Medicine and Health Sciences Commons^™

Early Genetic Evolution Of Driver Mutations In Uveal Melanoma, James J Dollar, Kisha D Piggott, Et Al.

2020-Current year OA Pubs

Uveal melanoma (UM) is an aggressive eye cancer that frequently results in metastatic death despite successful primary tumor treatment. Subclinical micrometastasis is thought to occur early, when tumors are small and difficult to distinguish from benign nevi. However, the early genetic evolution of UM is poorly understood, and biomarkers for malignant transformation are lacking. Here, we perform integrated genetic profiling of 1140 primary UMs, including 131 small tumors. A clinically available 15-gene expression profile (15-GEP) prospectively validated by our group is more accurate than driver mutations for predicting patient survival. Small tumors are significantly more likely to be in earlier …

Sex-Specific Angiogenic Responses In Endothelial Cells-Role Of The Pluripotency Factor Oct4, Junchul Shin, Junyoung Hong, Iuliia Molokotina, Irene Krukovets, Ellin Kim, Svyatoslav Tkachenko, Eugene Podrez, Tatiana V Byzova, Olga A Cherepanova

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The study investigates the sex-specific effects of the pluripotency factor OCT4 deficiency in endothelial cells (ECs) on angiogenesis. OCT4 is known for its role in embryonic stem cells, but we recently found that it plays a protective role in ECs during atherosclerosis. Herein, we utilized cultured mouse aortic ECs (MAECs) and several in vivo models, including skin wounding, melanoma tumor implantation, and hindlimb ischemia, to explore the role of OCT4 in angiogenesis in both male and female mice. Our findings revealed significant sexual dimorphism in wild type mice, along with sex differences in responses to OCT4 deficiency across all three …

Incomplete (A3) Versus Complete (A4) Thoracolumbar Burst Fractures: Results From A Prospective International Multicenter Cohort Study, Jin W. Tee, Barry T. S. Kweh, Alex R. Vaccaro, Klaus J. Schnake, Mohammad El-Sharkawi, Eugen C. Popescu, Shanmuganathan Rajasekaran, Lorin M. Benneker, Sebastian F. Bigdon, John France, Jerome Paquet, R. Todd Allen, William F. Lavelle, Miguel Hirschfeld, Spyridon Pneumaticos, Richard J. Bransford, Andrei F. Joaquim, Harvinder S. Chhabra, Ulrich Spiegl, Hauri Dimitri, F. Cumhur Oner, Marcel Dvorak, Gregory D. Schroeder, Charlotte Dandurand

Department of Orthopaedic Surgery Faculty Papers

OBJECTIVE: The objective was to compare incomplete (A3) versus complete (A4) thoracolumbar burst fractures managed nonoperatively or operatively with respect to reaching minimal clinically important difference (MCID) in Oswestry Disability Index (ODI) score.

METHODS: A prospective observational international multicenter cohort study was conducted. After stratification using the AO Spine Thoracolumbar Injury Classification System, A3 and A4 outcomes were analyzed separately within nonoperative and operative management groups. Outcomes included absolute and relative improvement in ODI scores between discharge and 12-month follow-up. Kaplan-Meier curves were generated and compared with the log-rank test. Multivariable Cox regression models were constructed. The Cox regression models …

A Qualitative Exploration Of Patient And Clinician Needs And Preferences For A Physical Activity Intervention During Breast Cancer Chemotherapy, D Carolina Andrade, Loni Parrish, Courtney Harriss, Lindsay L Peterson, Ryan P Duncan, Jingqin Luo, Maura M Kepper, Christine Marx, Mary C Politi, Elizabeth A Salerno

2020-Current year OA Pubs

BACKGROUND: Early intervention with physical activity (PA) during active cancer treatment is critical for improved health outcomes, but often difficult to deliver. We assessed patients' and clinicians' needs and preferences for a PA intervention during chemotherapy via semi-structured interviews.

METHODS: We conducted virtual semi-structured interviews from May 2022 to May 2023 with patients with stage I-III breast cancer and oncology clinicians recruited from a Midwestern comprehensive cancer center and community settings. We identified themes using deductive and inductive thematic analysis informed by the Consolidated Framework for Implementation Research.

RESULTS: Patients (n = 16) were mostly White, non-Hispanic (93.8%) females (100%) …

Emg-Guided Human-Machine Interaction Training Develops New Intermuscular Coordination Patterns In Stroke: A Pilot Study, Gang Seo, Manuel Portilla-Jiménez, Michael Houston, Jeong-Ho Park, Hangil Lee, Sheng Li, Yingchun Zhang, Hyung-Soon Park, Jinsook Roh

Faculty, Staff and Student Publications

Background: Stroke survivors often experience impaired upper extremity motor function due to abnormal muscle synergies. This pilot study evaluated the feasibility and preliminary effectiveness of electromyography-guided human-machine interaction training designed to expand the repertoire of intermuscular coordination patterns and improve upper extremity motor function in chronic stroke survivors.

Methods: Four chronic stroke survivors with mild-to-moderate upper extremity motor impairment and three age-matched healthy controls participated in a six-week electromyography-guided training intervention. Participants practiced selectively activating one elbow flexor muscle while suppressing another (brachioradialis or biceps brachii). Throughout the course of the intervention, the effect of the training on intermuscular coordination, …

A Nationwide Registry Study Of Surgical And Patient-Reported Outcomes Following Anterior Cervical Discectomy And Fusion: Part 2 - Cage With Versus Without Local Bone Graft, Daniel De Wilde, Victor Gabriel El-Hajj, Patrick Vigren, Victor E. Staartjes, Elias Atallah, Erik Edström, Adrian Elmi-Terander

Department of Neurosurgery Faculty Papers

BACKGROUND: Local bone grafts are commonly used as filling material in cages during anterior cervical discectomy and fusion (ACDF). Alternatively, cages without filling materials can be used. The literature comparing these approaches is limited, and their respective effects on patient-reported outcomes (PROM) have been scarcely studied. This study was conducted to compare surgical outcomes and PROMs between local bone graft-packed cages and empty cages in ACDF surgery.

METHODS: This observational study utilized data from the Swedish nationwide registry, Swespine. All adults who underwent ACDF between 2006 and 2020 were considered for inclusion. Exclusion criteria included missing baseline or outcome data. …

Structural Birth Defects And Leukemia Risk In Children With Down Syndrome, Ching-Ju Hsu, Jeremy M Schraw, Sonja A Rasmussen, Tiffany M Chambers, Tania A Desrosiers, Chad D Huff, Amanda E Janitz, Russell S Kirby, Eirini Nestoridi, Wendy N Nembhard, Jason L Salemi, Charles Shumate, Jean Paul Tanner, Mahsa M Yazdy, Michael E Scheurer, Karen R Rabin, Philip J Lupo

Faculty, Staff and Students Publications

Birth defects are associated with increased cancer risk in the general pediatric population, yet their impact on leukemia risk in children with Down syndrome (DS) remains uncertain. We assessed this using data from 26,660 children with DS in the Genetic Overlap Between Anomalies and Cancer in Kids Registry Linkage Study. Among them, 71.9% had at least one major birth defect, predominantly involving the cardiac (64.2%), musculoskeletal (21%), and gastrointestinal systems (6.8%). The cumulative incidence of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) was comparable in children with and without co-occurring defects. Adjusted hazard ratios (aHR) for ALL and …

Longitudinal Quality Improvement Project To Increase Colorectal Cancer Screening For An Underserved Population In A Resident Physician-Led Primary Care Clinic., Vivek Vardhan Jasti, Sarah N Grebennikov, Mariah Barlow, David Y Lo, Shail M Govani, Miram Chan, Aimee E Willett, Christopher Barlow

Medical Education Articles

BACKGROUND: The overall rates of colorectal cancer (CRC) in the US population have been declining steadily over the past 30 years, in large part due to timely cancer screenings. Despite the emergence of new screening modalities, a large portion of the population has not completed CRC screening in accordance with guidelines. Adequate and timely screening can prevent or detect CRC in earlier stages. Various factors have been identified that influence screening completion. Lower screening rates have been associated with the underserved population, especially in the immigrant community and patients with inadequate access to healthcare. In the USA, primary care clinics …

Seed Amplification Of Msa Alpha-Synuclein Aggregates Preserves The Biological And Structural Properties Of Brain-Derived Aggregates, Fei Wang, Victor Banerjee, Carla Barria, Santiago Ramirez, Tyler Allison, Damian Gorski, Haley Evans, Quynh Nguyen, Danielle Harrison, Rabab Al-Lahham, Nicole De Gregorio Carbonell, Michelle Pinho, Sanne Kaalund, Jonas Folke, Susana Aznar, Luis Concha-Marambio, Mohd Ishtikhar, Venkata Kps Mallampalli, Sandra Pritzkow, Mohammad Shahnawaz, Matthew L Baker, Irina Serysheva, Claudio Soto

Faculty, Staff and Student Publications

Parkinson's disease (PD), Dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are characterized by the misfolding and aggregation of alpha-synuclein (αSyn). Compelling evidence showed that αSyn aggregates exist as distinct conformational strains in different synucleinopathies. Recently, we reported that the αSyn Seed Amplification Assay (αSyn-SAA) can amplify and distinguish αSyn strains from PD and MSA. In this study, we investigate whether MSA-seeded, SAA-amplified αSyn fibrils retain the biological and structural properties of the αSyn seeds present in MSA brains. We study the biological activities of both brain-derived and SAA-amplified αSyn aggregates using an αSyn "biosensor" cell model and …

Camidanlumab Tesirine For Relapsed Or Refractory Classic Hodgkin Lymphoma: A Phase 2 Study, Alex F Herrera, Nancy L Bartlett, Et Al.

2020-Current year OA Pubs

Outcomes in classic Hodgkin lymphoma (cHL) have steadily improved; however, additional therapies are needed for patients who relapse or do not respond to novel agents. Here, we report the efficacy and safety of camidanlumab tesirine (Cami), an anti-CD25 antibody-drug conjugate, in patients with relapsed/refractory cHL after brentuximab vedotin/programmed cell death protein 1 inhibitor therapies from the phase 2 ADCT-301-201 study. Eligible patients were adults with cHL who had received ≥3 previous lines of systemic therapy (or ≥2 if ineligible for hematopoietic stem cell transplant). Patients received 45 μg/kg Cami (IV, once every 3 weeks) in cycles 1 to 2, followed …

Association Of Pet4 Response With Outcomes Of Bv-Chp Vs Chop In The Echelon-2 Trial In Cd30+ Peripheral T-Cell Lymphoma, Swaminathan Iyer, Neha Mehta-Shah, Nancy L Bartlett, Et Al.

2020-Current year OA Pubs

In the phase 3 ECHELON-2 trial, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (BV-CHP) significantly improved progression-free survival (PFS) and overall survival (OS) compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with CD30+ peripheral T-cell lymphoma, benefits that were maintained at 5 years. Interim positron emission tomography (PET) scan can be used to assess prognosis and risk-stratify patients. The prognostic value of interim PET was assessed in this post hoc exploratory analysis from ECHELON-2, evaluating interim 18F-fluorodeoxyglucose PET scans after cycle 4 (PET4) and end-of-treatment-based response, and correlated with PFS per investigator and OS. PET4 response was determined by …

Deep Profiling Of Human T Cells Defines Compartmentalized Clones And Phenotypic Trajectories Across Blood And Tonsils, Suhas Sureshchandra, Elizabeth Levendosky, Allyssa Daugherty, Samuel J H Murphy, Chandrani Thakur, Naresha Saligrama, Et Al.

2020-Current year OA Pubs

98% of T cells reside in tissues, yet nearly all human T cell analyses are performed on peripheral blood. We performed single-cell sequencing of 5.7 million T cells from autologous blood and tonsils of ten donors. We identified distinct patterns of clonal expansion associated with tonsil-restricted phenotypes. Clonal sharing between blood and tonsils was lower than previous estimates and increased with age. Identical T cell receptor (TCR) sequences exhibited limited concordance in their phenotypes across compartments. Furthermore, location dictated the frequencies, clonal dominance, and phenotypes of antigen-specific T cells. Using immune organoids, we showed that antigen exposure drives functionally distinct …

Precise Diagnosis Of Small Invasive Pulmonary Nodules Driven By Single-Cell Immune Signatures In Peripheral Blood, Yang Xia, Yin Zhu, Sai Zhang, Mo Zhou, Jiaqi Zhou, Guanxin Xu, Baiqin Zhao, Guofei Zhang, Qiyuan Wang, Bin Wang, Zexin Chen, Hongyu Shi, Xiuning Le, Tony Mok, Wei Chen, Junqiang Fan, Weiwei Yin, Wen Li

Faculty, Staff and Student Publications

Early detection of lung cancer is crucial for improving patient outcomes. However, accurately diagnosing invasive pulmonary nodules and predicting tumor invasiveness remain major clinical challenges. Given the established role of immune dysfunction in cancer development, we hypothesize that peripheral immune profiling could provide a strategy for managing pulmonary nodules. In this multi-center, prospective study, we combine peripheral immune profiling via mass cytometry with machine learning algorithms to develop an integrated pulmonary nodule management platform. This platform accurately distinguishes invasive from non-invasive pulmonary nodules (AUC = 0.952), outperforming established clinical and radiomics-based models. Furthermore, it effectively predicts tumor invasiveness, differentiating minimally …

Comprehensive Cmr Evaluation Including 4d Flow-Derived E/A Vorticity Ratio In Overweight Adults With And Without Type 2 Diabetes Mellitus, Sungho Park, Erin K Englund, Takashi Fujiwara, Daniel Enge, Michal Schäfer, Jochen Gerstner Saucedo, Ethan W Clark, Layla A Abushamat, Rebecca L Scalzo, Brian Fonseca, Kendall S Hunter, Mary D Sammel, Judith G Regensteiner, Jane E B Reusch, Alex J Barker

Faculty, Staff and Students Publications

Aims: This study aimed to assess the impacts of overweight and type 2 diabetes (T2D) on early hemodynamic and left ventricular (LV) changes using comprehensive cardiovascular magnetic resonance imaging (CMR) in three age- and sex-similar groups: lean individuals (LI group), BMI-similar overweight controls without T2D (CWO group) and overweight individuals with uncomplicated T2D (T2D group).

Methods: Middle-aged participants included 13 in the LI group, 37 in the CWO group, and 28 in the T2D group. Baseline assessments included cardiac and vascular function measured by CMR, thoracic echocardiography, insulin sensitivity, clinical measures, and cardiorespiratory fitness. 4D flow CMR was used to …

Myocardial Lipin1 Protects The Heart Against Ischemic Injury By Preserving Lipid Homeostasis, Jiaxi Guo, Brian N. Finck, Et Al.

2020-Current year OA Pubs

Impaired cardiac lipid metabolism has been reported to cause heart failure. Lipin1, a multifunctional protein, is a phosphatidate phosphatase that generates diacylglycerol from phosphatidic acid and a transcriptional cofactor that regulates lipid metabolism-related gene expression. Here, we investigated the roles of lipin1 in cardiac remodeling after myocardial infarction (MI). The expression levels of lipin1 significantly decreased in cardiomyocytes of the human failing heart and murine ischemic myocardium. Cardiomyocyte-specific Lpin1 knockout (cKO) mice showed left ventricle enlargement and reduced fractional shortening after MI, compared with control mice. This was accompanied by elevated cardiac fibrosis, accumulation of reactive oxygen species, and increased …

Liver Injury In A Preclinical Model Of Short Bowel Syndrome Is Associated With Impaired Autophagy, Daniel M Alligood, Alex Park, Kerry Swanson, Naima Pyarali, Evan Mayse, David M Alvarado, Xiuli Liu, Jae-Sung Kim, Nicholas O Davidson, Deborah C Rubin, Jun Guo, Brad W Warner

2020-Current year OA Pubs

Critical for cellular maintenance and repair, autophagy recycles damaged or redundant cellular components. Dysregulated autophagy is associated with progressive cellular injury in various liver pathologies. However, the role of autophagy in intestinal failure-associated liver disease has not previously been investigated. Using a preclinical murine model of short bowel syndrome, we explored the role of autophagy impairment at early and late time points. Regardless of sex, small bowel resected (SBR) mice demonstrated significant liver injury compared to sham controls, exhibiting elevated serum transaminases, altered liver histology, and increased mRNA expression of endoplasmic reticulum stress marker (Ddit3) and oxidative stress marker (Nqo1). …

Early Peripheral Blood Gene Expression Predicts 90-Day Outcomes Following Subarachnoid Hemorrhage, Bodie Knepp, Garreck H Lenz, Frank R Sharp, Fernando Rodriguez, Huimahn Alex Choi, Aaron M Gusdon, Glen Jickling, Lara L Zimmermann, Ryan Martin, Jeffrey Vitt, Ben Waldau, Brandon J Cord, Alan Yee, Kwan Ng, Nerissa U Ko, Heather Hull, Bradley P Ander, Boryana Stamova

Faculty, Staff and Student Publications

BACKGROUND: Previous clinical, radiological and machine learning studies have predicted 90-day outcomes following subarachnoid hemorrhage (SAH). The present study was designed to determine whether early changes in mRNA expression of immune, clotting and other genes expressed in peripheral blood can predict patient outcomes at 90 days after SAH and possibly provide insights into the molecular factors that promote good versus poor outcomes.

METHODS: Peripheral blood was drawn after SAH and from vascular risk factor controls (VRFC) and RNAseq performed to measure mRNA expression. A mixed effects regression model identified potential predictors and machine learning algorithms derived the best predictors of …

Proteome-Wide Association Study Of Prostate Cancer Risk Across Populations, Hua Zhong, Jingjing Zhu, Shuai Liu, Chong Wu, Liang Wang, Seamus P Whelton, Catherine H Marshall, Michael J Blaha, Peter Durda, Xiuqing Guo, Craig W Johnson, Henry J Lin, Kent D Taylor, Russell P Tracy, Ronit I Yarden, Ani W Manichaikul, Stephen S Rich, Jerome I Rotter, Rajat Deo, Ruth F Dubin, Peter Ganz, Lang Wu

Faculty, Staff and Student Publications

There is insufficient understanding of the molecular basis of prostate cancer (PCa) across different populations. We perform a large-scale proteome-wide association study (PWAS) to identify proteins with genetically regulated expression in plasma to be associated with PCa risk across populations. We develop genetic prediction models for expression of 1578, 1993, 1218, and 1390 proteins for African (n = 450), European (n = 758), Asian (n = 289), and Hispanic/Latino (n = 474) males, respectively, and evaluate associations of genetically regulated protein expression with PCa risk in 19,391 PCa cases and 61,608 controls of African population, 122,188 cases and 604,640 controls …

Inhibitory Control, Attentional Bias, And Palatable Food Consumption In Adolescents: A Laboratory Feasibility Randomized Controlled Trial., Carolina M. Bejarano, Adrian Ortega, Christopher C. Cushing

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Understanding relationships among inhibitory control, attentional bias to food cues, and food consumption in nonclinical adolescent samples can inform preventive efforts for disordered eating and associated health risks.

OBJECTIVE: This pilot study conducted preliminary testing of an inhibitory control training intervention on attentional bias toward food cues, hedonic appetite, and food consumption, as well as examined inhibitory control's relationship with hedonic appetite, food consumption, binge eating, and cognitive restraint.

METHODS: Participants (N=43; mean age 15.1, SD 1.7 years; 31/43, 72% female) were randomized to a food cue-specific go/no go inhibitory control training intervention or control group, took part in …

Fgf13 Regulates Vgsc-Independent Cardiomyocyte Impulse Propagation Via Cx43 Trafficking, Lala Tanmoy Das, Mattia Malvezzi, Aravind R Gade, Maiko Matsui, Margaret Mckay, Eric Q Wei, Matea J Zelich, Keon Mazdisnian, Jared Kushner, Bi-Xing Chen, Isabella Distefano, Daniel Roybal, Lin Yang, Lisa Stoll, James C Lo, Marian Kalocsay, Fadi G Akar, Steven O Marx, Geoffrey S Pitt

Faculty, Staff and Student Publications

Background: FHF (fibroblast growth factor homologous factor) variants associate with arrhythmias. Although FHFs are best characterized as regulators of voltage-gated sodium channel (VGSC) gating, recent studies suggest broader, non-VGSC-related functions, including regulation of Cx43 (connexin 43) gap junctions and hemichannels, mechanisms that have generally been understudied or disregarded.

Methods: We assessed cardiac conduction and cardiomyocyte action potentials in mice with constitutive cardiac-specific Fgf13 ablation (cFgf13KO) while targeting Cx43 gap junctions and hemichannels pharmacologically. We characterized FGF13 regulation of Cx43 abundance and subcellular distribution. With proximity labeling proteomics, we investigated novel candidate mechanisms underlying FGF13 regulation of Cx43. …

A Mouse Model Of Lipoatrophy Reveals Relationships Between Beige Fat Appearance And Female Fertility, Elizabeth S Anaya, William Dion, Pradip K Saha, Aaron R Cox, Evelyn De Groot, Avery A Ahmed, Jessica B Felix, Bokai Zhu, Stephanie A Pangas, Sean M Hartig

Faculty, Staff and Students Publications

White adipose tissue (WAT) performs vital metabolic and endocrine functions, but roles in female reproduction remain understudied and poorly understood. Here, we report that female mice experiencing progressive lipoatrophy after knockout of Ubc9 in adipocytes (Ubc9fKO) displayed disrupted estrous cycles, reduced ovarian reserve, and subfertility. During aging, female Ubc9fKO mice lose subcutaneous WAT more quickly than their male counterparts and weigh less than littermate controls. Subcutaneous WAT excised from female Ubc9fKO mice strongly enriched for thermogenesis genes generally associated with metabolic benefits. Female Ubc9fKO mice exhibited hypermetabolism and accumulated thermogenic, Uncoupling Protein 1-expressing beige fat cells in residual subcutaneous WAT …

Yap-Induced Glycolysis Drives Fibroinflammation And Disrupts Fibroblast Fidelity, Chang-Ru Tsai, Lin Liu, Yi Zhao, Jong H Kim, Paulo Czarnewski, Rich Gang Li, Fansen Meng, Mingjie Zheng, Jeffrey Steimle, Xiaolei Zhao, Francisco Grisanti, Zheng Sun, Jun Wang, Md Abul Hassan Samee, Xiao Li, James F Martin

Faculty, Staff and Students Publications

Background: Separation of the pulmonic and systemic circulation is essential for terrestrial life, and mammals have evolved distinct cardiac chambers with specialized structures and functions. Transcriptomics profiling revealed cellular heterogeneity between heart chambers. However, the mechanisms underlying chamber-specific transcriptomic and metabolic differences-and their functional significance-remain poorly understood. The Hippo/YAP (yes-associated protein) pathway is a conserved signaling network that regulates diverse cellular processes. The Hippo kinases inhibit YAP in cardiac fibroblasts (CF) to restrict fibrosis and inflammation. Nonetheless, how YAP regulates the metabolic microenvironment during homeostasis and fibroinflammation remains unclear.

Methods: We investigated YAP and glycolysis activity in the 4 cardiac …

Synergistic Potential Of Sipuleucel-T In Enhancing Immunotherapy For Metastatic Castration-Resistant Prostate Cancer, Kavita Rawat, Varnika Punia, Parker Mathews, Sara Mccoy, Wilbur Song, Muhammad A Saeed, Russell K Pachynski

2020-Current year OA Pubs

Clinical trials of immunotherapy in metastatic castration-resistant prostate cancer (mCRPC) have largely been unsuccessful despite promising preclinical studies and proven efficacy in other solid tumors. These disappointing clinical outcomes have been attributed to an immunosuppressive tumor microenvironment, a relative lack of infiltrating immune effector cells, and tumor-related and host-related factors, which collectively render prostate cancer a relatively immunologically "cold" tumor. Sipuleucel-T (Provenge), an autologous cellular immunotherapy, induces an immune response targeted against prostatic acid phosphatase. It received approval from the US Food and Drug Administration in 2010, marking the first immunotherapy to show an overall survival benefit in patients with …

Increased Intermembrane Space [Ca2+] Drives Mitochondrial Structural Damage In Cpvt, Shanna Hamilton, Radmila Terentyeva, Roland Veress, Fruzsina Perger, Zuzana Nichtova, Mark Bannister, Jinxi Wang, Sage Quiggle, Rachel Battershell, Matthew Gorr, Sandor Györke, Bum-Rak Choi, Christopher George, Andriy Belevych, György Csordás, Dmitry Terentyev

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Mitochondrial dysfunction caused by abnormally high RyR2 (ryanodine receptor) activity is a common finding in cardiovascular diseases. Mechanisms linking RyR2 gain of function with mitochondrial remodeling remain elusive. We hypothesized that RyR2 hyperactivity in cardiac disease increases [Ca 2+ ] in the mitochondrial intermembrane space (IMS) and activates the Ca 2+ -sensitive protease calpain, driving remodeling of mitochondrial cristae architecture through cleavage of structural protein OPA1 (optic atrophy protein 1).

METHODS: We generated a highly arrhythmogenic rat model of catecholaminergic polymorphic ventricular tachycardia, induced by RyR2 gain-of-function mutation S2236L(Ser2336Leu)(+/-) . We created a new biosensor to measure IMS-[Ca2+ ] …

Patient-Centered Televisit For Chronic Obstructive Pulmonary Disease Discharge Transitions: User-Centered Design Study, Joanna Abraham, Alicia Meng, Nicolas Caravelli, Leah Traeger, May Nguyen, Vineet Arora, Valerie G Press

2020-Current year OA Pubs

BACKGROUND: Chronic obstructive pulmonary disease (COPD) affects approximately 16 million Americans and often results in avoidable readmissions due, in part, to medication errors and lack of education. Telehealth interventions can support medication reconciliation and inhaler education following hospital discharge for patients with COPD.

OBJECTIVE: This study aimed to design and prototype TELE-TOC (Telehealth Education: Leveraging Electronic Transitions of Care), a post-discharge, in-home, televisit intervention, and to map its workflow to ensure integration into the routine discharge care transition process for patients with COPD.

METHODS: A user-centered design approach across 3 phases was followed to develop and prototype TELE-TOC. Participants included …

Protein-Protein Interaction–Interfering Peptide Rescues Dysregulated Nmda Receptor Signaling, Robert E. Featherstone, Hongbin Li, Ameet S. Sengar, Karin E. Borgmann-Winter, Olya Melnychenko, Lindsey M. Crown, Ray L. Gifford, Felix Amirfathi, Anamika Banerjee, Aivi Tran, Krishna Parekh, Margaret Heller, Wenyu Zhang, Robert J. Gallop, Adam D. Marc, Pragya Komal, Michael W. Salter, Steven J. Siegel, Chang-Gyu Hahn

Farber Institute for Neuroscience Faculty Papers

The complex and heterogeneous genetic architecture of neuropsychiatric illnesses compels us to look beyond individual risk genes for therapeutic strategies and target the interactive dynamics and convergence of their protein products. A mechanistic substrate for convergence of synaptic neuropsychiatric risk genes are protein-protein interactions (PPIs) in the N-methyl-D-aspartate receptor (NMDAR) complex. NMDAR hypofunction in schizophrenia is associated with hypoactivity of Src kinase, resulting from convergent alterations in PPIs of Src with its partners. Of these, the association of Src with PSD-95, which inhibits the activity of this kinase in the NMDAR complex, is known to be increased in schizophrenia. Here, …

Design Of An Open-Label Extension Trial Of Nerandomilast (Bi 1015550) In Patients With Idiopathic Pulmonary Fibrosis And Progressive Pulmonary Fibrosis (Fibroneer™-On), Wim A Wuyts, Luca Richeldi, Shervin Assassi, Arata Azuma, Vincent Cottin, Anna-Maria Hoffmann-Vold, Michael Kreuter, Justin M Oldham, Fernando J Martinez, Claudia Valenzuela, Marlies S Wijsenbeek, Madhu Kanakapura, Alexandra James, Gerrit Weimann, Cyril Drzewuski, Carl Coeck, Toby M Maher

Faculty, Staff and Student Publications

Background: There is a need for more effective treatments for idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). Nerandomilast (BI 1015550), an oral preferential inhibitor of phosphodiesterase 4B, is being evaluated in two randomized Phase III trials: FIBRONEER™-IPF (NCT05321069) and FIBRONEER™-ILD (NCT05321082). FIBRONEER™-ON is an open-label extension (OLE) of these studies that will evaluate the long-term safety and efficacy of nerandomilast. Here, we describe the study design of the OLE.

Methods: This prospective 98-week OLE will follow the Phase III parent trials, which are currently underway with 1177 patients enrolled in FIBRONEER™-IPF and 1178 patients …

Can Cta-Based Machine Learning Identify Patients For Whom Successful Endovascular Stroke Therapy Is Insufficient?, Jerome A Jeevarajan, Yingjun Dong, Anjan Ballekere, Sergio Salazar Marioni, Arash Niktabe, Rania Abdelkhaleq, Sunil A Sheth, Luca Giancardo

Faculty, Staff and Student Publications

Background and purpose: Despite advances in endovascular stroke therapy (EST) devices and techniques, many patients are left with substantial disability, even if the final infarct volumes (FIVs) remain small. Here, we evaluate the performance of a machine learning (ML) approach by using pretreatment CTA to identify this cohort of patients that may benefit from additional interventions.

Materials and methods: We identified consecutive subjects with large vessel occlusion (LVO) acute ischemic stroke (AIS) who underwent EST with successful reperfusion in a multicenter prospective registry cohort. We included only subjects with FIV < 30 mL and recorded 90-day outcome (mRS). A deep learning model was pretrained and then fine-tuned to predict 90-day mRS 0-2 by using pretreatment CTA images (DeepsymNet-v3 model pretrained on radiology reports and fine-tuned on detection of unexpected clinical outcomes using brain CTA images [DSN-CTA] model). The primary outcome was the predictive performance of the DSN-CTA model compared with a logistic regression model with clinical variables, measured by the area under the receiver operating characteristic curve (AUROC).

Results: The DSN-CTA model was pretrained on 1542 subjects and …

Brain Metabolic-Functional (De)Coupling From Health To Glioma Dysfunction, G Vallini, G Baron, E Silvestri, T Volpi, A G Vlassenko, M S Goyal, A Chiuso, D Cecchin, M Corbetta, A Bertoldo

2020-Current year OA Pubs

The interplay between brain metabolism and function supports the brain's adaptive capacity in cognitively demanding processes. Prior work has linked glucose metabolism to resting-state fMRI activity, but often overlooks both hemodynamic confounders in the BOLD signal and the brain's dynamic nature. To address this, we employed a novel effective connectivity decomposition, separating symmetric partial covariance, capturing "true" statistical dependencies between regions, from antisymmetric differential covariance, reflecting directional brain flow. In 42 healthy subjects, we show that partial covariance corresponds to metabolic connectivity across regions, while node directionality relates to standardized uptake value ratio, a proxy for local glucose consumption. We …

Restoration Of Sfrp3 Preserves The Neural Stem Cell Pool And Spatial Discrimination Ability In A Mouse Model Of Alzheimer's Disease, Chia-Hsuan Fu, Jin Park, Umberto Tosi, Francisco A Blanco, Manuel Silva-Pérez, Kavitha Muralidharan, Jason C You, Minjung Lee, Gabriel S Stephens, Xiaohong Zhang, Yi Zheng, Helen Scharfman, Kimberley F Tolias, Jeannie Chin

Faculty, Staff and Students Publications

Individuals with Alzheimer's disease (AD) have an increased incidence of seizures, which worsen cognitive decline. Using a transgenic mouse model of AD neuropathology that exhibits spontaneous seizures, we previously found that seizure activity stimulates and accelerates depletion of the hippocampal neural stem cell (NSC) pool, which was associated with deficits in neurogenesis-dependent spatial discrimination. However, the precise molecular mechanisms that drive seizure-induced activation and depletion of NSCs are unclear. Here, using mice of both sexes, we performed RNA-sequencing on the hippocampal dentate gyrus and identified differentially expressed regulators of neurogenesis in the Wnt signaling pathway that regulates many aspects of …