Digital Commons Network^™

Targeting Prmt3 Impairs Methylation And Oligomerization Of Hsp60 To Boost Anti-Tumor Immunity By Activating Cgas/Sting Signaling, Yunxing Shi, Zongfeng Wu, Shaoru Liu, Dinglan Zuo, Yi Niu, Yuxiong Qiu, Liang Qiao, Wei He, Jiliang Qiu, Yunfei Yuan, Guocan Wang, Binkui Li

Faculty, Staff and Student Publications

Immune checkpoint blockade (ICB) has emerged as a promising therapeutic option for hepatocellular carcinoma (HCC), but resistance to ICB occurs and patient responses vary. Here, we uncover protein arginine methyltransferase 3 (PRMT3) as a driver for immunotherapy resistance in HCC. We show that PRMT3 expression is induced by ICB-activated T cells via an interferon-gamma (IFNγ)-STAT1 signaling pathway, and higher PRMT3 expression levels correlate with reduced numbers of tumor-infiltrating CD8+ T cells and poorer response to ICB. Genetic depletion or pharmacological inhibition of PRMT3 elicits an influx of T cells into tumors and reduces tumor size in HCC mouse models. Mechanistically, …

Clinical Outcomes After Idecabtagene Vicleucel In Older Patients With Multiple Myeloma: A Multicenter Real-World Experience, Nilesh M Kalariya, Michelle A T Hildebrandt, Doris K Hansen, Surbhi Sidana, Jack Khouri, Christopher J Ferreri, William N Doyle, Omar Castaneda-Puglianini, Ciara L Freeman, Vanna Hovanky, Hitomi Hosoya, Leyla O Shune, Krina K Patel

Faculty, Staff and Student Publications

The safety and efficacy of chimeric antigen receptor T-cell therapy is not well described in older patients, a population that has higher frailty and comorbidities. In this multicenter retrospective study, we evaluated clinical outcomes along with frailty and geriatric characteristics such as comorbidities, polypharmacy, falls, neuropathy, organ dysfunction, and performance status in younger (aged < 65 years) vs older (aged ≥65 years) patients who received commercial idecabtagene vicleucel (ide-cel). A total of 156 patients (n = 75, aged ≥65 years) were infused with ide-cel by data cutoff. In older patients (median age: 69 years; range, 65-83; 66.7% frail; 77.3% did not meet KarMMa eligibility criteria), with a median follow-up duration of 14.2 months, best overall response rate (ORR) was 86.7%, which was comparable with pivotal KarMMa study results (ORR: 73%). Median progression-free survival and overall survival in older patients were 9.1 months and 26.5 months, respectively. Grade ≥3 cytokine-release syndrome and immune effector cell-associated neurotoxicity syndrome were observed in 1% and 4% of older patients, respectively. Compared with younger patients, the older patients had significantly higher prevalence of frailty, geriatric characteristics such as polypharmacy (≥5 drugs; 97%), ≥4 comorbidities (69%), and organ dysfunction (35%; P < .05). The safety and efficacy of ide-cel therapy were similar in younger and older patients. Frailty and geriatric characteristics such as polypharmacy, comorbidities, and organ dysfunction in older patients did not confer an inferior overall outcome.

Transcriptomic And Proteomic Differences In Btk-Wt And Btk-Mutated Cll And Their Changes During Therapy With Pirtobrutinib, Burcu Aslan, Ganiraju Manyam, Lakesla R Iles, Shady I Tantawy, Sai Prasad Desikan, William G Wierda, Varsha Gandhi

Faculty, Staff and Student Publications

Covalent Bruton tyrosine kinase inhibitors (cBTKis), which bind to the BTK C481 residue, are now primary therapeutics for chronic lymphocytic leukemia (CLL). Alterations at C481, primarily C481S, prevent cBTKi binding and lead to the emergence of resistant clones. Pirtobrutinib is a noncovalent BTKi that binds to both wild-type (WT) and C481S-mutated BTK and has shown efficacy in BTK-WT and -mutated CLL patient groups. To compare baseline clinical, transcriptomic, and proteomic characteristics and their changes during treatment in these 2 groups, we used 67 longitudinal peripheral blood samples obtained during the first 3 cycles of treatment with pirtobrutinib from 18 patients …

A Smart Water Bottle And Companion App (Hidratespark 3) To Improve Bladder-Filling Compliance In Patients With Prostate Cancer Receiving Radiotherapy: Nonrandomized Trial Of Feasibility And Acceptability, William Jin, Christopher Montoya, Benjamin James Rich, Crystal Seldon Taswell, Miguel Noy, Deukwoo Kwon, Benjamin Spieler, Brandon Mahal, Matthew Abramowitz, Raphael Yechieli, Alan Pollack, Alan Dal Pra

Faculty, Staff and Student Publications

Background: Patients with prostate cancer undergoing radiation therapy (RT) need comfortably full bladders to reduce toxicities during treatment. Poor compliance is common with standard of care written or verbal instructions, leading to wasted patient value (PV) and clinic resources via poor throughput efficiency (TE).

Objective: Herein, we assessed the feasibility and acceptability of a smartphone-based behavioral intervention (SBI) to improve bladder-filling compliance and methods for quantifying PV and TE.

Methods: In total, 36 patients with prostate cancer were enrolled in a single-institution, closed-access, nonrandomized feasibility trial. The SBI consists of a fully automated smart water bottle and smartphone app. Both …

Variants In Lrrc7 Lead To Intellectual Disability, Autism, Aggression And Abnormal Eating Behaviors, Jana Willim, Weimin Yuan, Anika Lindsey, Omar Itani, Gary A Silverman, Stephen C Pak, Tim Schedl, Et Al.

2020-Current year OA Pubs

Members of the leucine rich repeat (LRR) and PDZ domain (LAP) protein family are essential for animal development and histogenesis. Densin-180, encoded by LRRC7, is the only LAP protein selectively expressed in neurons. Densin-180 is a postsynaptic scaffold at glutamatergic synapses, linking cytoskeletal elements with signalling proteins such as the α-subunit of Ca

Long-Term Dementia Risk In Parkinson Disease, Julia Gallagher, Caroline Gochanour, Chelsea Caspell-Garcia, Roseanne D Dobkin, Dag Aarsland, Roy N Alcalay, Matthew J Barrett, Lana Chahine, Alice S Chen-Plotkin, Christopher S Coffey, Nabila Dahodwala, Jamie L Eberling, Alberto J Espay, James B Leverenz, Irene Litvan, Eugenia Mamikonyan, James Morley, Irene H Richard, Liana Rosenthal, Andrew D Siderowf, Tatyana Simuni, Michele K York, Allison W Willis, Sharon X Xie, Daniel Weintraub, Parkinson's Progression Markers Initiative

Faculty, Staff and Students Publications

BACKGROUND AND OBJECTIVES: It is widely cited that dementia occurs in up to 80% of patients with Parkinson disease (PD), but studies reporting such high rates were published over two decades ago, had relatively small samples, and had other limitations. We aimed to determine long-term dementia risk in PD using data from two large, ongoing, prospective, observational studies.

METHODS: Participants from the Parkinson's Progression Markers Initiative (PPMI), a multisite international study, and a long-standing PD research cohort at the University of Pennsylvania (Penn), a single site study at a tertiary movement disorders center, were recruited. PPMI enrolled de novo, untreated …

Mitochondrial Reprogramming By Activating Oxphos Via Glutamine Metabolism In African American Patients With Bladder Cancer, Karthik Reddy Kami Reddy, Danthasinghe Waduge Badrajee Piyarathna, Jun Hyoung Park, Vasanta Putluri, Chandra Sekhar Amara, Abu Hena Mostafa Kamal, Jun Xu, Daniel Kraushaar, Shixia Huang, Sung Yun Jung, Livia S Eberlin, Jabril R Johnson, Rick A Kittles, Leomar Y Ballester, Krishna Parsawar, M Minhaj Siddiqui, Jianjun Gao, Adriana Langer Gramer, Roni J Bollag, Martha K Terris, Yair Lotan, Chad J Creighton, Seth P Lerner, Arun Sreekumar, Benny Abraham Kaipparettu, Nagireddy Putluri

Faculty, Staff and Students Publications

Bladder cancer (BLCA) mortality is higher in African American (AA) patients compared with European American (EA) patients, but the molecular mechanism underlying race-specific differences are unknown. To address this gap, we conducted comprehensive RNA-Seq, proteomics, and metabolomics analysis of BLCA tumors from AA and EA. Our findings reveal a distinct metabolic phenotype in AA BLCA characterized by elevated mitochondrial oxidative phosphorylation (OXPHOS), particularly through the activation of complex I. The results provide insight into the complex I activation-driven higher OXPHOS activity resulting in glutamine-mediated metabolic rewiring and increased disease progression, which was also confirmed by [U]13C-glutamine tracing. Mechanistic studies further …

Final Outcomes From A Phase 2 Trial Of Posoleucel In Allogeneic Hematopoietic Cell Transplant Recipients, Sanjeet S Dadwal, Rajat Bansal, Michael W Schuster, Jean A Yared, Gary Douglas Myers, Michelle Matzko, Sama Adnan, David Mcneel, Julie Ma, Sarah A Gilmore, Spyridoula Vasileiou, Ann M Leen, Joshua A Hill, Jo-Anne H Young

Faculty, Staff and Students Publications

Allogeneic hematopoietic cell transplantation (allo-HCT) recipients are susceptible to viral infections. We conducted a phase 2 trial evaluating the safety and rate of clinically significant infections (CSIs; viremia requiring treatment or end-organ disease) after infusion of posoleucel, a partially HLA-matched, allogeneic, off-the-shelf, multivirus-specific T-cell investigational product for preventing CSIs with adenovirus, BK virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus-6, or JC virus. This open-label trial enrolled allo-HCT recipients at high risk based on receiving grafts from umbilical cord blood, haploidentical, mismatched, or matched unrelated donors; post-HCT lymphocytes of < 180/mm3; or use of T-cell depletion. Posoleucel dosing was initiated within 15 to 49 days of allo-HCT and subsequently every 14 days for up to 7 doses. The primary end point was the number of CSIs due to the 6 target viruses by week 14. Of the 26 patients enrolled, only 3 (12%) had a CSI by week 14, each with a single target virus. In vivo expansion of functional virus-specific T cells detected via interferon-γ enzyme-linked immunosorbent spot assay was associated with viral control. Persistence of posoleucel-derived T-cell clones for up to 14 weeks after the last infusion was confirmed by T-cell–receptor deep sequencing. Five patients (19%) had acute graft-versus-host disease grade 2 to 4. No patient experienced cytokine release syndrome. All 6 deaths were due to relapse or disease progression. allo-HCT recipients at high risk who received posoleucel had low rates of CSIs from 6 targeted viruses. Repeat posoleucel dosing was generally safe and well tolerated and associated with functional immune reconstitution.

Lessons Learned From Developing Dashboards To Support Decision-Making For Community Opioid Response By Community Stakeholders: Mixed Methods And Multisite Study., Naleef Fareed, Ramona G. Olvera, Yiting Wang, Michael Hayes, Elizabeth Liz Larimore, Peter Balvanz, Ronald Langley, Corinna A. Noel, Peter J. Rock, Daniel Redmond, Jessica Neufeld, Sarah Kosakowski, Daniel R. Harris, Marc Larochelle, Timothy R. Huerta, Lashawn Glasgow, Emmanuel Oga, Jennifer Villani, Elwin Wu

Center on Drug and Alcohol Research Faculty Publications

BACKGROUND: Data dashboards are published tools that present visualizations; they are increasingly used to display data about behavioral health, social determinants of health, and chronic and infectious disease risks to inform or support public health endeavors. Dashboards can be an evidence-based approach used by communities to influence decision-making in health care for specific populations. Despite widespread use, evidence on how to best design and use dashboards in the public health realm is limited. There is also a notable dearth of studies that examine and document the complexity and heterogeneity of dashboards in community settings.

OBJECTIVE: Community stakeholders engaged in the …

Genome-Wide Association Study Meta-Analysis Of Neurofilament Light (Nfl) Levels In Blood Reveals Novel Loci Related To Neurodegeneration, Shahzad Ahmad, Mohammad Aslam Imtiaz, Aniket Mishra, Ruiqi Wang, Marisol Herrera-Rivero, Joshua C Bis, Myriam Fornage, Gennady Roshchupkin, Edith Hofer, Mark Logue, W T Longstreth, Rui Xia, Vincent Bouteloup, Thomas Mosley, Lenore J Launer, Michael Khalil, Jens Kuhle, Robert A Rissman, Genevieve Chene, Carole Dufouil, Luc Djoussé, Michael J Lyons, Kenneth J Mukamal, William S Kremen, Carol E Franz, Reinhold Schmidt, Stephanie Debette, Monique M B Breteler, Klaus Berger, Qiong Yang, Sudha Seshadri, N Ahmad Aziz, Mohsen Ghanbari, M Arfan Ikram

Faculty, Staff and Student Publications

Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels could provide new insights into molecular mechanisms underlying neurodegenerative disorders. In this meta-analysis of genome-wide association studies (GWAS) of blood NfL levels from eleven cohorts of European ancestry, we identify two genome-wide significant loci at 16p12 (UMOD) and 17q24 (SLC39A11). We observe association of three loci at 1q43 (FMN2), 12q14, and 12q21 with blood NfL levels in the meta-analysis of African-American ancestry. In the trans-ethnic meta-analysis, we identify …

Long-Term Longitudinal Analysis Of 4,187 Participants Reveals Insights Into Determinants Of Clonal Hematopoiesis, Md Mesbah Uddin, Seyedmohammad Saadatagah, Abhishek Niroula, Bing Yu, Whitney E Hornsby, Shriienidhie Ganesh, Kim Lannery, Art Schuermans, Michael C Honigberg, Alexander G Bick, Peter Libby, Benjamin L Ebert, Christie M Ballantyne, Pradeep Natarajan

Faculty, Staff and Student Publications

Clonal hematopoiesis of indeterminate potential (CHIP) is linked to diverse aging-related diseases, including hematologic malignancy and atherosclerotic cardiovascular disease (ASCVD). While CHIP is common among older adults, the underlying factors driving its development are largely unknown. To address this, we performed whole-exome sequencing on 8,374 blood DNA samples collected from 4,187 Atherosclerosis Risk in Communities Study (ARIC) participants over a median follow-up of 21 years. During this period, 735 participants developed incident CHIP. Splicing factor genes (SF3B1, SRSF2, U2AF1, and ZRSR2) and TET2 CHIP grow significantly faster than DNMT3A non-R882 clones. We find that age at baseline and sex significantly …

Cardiomyocyte-Derived Small Extracellular Vesicle: A New Mechanism Driving Diabetic Cardiac Fibrosis And Cardiomyopathy, Yu Li, Yunhui Du, Yang Liu, Xiuhuan Chen, Xinxin Li, Yanru Duan, Yanwen Qin, Huirong Liu, Xinliang Ma, Shaoping Nie, Huina Zhang

Department of Emergency Medicine Faculty Papers

Rationale: Diabetic cardiomyopathy is one of the major diabetic cardiovascular complications in which fibrosis plays a critical pathogenetic role. However, the precise mechanisms by which diabetes triggers cardiac fibrosis in the heart remain elusive. Small extracellular vesicles (sEVs) play an important role in the cellular communication. Nevertheless, whether and how diabetes may adversely alter sEVs-mediated cardiomyocyte-fibroblast communication, promoting diabetic cardiac fibrosis and contributing to diabetic cardiomyopathy, has not been previously investigated. Methods and results: High-fat diet (HFD)-induced and genetic (db/db) type 2 diabetic models were utilized. Cardiomyocyte sEVs (Myo-sEVs) were isolated by ultracentrifugation. Normal cardiomyocyte-derived Myo-sEVs attenuated diabetic cardiac fibrosis …

Project Give: Using A Virtual Genetics Service Platform To Reduce Health Inequities And Improve Access To Genomic Care In An Underserved Region Of Texas, Blake Vuocolo, Roberta Sierra, Daniel Brooks, Christopher Holder, Lauren Urbanski, Keila Rodriguez, Jose David Gamez, Surya Narayan Mulukutla, Ana Hernandez, Alberto Allegre, Humberto Hidalgo, Sarah Rodriguez, Sandy Magallan, Jeremy Gibson, Juan Carlos Bernini, Melanie Watson, Robert Nelson, Lizbeth Mellin-Sanchez, Nancy Garcia, Lori Berry, Hongzheng Dai, Claudia Soler-Alfonso, Kent Carter, Brendan Lee, Seema R Lalani

Faculty, Staff and Students Publications

BACKGROUND: The utilization of genomic information to improve health outcomes is progressively becoming more common in clinical practice. Nonetheless, disparities persist in accessing genetic services among ethnic minorities, individuals with low socioeconomic status, and other vulnerable populations. The Rio Grande Valley (RGV) at the Texas-Mexico border is predominantly Hispanic/Latino with a high poverty rate and very limited access to genetic services. Funded by the National Center for Advancing Translational Sciences, Project GIVE (Genetic Inclusion by Virtual Evaluation) was launched in 2022 to reduce the time to diagnosis and increase provider knowledge of genomics in this region, with the goal of …

Early Identification Of Hepatocellular Carcinoma Patients At High-Risk Of Recurrence Using The Adv Score: A Multicenter Retrospective Study, Shuya Cao, Zheyu Zhou, Chaobo Chen, Wenwen Li, Jinsong Liu, Jiawei Xu, Chunlong Zhao, Yihang Yuan, Zhenggang Xu, Huaiyu Wu, Guwei Ji, Xiaoliang Xu, Ke Wang

Faculty, Staff and Student Publications

BACKGROUND: Postoperative recurrence is a vital reason for poor 5-year overall survival in hepatocellular carcinoma (HCC) patients. The ADV score is considered a parameter that can quantify HCC aggressiveness. This study aimed to identify HCC patients at high-risk of recurrence early using the ADV score.

METHODS: The medical data of consecutive HCC patients undergoing hepatectomy from The First Affiliated Hospital of Nanjing Medical University (TFAHNJMU) and Nanjing Drum Tower Hospital (NJDTH) were retrospectively reviewed. Based on the status of microvascular invasion and the Edmondson-Steiner grade, HCC patients were divided into three groups: low-risk group (group 1: no risk factor exists), …

Smoking And Alcohol By Hpv Status In Head And Neck Cancer: A Mendelian Randomization Study, Abhinav Thakral, Laura Bierut, Et Al.

2020-Current year OA Pubs

HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are recognized as distinct entities. There remains uncertainty surrounding the causal effects of smoking and alcohol on the development of these two cancer types. Here we perform multivariable Mendelian randomization (MR) to evaluate the causal effects of smoking and alcohol on the risk of HPV-positive and HPV-negative HNSCC in 3431 cases and 3469 controls. Lifetime smoking exposure, as measured by the Comprehensive Smoking Index (CSI), is associated with increased risk of both HPV-negative HNSCC (OR = 3.03, 95%CI:1.75-5.24, P = 7.00E-05) and HPV-positive HNSCC (OR = 2.73, 95%CI:1.39-5.36, P = …

Small Gtp-Binding Protein Gdp Dissociation Stimulator Influences Cisplatin-Induced Acute Kidney Injury Via Perk-Dependent Er Stress, Yuxue Yang, Ting Xiong, Ti Wang, Xiwei Chen, Ziwei Ma, Bangyun Zuo, Dong Ning, Ruilong Song, Xuesong Liu, Daxin Wang

Children’s Nutrition Research Center Staff Publications

Cisplatin is a common anticancer drug, but its frequent nephrotoxicity limits its clinical use. Small GTP-binding protein GDP dissociation stimulator (smgGDS), a small GTPase chaperone protein, was considerably downregulated during cisplatin-induced acute kidney injury (CDDP-AKI), especially in renal tubular epithelial cells. SmgGDS-knockdown mice was established and found that smgGDS knockdown promoted CDDP-AKI, as demonstrated by an increase in serum creatine, blood urea nitrogen levels and the appearance of tubular patterns. RNA sequencing suggested that protein kinase RNA-like ER kinase (PERK), which bridges mitochondria-associated ER membranes, was involved in smgGDS knockdown following CDDP-AKI, and then identified that smgGDS knockdown increased phosphorylated-PERK …

Substitution Of A Single Non-Coding Nucleotide Upstream Of Tmem216 Causes Non-Syndromic Retinitis Pigmentosa And Is Associated With Reduced Tmem216 Expression, Samantha Malka, Pooja Biswas, Anne-Marie Berry, Riccardo Sangermano, Mukhtar Ullah, Siying Lin, Matteo D'Antonio, Aleksandr Jestin, Xiaodong Jiao, Mathieu Quinodoz, Lori Sullivan, Jessica C Gardner, Emily M Place, Michel Michaelides, Karolina Kaminska, Omar A Mahroo, Elena Schiff, Genevieve Wright, Francesca Cancellieri, Veronika Vaclavik, Cristina Santos, Atta Ur Rehman, Sudeep Mehrotra, Hafiz Muhammad Azhar Baig, Muhammad Iqbal, Muhammad Ansar, Luisa Coutinho Santos, Ana Berta Sousa, Viet H Tran, Hiroko Matsui, Anjana Bhatia, Muhammad Asif Naeem, Shehla J Akram, Javed Akram, Sheikh Riazuddin, Carmen Ayuso, Eric A Pierce, Alison J Hardcastle, S Amer Riazuddin, Kelly A Frazer, J Fielding Hejtmancik, Carlo Rivolta, Kinga M Bujakowska, Gavin Arno, Andrew R Webster, Radha Ayyagari

Faculty, Staff and Student Publications

Genome analysis of individuals affected by retinitis pigmentosa (RP) identified two rare nucleotide substitutions at the same genomic location on chromosome 11 (g.61392563 [GRCh38]), 69 base pairs upstream of the start codon of the ciliopathy gene TMEM216 (c.-69G>A, c.-69G>T [GenBank: NM_001173991.3]), in individuals of South Asian and African ancestry, respectively. Genotypes included 71 homozygotes and 3 mixed heterozygotes in trans with a predicted loss-of-function allele. Haplotype analysis showed single-nucleotide variants (SNVs) common across families, suggesting ancestral alleles within the two distinct ethnic populations. Clinical phenotype analysis of 62 available individuals from 49 families indicated a similar clinical presentation …

Adjunctive Intravenous Argatroban Or Eptifibatide For Ischemic Stroke, Opeolu Adeoye, Peter Panagos, Stephanie Pizzella, Et Al.

2020-Current year OA Pubs

BACKGROUND: Intravenous thrombolysis is a standard treatment of acute ischemic stroke. The efficacy and safety of combining intravenous thrombolysis with argatroban (an anticoagulant agent) or eptifibatide (an antiplatelet agent) are unclear.

METHODS: We conducted a phase 3, three-group, adaptive, single-blind, randomized, controlled clinical trial at 57 sites in the United States. Patients with acute ischemic stroke who had received intravenous thrombolysis within 3 hours after symptom onset were assigned to receive intravenous argatroban, eptifibatide, or placebo within 75 minutes after the initiation of thrombolysis. The primary efficacy outcome, the utility-weighted 90-day modified Rankin scale score (range, 0 to 10, with …

Tulips Decorate The Three-Dimensional Genome Of Pfa Ependymoma, Michael J Johnston, John J Y Lee, Bo Hu, Ana Nikolic, Elham Hasheminasabgorji, Audrey Baguette, Seungil Paik, Haifen Chen, Sachin Kumar, Carol C L Chen, Selin Jessa, Polina Balin, Vernon Fong, Melissa Zwaig, Kulandaimanuvel Antony Michealraj, Xun Chen, Yanlin Zhang, Srinidhi Varadharajan, Pierre Billon, Nikoleta Juretic, Craig Daniels, Amulya Nageswara Rao, Caterina Giannini, Eric M Thompson, Miklos Garami, Peter Hauser, Timea Pocza, Young Shin Ra, Byung-Kyu Cho, Seung-Ki Kim, Kyu-Chang Wang, Ji Yeoun Lee, Wieslawa Grajkowska, Marta Perek-Polnik, Sameer Agnihotri, Stephen Mack, Benjamin Ellezam, Alex Weil, Jeremy Rich, Guillaume Bourque, Jennifer A Chan, V Wee Yong, Mathieu Lupien, Jiannis Ragoussis, Claudia Kleinman, Jacek Majewski, Mathieu Blanchette, Nada Jabado, Michael D Taylor, Marco Gallo

Faculty, Staff and Students Publications

Posterior fossa group A (PFA) ependymoma is a lethal brain cancer diagnosed in infants and young children. The lack of driver events in the PFA linear genome led us to search its 3D genome for characteristic features. Here, we reconstructed 3D genomes from diverse childhood tumor types and uncovered a global topology in PFA that is highly reminiscent of stem and progenitor cells in a variety of human tissues. A remarkable feature exclusively present in PFA are type B ultra long-range interactions in PFAs (TULIPs), regions separated by great distances along the linear genome that interact with each other in …

Asymmetric Distribution Of Color-Opponent Response Types Across Mouse Visual Cortex Supports Superior Color Vision In The Sky, Katrin Franke, Chenchen Cai, Kayla Ponder, Jiakun Fu, Sacha Sokoloski, Philipp Berens, Andreas Savas Tolias

Faculty, Staff and Students Publications

Color is an important visual feature that informs behavior, and the retinal basis for color vision has been studied across various vertebrate species. While many studies have investigated how color information is processed in visual brain areas of primate species, we have limited understanding of how it is organized beyond the retina in other species, including most dichromatic mammals. In this study, we systematically characterized how color is represented in the primary visual cortex (V1) of mice. Using large-scale neuronal recordings and a luminance and color noise stimulus, we found that more than a third of neurons in mouse V1 …

Regional Desynchronization Of Microglial Activity Is Associated With Cognitive Decline In Alzheimer's Disease, Artem Zatcepin, Samira Parhizkar, Et Al.

2020-Current year OA Pubs

BACKGROUND: Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker.

METHODS: To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia …

Physiological And Communicative Emotional Disconcordance In Children On The Autism Spectrum, Emma Finkel, Eric Sah, Mckenna Spaulding, John Herrington, Liza Tomczuk, Aaron Masino, Xueqin Pang, Anushua Bhattacharya, Darren Hedley, Yelena Kushleyeva, Phoebe Thomson, Natalie Doppelt, Jessica Tan, Jeffrey Pennington, Cheryl Dissanayake, Christopher Bonafide, Heather Nuske

SKMC Student Presentations and Publications

BACKGROUND: Individuals on the autism spectrum commonly have differences from non-autistic people in expressing their emotions using communicative behaviors, such as facial expressions. However, it is not yet clear if this reduced expressivity stems from reduced physiological reactivity in emotional contexts or if individuals react internally, but do not show these reactions externally to others. We hypothesized that autism is characterized by a discordance between in-the-moment internal psychophysiological arousal and external communicative expressions of emotion.

METHODS: Forty-one children on the autism spectrum and 39 non-autistic, typically developing (TD) children of two age groups (2-4 and 8-12 years) participated in a …

Different Sensory Information Is Used For State Estimation When Stationary Or Moving., Aaron Wong, Alyssa Eyssalenne, Luke Carter, Amanda S Therrien

Moss-Magee Rehabilitation Papers

The accurate estimation of limb state is necessary for movement planning and execution. While state estimation requires both feedforward and feedback information, we focus here on the latter. Prior literature has shown that integrating visual and proprioceptive feedback improves estimates of static limb position. However, differences in visual and proprioceptive feedback delays suggest that multisensory integration could be disadvantageous when the limb is moving. We formalized this hypothesis by modeling feedback-based state estimation using the long-standing maximum likelihood estimation model of multisensory integration, which we updated to account for sensory delays. Our model predicted that the benefit of multisensory integration …

Intracellular Islatravir-Triphosphate Half-Life Supports Extended Dosing Intervals, Xiaowei Zang, Wendy Ankrom, Walter K. Kraft, Ryan Vargo, S Aubrey Stoch, Marian Iwamoto, Randolph P Matthews

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Antiretroviral therapy has substantially reduced morbidity, mortality, and disease transmission in people living with HIV. Islatravir is a nucleoside reverse transcriptase translocation inhibitor that inhibits HIV-1 replication by multiple mechanisms of action, and it is in development for the treatment of HIV-1 infection. In preclinical and clinical studies, islatravir had a long half-life (t½) of 3.0 and 8.7 days (72 and 209 hours, respectively); therefore, islatravir is being investigated as a long-acting oral antiretroviral agent. A study was conducted to definitively elucidate the terminal t½ of islatravir and its active form islatravir-triphosphate (islatravir-TP). A single-site, open-label, non-randomized, single-dose phase 1 …

Cystic Fibrosis-Related Diabetes Screening At A Large Pediatric Center, Anil K Chokkalla, Pamela Tuley, Miray Kurtca, Herda Ona, Fadel E Ruiz, Sridevi Devaraj

Faculty, Staff and Students Publications

Objective: Cystic Fibrosis Foundation guidelines recommend annual diabetes screening by oral glucose tolerance test (OGTT) in pediatric patients with cystic fibrosis (CF) starting at the age of 10 years. Adherence to these guidelines proves to be challenging, and the nationwide screening rates are still considered suboptimal. The aim of this study was to assess and improve the screening rates at our large pediatric center.

Methods: A 4-year retrospective audit of OGTT completion among pediatric patients with CF of age ≥10 years who are not yet diagnosed with diabetes was conducted. A collaborative working group was formed to identify the barriers …

Development And Preliminary Validation Of A Screener For Digital Health Readiness, Kristin Rising, Amanda Guth, Alexzandra Gentsch, Karla Martin Gonzalez, Richard Hass, Lindsey Shughart, Serena Gelfer, Megan Mcvane, Brooke Worster, Amy Leader

Department of Medicine Faculty Papers

IMPORTANCE: While telehealth use has grown, patient uptake is variable, which has the potential to increase health disparities. Identifying and understanding individuals' barriers to digital health readiness can help health systems efficiently deploy resources to provide personalized patient-centered support.

OBJECTIVE: To develop and validate an instrument to evaluate digital health readiness to identify and quantify barriers to digital readiness.

DESIGN, SETTING, AND PARTICIPANTS: In this qualitative mixed-methods study conducted from April 26, 2022, to June 8, 2023, the instrument was created in 4 phases. Patients and health care professionals were interviewed to explore barriers to telehealth use, scale items were …

Residual Stroke Risk Among Patients With Atrial Fibrillation Prescribed Oral Anticoagulants: A Patient-Level Meta-Analysis From Combine Af, Linda Johnson, Alexander Benz, Ashkan Shoamanesh, John W Eikelboom, Michael Ezekowitz, Robert Giugliano, Lars Wallentin, Christian Ruff, Renato Lopes, Sanjit Jolly, Richard Whitlock, Christopher Granger, Stuart Connolly, Jeffrey Healey

Division of Cardiology Faculty Papers

Background: Despite oral anticoagulation, patients with atrial fibrillation (AF) remain at risk of ischemic stroke and systemic embolism (SE) events. For patients whose residual risk is sufficiently high, additional therapies might be useful to mitigate stroke risk.

Methods and results: Individual patient data from 5 landmark trials testing oral anticoagulation in AF were pooled in A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in AF (COMBINE AF). We calculated the rate of ischemic stroke/SE among oral anticoagulation-treated patients with a CHA₂DS₂-VASc score≥2, across strata of CHA₂DS₂-VASc …

Racial And Ethnic Representation In Food Allergen Immunotherapy Trial Participants: A Systematic Review., Hannah Suffian, Aarti Pandya, Lauren Davidson, Vincent Staggs, Bridgette Jones

Manuscripts, Articles, Book Chapters and Other Papers

IMPORTANCE: The lack of inclusion of diverse population samples in food allergy immunotherapy clinical trials not only leads to decreased applicability to the general population in terms of results and treatments but can also be seen as a broader social injustice contributing to inequity within the health care system.

OBJECTIVES: To investigate the racial and ethnic distribution of participants included in food allergy immunotherapy clinical trials, and determine whether the racial and ethnic representation in trials accurately reflects the patients who experience food allergy.

EVIDENCE REVIEW: Data were collected from articles found on PubMed and ClinicalTrials.gov using key terms of …

Segregation By Payer In Obstetrics And Gynecology Residency Ambulatory Care Sites, Kavita Vinekar, Neena Qasba, Hannah Reiser, Erika Banks, Kavita Arora, Brownsyne Edmonds, Karen George

Department of Obstetrics and Gynecology Faculty Papers

IMPORTANCE: Many teaching hospitals in the US segregate patients by insurance status, with resident clinics primarily composed of publicly insured or uninsured patients and faculty practices seeing privately insured patients. The prevalence of this model in obstetrics and gynecology residencies is unknown.

OBJECTIVES: To examine the prevalence of payer-based segregation in obstetrics and gynecology residency ambulatory care sites nationally and to compare residents' and program directors' perceptions of differences in quality of care between payer-segregated and integrated sites.

DESIGN, SETTING, AND PARTICIPANTS: This national survey study included all 6060 obstetrics and gynecology residents and 293 obstetrics and gynecology residency program …

Association Between Obesity And Risk Of Total And Obesity-Related Cancer In People With Incident Cardiovascular Disease., Sarah Malik, Avirup Guha, Xiaoling Wang, Neal L. Weintraub, Ryan Harris, Biplab Datta, Justin Moore, Priyanshu Nain, Sagar A. Patel, Steven Coughlin, Elizabeth Polter, Anna Prizment, Anne Blaes, Roberta Florido, Shelby Kutty, Alvaro Alonso, Corinne E. Joshu, Elizabeth A. Platz

Markey Cancer Center Faculty Publications

BACKGROUND: Cardiovascular disease (CVD) and cancer frequently co-occur due to shared risk factors such as obesity, which is linked to CVD and 14 cancer types. This study explores whether CVD pathophysiologies, combined with obesity, increase cancer risk, impacting clinical management.

METHODS AND RESULTS: Data from the ARIC (Atherosclerosis Risk in Communities) study, spanning 28 years, were analyzed. The cohort included 5127 participants with incident CVD (myocardial infarction, stroke, heart failure, coronary heart disease), of whom 1511 developed a first primary cancer. Follow-up began at CVD diagnosis after Visit 1. Obesity was assessed using body mass index, waist circumference, and waist-to-hip …