropriate evidence-based programs may mitigate these inequities. However, numerous barriers limit the adoption and implementation of evidence-based adolescent health promotion programs in AI/AN communities.

Objective: This study examines user reach and engagement from 2022 to 2024 of web-based decision support (the Healthy Native Youth [HNY] website and the embedded HNY Implementation Toolbox), designed to increase the implementation of evidence-based adolescent health promotion programming in AI/AN communities.

Methods: Promotional strategies were designed for optimal geographic reach to …

Short- And Long-Term Effects Of Early Versus Delayed Treatment With Ocrelizumab On Cerebellar Volume Loss In Patients With Rms And Ppms, Douglas L Arnold, Shannon Kolind, Haz-Edine Assemlal, Amit Bar-Or, Matilde Inglese, Ludwig Kappos, Katrin Parmar, Till Sprenger, Anthony Traboulsee, Irene M Vavasour, Jerry S Wolinsky, Corrado Bernasconi, Ulrike Bonati, Stefano Magon, Björn Tackenberg, Laura Gaetano

Faculty, Staff and Student Publications

Background: The cerebellum is a functionally and anatomically complex structure, which, in multiple sclerosis (MS), is affected by focal white/gray matter lesions and by secondary neurodegeneration of afferent/efferent connections to the supratentorial brain and the spinal cord.

Objectives: To assess the efficacy of ocrelizumab compared with interferon β-1a (IFN β-1a)/placebo on cerebellar volume loss and the effect of switching to ocrelizumab on volume change in the Phase III trials in relapsing MS (RMS, OPERA I/II) and in primary progressive MS (PPMS, ORATORIO).

Methods: Cerebellar volume change was computed using paired Jacobian integration and analyzed using a mixed-effect repeated measurement model. …

Deep Learning-Based Automatic Segmentation Of Cerebral Infarcts On Diffusion Mri, Wi-Sun Ryu, Dawid Schellingerhout, Jonghyeok Park, Jinyong Chung, Sang-Wuk Jeong, Dong-Seok Gwak, Beom Joon Kim, Joon-Tae Kim, Keun-Sik Hong, Kyung Bok Lee, Tai Hwan Park, Sang-Soon Park, Jong-Moo Park, Kyusik Kang, Yong-Jin Cho, Hong-Kyun Park, Byung-Chul Lee, Kyung-Ho Yu, Mi Sun Oh, Soo Joo Lee, Jae Guk Kim, Jae-Kwan Cha, Dae-Hyun Kim, Jun Lee, Man Seok Park, Dongmin Kim, Oh Young Bang, Eung Yeop Kim, Chul-Ho Sohn, Hosung Kim, Hee-Joon Bae, Dong-Eog Kim

Faculty, Staff and Student Publications

We explored effects of (1) training with various sample sizes of multi-site vs. single-site training data, (2) cross-site domain adaptation, and (3) data sources and features on the performance of algorithms segmenting cerebral infarcts on Magnetic Resonance Imaging (MRI). We used 10,820 annotated diffusion-weighted images (DWIs) from 10 university hospitals. Algorithms based on 3D U-net were trained using progressively larger subsamples (ranging from 217 to 8661), while internal testing employed a distinct set of 2159 DWIs. External validation was conducted using three unrelated datasets (n = 2777, 50, and 250). For domain adaptation, we utilized 50 to 1000 subsamples from …

Exploring The Acute Effects Of Sedentary Behaviors On Cardiometabolic Risk In Hispanic Adolescents With Obesity: A Randomized Crossover Study, Erica G Soltero, Osamah Salim, Yiming Mirabile, Salma M Musaad

Children’s Nutrition Research Center Staff Publications

Background/Objectives: Time spent in sedentary pursuits is associated with adverse metabolic profiles. Adolescents spend 65-75% of their day in sedentary pursuits; however, evidence among youth is less conclusive. This study examined the effects of an acute 4 h bout of sedentary behaviors on cardiometabolic outcomes and energy expenditure in Hispanic adolescents (12-16 years old) with obesity (BMI% ≥ 95th).

Methods: This study used a randomized cross-over design to engage participants (N = 12) in two sedentary conditions, an active condition where youth were engaged in two hours of 'active' sitting activities (e.g., reading and puzzles) and two hours …

All Roads That Lead To The Myocardium: Assessment Of Anomalies Of Coronary Artery Course, Ibrahim Khayyat, Silvana Molossi, Ada C Stefanescu Schmidt

Faculty, Staff and Students Publications

No abstract provided.

G-Protein-Coupled Estrogen Receptor 1 And Pregnancy Confer Protection Against Hypertension In Older Females, Ravneet Singh, Supaporn Kulthinee, Victoria L Nasci, Elvis A Akwo, Chibundu Juliet Umunna, Rawan N Almutlaq, Oleh M Pochynyuk, Cassianne Robinson-Cohen, Eman Y Gohar

Faculty, Staff and Student Publications

No abstract provided.

Distinguishing Multisystem Inflammatory Syndrome In Children From Typhus Using Artificial Intelligence: Mis-C Versus Endemic Typhus (Ai-Met), Angela Chun, Abraham Bautista-Castillo, Isabella Osuna, Kristiana Nasto, Flor M Munoz, Gordon E Schutze, Sridevi Devaraj, Eyal Muscal, Marietta M De Guzman, Kristen Sexson Tejtel, Tiphanie P Vogel, Ioannis A Kakadiaris

Faculty, Staff and Students Publications

Background: The pandemic emergent disease multisystem inflammatory syndrome in children (MIS-C) following coronavirus disease-19 infection can mimic endemic typhus. We aimed to use artificial intelligence (AI) to develop a clinical decision support system that accurately distinguishes MIS-C versus endemic typhus (MET).

Methods: Demographic, clinical, and laboratory features rapidly available following presentation were extracted for 133 patients with MIS-C and 87 patients hospitalized due to typhus. An attention module assigned importance to inputs used to create the 2-phase AI-MET. Phase 1 uses 17 features to arrive at a classification manually (MET-17). If the confidence level is not surpassed, 13 additional features …

Left Ventricular Entry To Reduce Brain Lesions During Catheter Ablation: A Randomized Trial, Gregory M Marcus, Roderick Tung, Edward P Gerstenfeld, Trisha F Hue, Feng Lin, Jing Cheng, J Peter Weiss, Wendy S Tzou, Henry Hsia, Ashkan Ehdaie, Daniel H Cooper, T Jared Bunch, Jeffrey Arkles, Babak Nazer, Adam Lee, Alexios Hadjis, Duy T Nguyen, Mihail G Chelu, Joshua Moss, Jonathan C Hsu, Miguel Valderrábano, Prashant D Bhave, Andrew D Beaser, Arvindh Kanagasundram, Oussama Wazni, Jason Bradfield, Grace Wall, Kathleen Chang, Michelle Yang, Gabrielle Montenegro, Sabrina Jarrott, Joel H Kramer, Anthony S Kim, Yvonne M Morris, William P Dillon

Faculty, Staff and Students Publications

Background: Catheter ablation of ventricular arrhythmias, one of the most rapidly growing procedures in cardiac electrophysiology, is associated with magnetic resonance imaging-detected brain lesions in more than half of cases. Although a retrograde aortic approach is conventional, modern tools enable entry through a transseptal approach that may avoid embolization of debris from the arterial system. We sought to test the hypothesis that a transseptal puncture would mitigate brain injury compared with a retrograde aortic approach.

Methods: The TRAVERSE trial (Transseptal Versus Retrograde Aortic Ventricular Entry to Reduce Systemic Emboli) was a multicenter randomized controlled comparative effectiveness trial. Patients with left …

Comprehensive Assessment Of Initial Adaptation Of Extended-Spectrum Β-Lactamase-Positive St131 Escherichia Coli To Carbapenem Exposure, William C Shropshire, Xinhao Song, Jordan Bremer, Seokju Seo, Susana Rodriguez, Selvalakshmi Selvaraj Anand, An Q Dinh, Micah M Bhatti, Anna Konovalova, Cesar A Arias, Awdhesh Kalia, Yousif Shamoo, Samuel A Shelburne

Faculty, Staff and Student Publications

Background: It remains unclear how high-risk Escherichia coli lineages, like sequence type (ST) 131, initially adapt to carbapenem exposure in their progression to carbapenem resistance.

Methods: Carbapenem mutation frequency was measured in multiple subclades of extended-spectrum β-lactamase (ESBL)-positive ST131 clinical isolates using a fluctuation assay followed by whole genome sequencing (WGS) characterization. Genomic, transcriptomic, and porin analyses of the ST131 C2/H30Rx isolate MB1860, under prolonged, increasing carbapenem exposure was performed using 2 experimental evolutionary platforms to measure fast versus slow adaptation.

Results: All 13 ESBL-positive ST131 strains selected from a diverse (n = 184) ST131 bacteremia cohort had detectable ertapenem …

Integrated Analysis Of Molecular And Clinical Features Associated With Overall Survival In Melanoma Patients With Brain Metastasis, Swaminathan Kumar, Meredith S Pelster, Merve Hasanov, Renato A Guerrieri, Courtney W Hudgens, Debora A Ledesma, Fuchenchu Wang, Grant M Fischer, Julie M Simon, Lauren E Haydu, Kalman V Katlowitz, Y N Vashisht Gopal, Jennifer L Mcquade, Lawrence N Kwong, Jason T Huse, Alexander J Lazar, Michael T Tetzlaff, Jeffrey E Gershenwald, Aron Y Joon, Ken Chen, Ziyi Li, Prahlad T Ram, Sherise D Ferguson, Michael A Davies

Faculty, Staff and Student Publications

Melanoma brain metastases (MBMs) are diagnosed in up to 60% of metastatic melanoma patients. Previous studies have identified clinical factors that correlate with overall survival (OS) after MBM diagnosis. However, molecular and immune features associated with OS are poorly understood. An improved understanding of the molecular and immune correlates of OS could provide insights into MBM patient outcomes and guide therapeutic development. Thus, we analyzed clinical features and outcomes of 74 melanoma patients who underwent surgical resection (via craniotomy) between 1991 and 2015 at our institution with RNA-seq data generated from their MBMs. The median post-operative OS was 8.6 months …

Single-Cell Analyses Reveal A Functionally Heterogeneous Exhausted Cd8+ T-Cell Subpopulation That Is Correlated With Response To Checkpoint Therapy In Melanoma, Kelly M Mahuron, Osmaan Shahid, Prachi Sao, Clinton Wu, Alexandra M Haugh, Laura A Huppert, Lauren S Levine, Margaret M Lowe, Michael Alvarado, Markee Micu, Katy K Tsai, Melissa Chow, Meromit Singer, Jason M Schenkel, Arlene H Sharpe, Michael D Rosenblum, Kristen E Pauken, Adil I Daud

Faculty, Staff and Student Publications

PD-1 pathway inhibitors have revolutionized cancer therapy. However, most patients do not durably benefit, highlighting the need for biomarkers to stratify patients as responders or nonresponders. Although CD8+ tumor-infiltrating lymphocytes (TIL) have been associated with immune checkpoint therapy response, there is no consensus on which CD8+ TIL subpopulations have the most prognostic value. Preclinical studies have focused on progenitor-like exhausted CD8+ T cells (TPEX) because TPEX proliferate more in response to PD-1 inhibitors than other exhausted T-cell (TEX) subpopulations. However, immune checkpoint inhibitor treatment drives TPEX differentiation into other TEX populations that can mediate antitumor immunity. These data complicate the …

Volumetric Changes In Cerebellar Transverse Zones: Age And Sex Effects In Health And Neurological Disorders, Farshid Ghiyamihoor, Payam Paymani, Jarrad Perron, Azam Asemi-Rad, Mehdi Marzban, Aashka Mohite, Karen Ardila, Bara Aljada, Asghar Marzban, Mehnosh Toback, Sherif Eltonsy, Ji Hyun Ko, Tabrez J Siddiqui, Christopher J Steele, Jiming Kong, Mario Manto, M Ethan Macdonald, Jason S Gill, Roy V Sillitoe, Fuat Balcı, Iman Beheshti, Hassan Marzban

Duncan NRI Faculty and Staff Publications

Cerebellar volumetric changes are intricately linked to aging, with distinct patterns across its transverse zones, the functional subdivisions characterized by unique cytoarchitectural and connectivity profiles. Despite research efforts, the cerebellar aging process in health and neurological disorders remains poorly understood. In this study, we investigated the effects of age and sex on total cerebellum, transverse zone, and lobule volumes using MRI data from over 45,000 participants compiled from six neuroimaging datasets. We also propose a framework for estimating cerebellum age as an indicator of cerebellar health. Significant age‐dependent volume reductions were observed across transverse zones, with the …

Morphogenic, Molecular And Cellular Adaptations For Unidirectional Airflow In The Chicken Lung, Kamryn N Gerner-Mauro, Lisandra Vila Ellis, Guolun Wang, Richa Nayak, Peter Y Lwigale, Ross A Poché, Jichao Chen

Faculty, Staff and Students Publications

Unidirectional airflow in the avian lung enables gas exchange during both inhalation and exhalation. The underlying developmental process and how it deviates from that of the bidirectional mammalian lung are poorly understood. Sampling key developmental stages with multiscale 3D imaging and single-cell transcriptomics, we delineate morphogenic, molecular and cellular features that accommodate the unidirectional airflow in the chicken lung. Primary termini of hyper-elongated branches undergo proximal-short and distal-long fusions, forming parabronchi for air conduction. Through the parabronchial smooth muscle, neoform termini extend radially to form gas-exchanging alveoli. Supporting this radial alveologenesis, branch stalks halt their proximalization, defined by SOX9-SOX2 transition, …

A Screening Question To Assess Risk Of Using Antibiotics Without A Prescription: A Diagnostic Study, Ashley Collazo, Eva Amenta, Kiara Olmeda, Marissa Valentine-King, Lindsey Laytner, Azalia Mancera, Roger Zoorob, Michael K Paasche-Orlow, Richard L Street, Barbara W Trautner, Larissa Grigoryan

Faculty, Staff and Students Publications

Objectives: Non-prescription antibiotic use (using antibiotics without medical advice) is potentially unsafe and promotes antimicrobial resistance. We studied predictors of prior non-prescription use and whether screening for prior non-prescription antibiotic use predicted intention of future non-prescription antibiotic use.

Methods: The survey was performed from January 2020 - June 2021 in six public primary care clinics and two private emergency departments. Prior non-prescription users were respondents who reported taking oral antibiotics for symptoms without contacting a clinician. Intended use was defined by answering yes to the question, "would you use antibiotics without contacting a doctor/nurse/dentist/clinic." We examined predictors for prior non-prescription …

Lineage Tracing And Single-Cell Rna Sequencing Reveal A Common Transcriptional State In Breast Cancer Tumor-Initiating Cells Characterized By Ifn/Stat1 Activity, Eric P Souto, Ping Gong, John D Landua, Ramakrishnan Rajaram Srinivasan, Abhinaya Ganesan, Lacey E Dobrolecki, Stephen C Purdy, Xingxin Pan, Michael Zeosky, Anna Chung, S Stephen Yi, Heide L Ford, Michael T Lewis

Faculty, Staff and Students Publications

A tumor cell subpopulation of tumor-initiating cells (TIC) or "cancer stem cells" is associated with therapeutic resistance, as well as both local and distant recurrences. Signal transducer and activator of transcription (STAT) activity is elevated in TICs in claudin-low models of human triple-negative breast cancer, which enables enrichment of TICs using a STAT-responsive reporter. Lineage tracing of TICs as they undergo cell state changes could enable a better understanding of the molecular phenotypes of TIC and uncover strategies to selectively target TICs. In this study, we developed a STAT-responsive lineage-tracing system and used it in conjunction with the original reporter …

Nitrate Ameliorates Alcohol-Induced Cognitive Impairment Via Oral Microbiota, Xiangxue Li, Zhaojun Ni, Weixiong Shi, Kangqing Zhao, Yanjie Zhang, Lina Liu, Zhong Wang, Jie Chen, Zhoulong Yu, Xuejiao Gao, Ying Qin, Jingwen Zhao, Wenjuan Peng, Jie Shi, Thomas R Kosten, Lin Lu, Lei Su, Yanxue Xue, Hongqiang Sun

Faculty, Staff and Students Publications

Alcohol use is associated with cognitive impairment and dysregulated inflammation. Oral nitrate may benefit cognitive impairment in aging through altering the oral microbiota. Similarly, the beneficial effects of nitrate on alcohol-induced cognitive decline and the roles of the oral microbiota merit investigation. Here we found that nitrate supplementation effectively mitigated cognitive impairment induced by chronic alcohol exposure in mice, reducing both systemic and neuroinflammation. Furthermore, nitrate restored the dysbiosis of the oral microbiota caused by alcohol consumption. Notably, removing the oral microbiota led to a subsequent loss of the beneficial effects of nitrate. Oral microbiota from donor alcohol use disordered …

Integrating Short-Read And Long-Read Single-Cell Rna Sequencing For Comprehensive Transcriptome Profiling In Mouse Retina, Meng Wang, Yumei Li, Jun Wang, Soo Hwan Oh, Yexuan Cao, Rui Chen

Faculty, Staff and Students Publications

The vast majority of protein-coding genes in the human genome produce multiple mRNA isoforms through alternative splicing, significantly enhancing the complexity of the transcriptome and proteome. To establish an efficient method for characterizing transcript isoforms within tissue samples, we conducted a systematic comparison between single-cell long-read and conventional short-read RNA sequencing techniques. The transcriptome of approximately 30,000 mouse retina cells was profiled using 1.54 billion Illumina short reads and 1.40 billion Oxford Nanopore Technologies long reads. Consequently, we identify 44,325 transcript isoforms, with a notable 38% previously uncharacterized and 17% expressed exclusively in distinct cellular subclasses. We observe that long-read …

Vacuum Erectile Devices For Erectile Dysfunction: Recommendations From The 5th International Consultation On Sexual Medicine, Run Wang, Francisco E Martins, David Ralph, Georgios Hatzichristodoulou, Daniar Osmonov, Justin Parker, Sung Hun Sean Park, Ignacio Moncada, Carlo Bettocchi, Ricardo Munarriz, Tobias Köhler

Faculty, Staff and Student Publications

Introduction: Vacuum erectile device (VED) is 1 of the main approved therapies for erectile dysfunction (ED). The introduction of phosphodiesterase type 5 inhibitor (PDE5i) for ED significantly changed the roles of VED in contemporary sexual medicine.

Objective: To provide updated clinical evidence to inform health care providers on best practices with VED.

Methods: A consensus panel was held with leading sexual medicine experts during the 5th International Consultation on Sexual Medicine (ICSM). Relevant peer-reviewed literature was reviewed with focus on research from the last 10 years, but not limited to the last 10 years. The expert panel generated consensus statements …

Leveraging Pretrained Language Models For Seizure Frequency Extraction From Epilepsy Evaluation Reports, Rashmie Abeysinghe, Shiqiang Tao, Samden D Lhatoo, Guo-Qiang Zhang, Licong Cui

Faculty, Staff and Student Publications

Seizure frequency is essential for evaluating epilepsy treatment, ensuring patient safety, and reducing risk for Sudden Unexpected Death in Epilepsy. As this information is often described in clinical narratives, this study presents an approach to extracting structured seizure frequency details from such unstructured text. We investigated two tasks: (1) extracting phrases describing seizure frequency, and (2) extracting seizure frequency attributes. For both tasks, we fine-tuned three BERT-based models (bert-large-cased, biobert-large-cased, and Bio_ClinicalBERT), as well as three generative large language models (GPT-4, GPT-3.5 Turbo, and Llama-2-70b-hf). The final structured output integrated the results from both tasks. GPT-4 attained the best performance …

Long-Read Single-Cell Rna Sequencing Enables The Study Of Cancer Subclone-Specific Genotypes And Phenotypes In Chronic Lymphocytic Leukemia, Gage S Black, Xiaomeng Huang, Yi Qiao, Philip Moos, Deepa Sampath, Deborah M Stephens, Jennifer A Woyach, Gabor T Marth

Faculty, Staff and Student Publications

Bruton tyrosine kinase (BTK) inhibitors are effective for the treatment of chronic lymphocytic leukemia (CLL) due to BTK's role in B cell survival and proliferation. Treatment resistance is most commonly caused by the emergence of the hallmark BTKC481S mutation that inhibits drug binding. In this study, we aimed to investigate cancer subclones harboring a BTKC481S mutation and identify cells with co-occurring CLL driver mutations. In addition, we sought to determine whether BTK-mutated subclones exhibit distinct transcriptomic behavior when compared to other cancer subclones. To achieve these goals, we use scBayes, which integrates bulk DNA sequencing and single-cell …

Results Of The Phase I/Ii Study And Preliminary B-Cell Gene Signature Of Combined Inhibition Of Glutamine Metabolism And Egfr In Colorectal Cancer, Kristen K Ciombor, Seong-Woo Bae, Jennifer G Whisenant, Gregory D Ayers, Quanhu Sheng, Todd E Peterson, Gary T Smith, Kangyu Lin, Saikat Chowdhury, Preeti Kanikarla Marie, Alexey Sorokin, Allison S Cohen, Laura W Goff, Dana B Cardin, John Paul Shen, Scott Kopetz, Cathy Eng, Yu Shyr, Jordan Berlin, H Charles Manning

Faculty, Staff and Student Publications

Purpose: EGFR-targeting mAbs are essential for managing rat sarcoma virus wild-type metastatic colorectal cancer (mCRC), but their limited efficacy necessitates exploring immunologic and metabolic factors influencing response. This study evaluated glutamine metabolism targeting with EGFR inhibition to identify response biomarkers in patients with prior anti-EGFR treatment progression.

Patients and methods: We conducted a phase I/II trial in patients with KRAS wild-type mCRC, combining panitumumab (6 mg/kg) and CB-839 (600 mg/kg or 800 mg/kg), hypothesizing that the dual inhibition of glutamine metabolism and MAPK signaling would enhance outcomes. As study correlatives, we investigated the B-cell activation signature "B-score" and glutamine PET …

Germline Pathogenic Drosha Variants Are Linked To Pineoblastoma And Wilms Tumor Predisposition, Peter N Fiorica, Lisa Golmard, Jung Kim, Riyue Bao, Frank Y Lin, Angshumoy Roy, Allison Pribnow, Melissa R Perrino, Julien Masliah-Planchon, Sophie Michalak-Provost, Jennifer Wong, Mathilde Filser, Dominique Stoppa-Lyonnet, Franck Bourdeaut, Afane Brahimi, Olivier Ingster, Giselle Saulnier Sholler, Sarah A Jackson, Mark M Sasaki, Trent Fowler, Anita Ng, Ryan J Corbett, Rebecca S Kaufman, Jeremy S Haley, David J Carey, Kuan-Lin Huang, Sharon J Diskin, Jo Lynne Rokita, Hussam Al-Kateb, Rose B Mcgee, Joshua D Schiffman, Kenneth S Chen, Douglas R Stewart, D Williams Parsons, Sharon E Plon, Kris Ann P Schultz, Kenan Onel

Center for Medical Ethics and Health Policy Staff Publications

Purpose: DROSHA, DGCR8, and DICER1 regulate miRNA biogenesis and are commonly mutated in cancer. Although DGCR8 and DICER1 germline pathogenic variants (GPV) cause autosomal dominant tumor predisposition, no association between DROSHA GPVs and clinical phenotypes has been reported.

Experimental design: After obtaining informed consent, sequencing was performed on germline and tumor samples from all patients. The occurrence of germline DROSHA GPVs was investigated in large pediatric and adult cancer datasets. The population prevalence of DROSHA GPVs was investigated in the UK Biobank and Geisinger DiscovEHR cohorts.

Results: We describe nine children from eight families with heterozygous DROSHA GPVs and a …

Surgical Mitral Valve Repair Vs Replacement After Failed Mitral Transcatheter Edge-To-Edge Repair: The Cutting-Edge Registry., Mateo Marin-Cuartas, Jagdip Kang, Thilo Noack, Manuela De La Cuesta, Markus Krane, Volkmar Falk, Lenard Conradi, Christian Hagl, Maurizio Taramasso, Tom C Nguyen, D Scott Lim, Gorav Ailawadi, Michael J Mack, Robert L Smith, Anita W Asgar, Kendra J Grubb, Luigi Pirelli, Paolo Denti, Thomas Modine, Michael J Reardon, Tamim M Nazif, Vinayak N Bapat, Tsuyoshi Kaneko, Philipp Kiefer, Michael A Borger, Gilbert H L Tang, Syed Zaid

Faculty, Staff and Students Publications

Background: The impact of mitral valve (MV) surgery type after failed mitral transcatheter edge-to-edge repair (M-TEER) has not been well studied.

Objectives: The aim of this study was to compare the outcomes of MV repair vs replacement after failed M-TEER.

Methods: From 2009 to 2020, a total of 332 patients across 34 centers from the CUTTING-EDGE registry underwent MV surgery after M-TEER. Outcomes were compared between MV repair and replacement. Primary outcomes included 30-day mortality and 1-year survival after MV surgery.

Results: Among enrolled patients (mean age 73.8 ± 10.1 years, median Society of Thoracic Surgeons Predicted Risk of Mortality …