Digital Commons Network^™

Insm1 Governs A Neuronal Progenitor State That Drives Glioblastoma In A Human Stem Cell Model, Patrick A Desouza, Matthew Ishahak, Xuan Qu, Colin Mccornack, Devi Annamalai, Diane D Mao, Rajanikanth Vangipurapu, Yiwei Fu, Alexandre T Vessoni, Ryan T Cleary, Rowland H Han, Punn Augsornworawat, Timothy Woodiwiss, Darby Agovino, Braxton Sizemore, Jessica Kline, Maryam Borhani-Haghighi, Hao Chen, Sangami Pugazenthi, Hiroko Yano, Ting Wang, Luis F Z Batista, Jeffrey R Millman, Albert H Kim

2020-Current year OA Pubs

Glioblastoma is a lethal brain cancer marked by functional plasticity driven by tumor cell-intrinsic mutations and their interplay with developmental programs. To investigate how canonical glioblastoma mutations promote functional plasticity, we have developed an isogenic human neural stem cell (NSC) model of glioblastoma by sequential addition of TERT promoter, TP53, and PDGFRA point mutations. TP53 loss-of-function increases TERT expression during serial mutagenesis, but only triple mutant NSCs reliably form lethal brain tumors in vivo that recapitulate glioblastoma. Tumor cell evolution triggers stress-related metabolic changes and transitions toward a neuronal progenitor network driven by transcription factor INSM1. INSM1 is highly expressed …

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 …

Actin Dysregulation Induces Neuroendocrine Plasticity And Immune Evasion: A Vulnerability Of Small Cell Lung Cancer, Yoojeong Seo, Shengzhe Zhang, Jinho Jang, Kyung-Pil Ko, Kee-Beom Kim, Yuanjian Huang, Dong-Wook Kim, Bongjun Kim, Gengyi Zou, Jie Zhang, Sohee Jun, Wonhong Chu, Nicole A Kirk, Ye Eun Hwang, Young Ho Ban, Shilpa S Dhar, Joseph M Chan, Min Gyu Lee, Charles M Rudin, Kwon-Sik Park, Jae-Il Park

Faculty, Staff and Student Publications

Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. Capping protein inhibiting regulator of actin dynamics (CRACD) that promotes actin polymerization, is frequently inactivated in SCLC. However, the role of CRACD loss in SCLC is unknown. Here we show that CRACD depletion drives neuroendocrine (NE) cell plasticity and immune evasion in SCLC. Mechanistically, CRACD inactivation disrupts actin organization, leading to suppression of Yap1-NOTCH signaling and subsequent NE gene upregulation. Simultaneously, CRACD loss drives EZH2-mediated histone methylation via nuclear actin disruption, leading to repression of MHC-I genes and depletion of CD8⁺ T cells. Consequently, CRACD-downregulated tumors exhibit …

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 …

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 …

Pitx2 Dosage-Dependent Changes In Pacemaker Cell State Underlie Sinus Node Dysfunction And Atrial Arrhythmias, Lieve E Van Der Maarel, M Ridwane Mungroo, Otto J Mulleners, Mathilde R Rivaud, Arie O Verkerk, Karel Van Duijvenboden, Freek H T Tiel Groenestege, Jeffrey D Steimle, Lianne Fokkert, Corrie De Gier-De Vries, Mischa Klerk, Arie R Boender, James F Martin, Bjarke Jensen, Gerard J J Boink, Harsha D Devalla, Vincent M Christoffels

Faculty, Staff and Students Publications

Physiologically relevant increases in transcription factor dosage and their role in development and disease remain largely unexplored. Genomic deletions upstream of the Paired-like homeodomain transcription factor gene (PITX2), identified in patients with sinus node dysfunction and atrial fibrillation and modeled in mice (delB), rewire the local epigenetic landscape, increasing PITX2 expression. Here, we demonstrate that pacemaker cardiomyocytes in the embryonic delB sinus node ectopically express PITX2 at physiological dosages in a heterogeneous pattern. The prenatal delB sinus node forms discrete subdomains showing PITX2 dosage-dependent mild or severe loss of pacemaker cardiomyocyte identity. Respective subdomain sizes and severity of sinus node …

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 …

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 …

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, …

Laboratory Monitoring In Patients With Moderate To Severe Plaque Psoriasis, Jonathan M. Fenkel, John A. Osborne, April W. Armstrong, Bruce Strober, Linda Stein Gold, Michael Cameron, Mark Lebwohl

Department of Medicine Faculty Papers

OBJECTIVES: Plaque psoriasis is a common immune-mediated disease associated with various comorbidities, including cardiovascular disease, diabetes, psoriatic arthritis, liver disease, and mood disorders. Biologic and small-molecule therapies are efficacious and well tolerated in adults with moderate to severe plaque psoriasis. However, dermatologists may be uncertain about appropriate laboratory monitoring in patients treated with these therapies, especially those with comorbidities.

METHODS: This review summarizes prescribing information and provides expert recommendations based on real-world experience in the monitoring of concerning laboratory values in patients with psoriasis.

RESULTS: Individualized monitoring is essential for maximizing the benefits and minimizing the risks associated with biologic …

The Clinical Pharmacogenetics Implementation Consortium's Consensus-Based Framework For Assigning Allele Function., Bailey M. Tibben, Andrea Gaedigk, Li Gong, Katrin Sangkuhl, Michelle Whirl-Carrillo, Mary V. Relling, Roseann S. Donnelly, Teri E. Klein, Kelly E. Caudle

Manuscripts, Articles, Book Chapters and Other Papers

The Clinical Pharmacogenetics Implementation Consortium (CPIC) is dedicated to integrating pharmacogenetic testing into clinical practice by developing and disseminating peer-reviewed, evidence-based gene-drug clinical practice guidelines. A critical component of this effort is the assignment of clinical function to pharmacogene alleles, which informs the translation of genetic test results into actionable prescribing decisions. This technology review outlines the standardized procedures and framework used by CPIC to assign allele clinical functional status through the work of Pharmacogene Curation Expert Panels (PCEPs). These panels, comprising multidisciplinary experts, systematically review and evaluate evidence to assign functional status to pharmacogenetic haplotypes. The process includes rigorous …

Discovery Of A Small Molecule Tlr3 Agonist Adjuvant, Branden Lee, Danica Dong, Etsuro Nanishi, John Mark Awad, Kimia Abedi, Yoshine Saito, Francesco Borriello, Soumik Barman, Byron Brook, Aisling Kelly, Manisha Menon, Constance Marques-Mourlet, Maansi Gupta, Ida Lister, Chiwoo Oh, Kevin Lyskawa, Morgan Goetz, Kristina Walker, Wing Ki Cheng, Spencer Brightman, Pankaj Sharma, Timothy O'Meara, Katherine Chew, Daniel Vieira, Kevin Ryff, Cali Sweitzer, Sanya Thomas, Simon Van Haren, Matthew Pettengill, Hyuk-Soo Seo, Sirano Dhe-Paganon, Wei Zhang, Ofer Levy, David Dowling

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Pattern-recognition receptor (PRR) agonists are valuable agents across multiple medical applications, from vaccinology to immune-oncology. However, well-defined and potent small molecule agonists for many PRRs still await discovery and development. Screening of chemical libraries of ~200,000 small molecules for maturation of human monocytic cells by quantifying NF-κB activation and cell adherence was completed. From this screen, we selected a thiazole benzamide derivative, PVP-057, for its robust immunomodulatory properties, low toxicity profile, and concentration-dependent activity. In vitro investigation of pathway and receptor activation reveals that PVP-057 is a Toll-like receptor 3 (TLR3) agonist. As a single-component adjuvant, administered intramuscularly or intradermally …

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 …

Hsp90 Buffers Deleterious Genetic Variations In Brca1, Brant Gracia, Xing-Han Zhang, Patricia Montes, Tin Chanh Pham, Min Huang, Junjie Chen, Georgios Ioannis Karras

Faculty, Staff and Student Publications

Protein-folding chaperone heat shock protein 90 (HSP90) buffers genetic variation in diverse organisms, but the clinical significance of HSP90 buffering in human disease remains unclear. Here, we show that HSP90 buffers mutations in the BRCT domain of BRCA1. HSP90-buffered BRCA1 mutations result in protein variants that retain interactions with partner proteins and strongly rely on HSP90 for protein stability and function in cell survival. Moreover, HSP90-buffered BRCA1 variants confer poly (ADP-ribose) polymerase (PARP) inhibitor resistance in cancer cells. Low-level HSP90 inhibition overcomes this resistance, revealing a cryptic and mutant-specific HSP90-contingent synthetic lethality. Furthermore, by stabilizing metastable variants across the entirety …

Functional Classification Of Platelet Gene Variants Using Crispr Hdr In Cd34+ Cell-Derived Megakaryocytes, Yasuhiro Kosaka, Brandon Lopez, Nina Kishimoto, Shancy Jacob, Emilie Montenont, Rodrigo Huallanca, Graeson Coughenour, Jorge Di Paola, Justyne Ross, Kristy Lee, Matthew T Rondina, Paul F Bray, Jesse W Rowley

2020-Current year OA Pubs

The interpretation of genetic variants in inherited diseases, such as inherited platelet disorders (IPDs), remains a major clinical challenge, as most are classified as variants of uncertain significance (VUSs). A key barrier to functional evaluation is the lack of accessible, lineage-appropriate assays that reliably reflect native gene regulation and cell-specific biology. To address this gap, we developed CRIMSON HD (CRISPR-edited megakaryocytes [MKs] for surveying platelet variant functions through homology-directed repair [HDR]), a CRISPR-Cas9 HDR-based genome-editing platform applicable to CD34

Revealing The Nervous System Requirements Of Alzheimer Disease Risk Genes In Drosophila, Jennifer M Deger, Shabab B Hannan, Mingxue Gu, Colleen E Strohlein, Lindsey D Goodman, Sasidhar Pasupuleti, Zahid Shaik, Liwen Ma, Yarong Li, Jiayang Li, Morgan C Stephens, Michal Tyrlík, Zhandong Liu, Ismael Al-Ramahi, Juan Botas, Chad A Shaw, Oguz Kanca, Hugo J Bellen, Joshua M Shulman

Faculty, Staff and Students Publications

Most Alzheimer disease (AD) susceptibility genes have poorly understood roles in the central nervous system (CNS). To address this gap, we systematically characterized 100 conserved candidate AD risk genes using a cross-species strategy in the fruit fly, Drosophila melanogaster. Genes were prioritized based primarily on human functional genomic evidence. We generated custom loss-of-function alleles for each of the conserved fly orthologs. Most of the genes are expressed in the adult brain, including 24 neuron- and 13 glia-specific expression patterns. Overall, we identify 50 candidate AD risk gene homologs with requirements for CNS structure or function, including 18 whose loss of …

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 …

Investigating Dysfunctional Cognition Change As A Putative Mechanism Of Cbt For Youth Anxiety, Ocd And Ptsd: Protocol For An Individual Participant Data Meta-Analysis, Ivana Buric, Anke Klein, Ronald M Rapee, Brooke Levis, Philip C Kendall, Eric A Storch, Lynn Mobach

Faculty, Staff and Students Publications

Introduction: Anxiety disorders, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD) are common in children and adolescents and can lead to significant impairment. Cognitive behavioural therapy (CBT) with exposure is the first-line treatment, yet approximately half of treated youth do not achieve full remission. Dysfunctional cognitions-negative automatic thoughts, maladaptive beliefs and distorted interpretations-are considered key targets of CBT, but evidence in youth is mixed and underpowered. This study will examine whether change in dysfunctional cognitions mediates treatment outcome in anxiety, OCD and PTSD symptoms and whether this association varies across individual characteristics.

Methods and analysis: An individual participant data meta-analysis …

Unconventional Binding Of Calmodulin To Chk2 Kinase Inhibits Catalytic Activity, Christopher R Horne, Tingting Wang, Samuel N Young, Toby A Dite, Hunter G Nyvall, Sushant Suresh, Katherine A Davies, Abner Gonzalez Castro, Vineet Vaibhav, Lucy J Mather, Laura F Dagley, Matthew J Belousoff, Gerard Manning, Anthony R Means, John E Burke, Janni Petersen, John W Scott, James M Murphy

Faculty, Staff and Students Publications

Calmodulin (CaM) serves an essential role in eukaryotic cells as a Ca2+ sensor. Ca2+ binding leads to conformation changes in CaM that enable engagement of a repertoire of enzymes and the regulation of their catalytic activities. Classically, Ca2+-CaM binds to an inhibitory pseudosubstrate sequence C-terminal to the kinase domain in members of the Ca2+-CaM-dependent protein kinase (CAMK) family and relieves inhibition to promote catalytic activity. Here, we report an unexpected mechanism by which CaM can bind CHK2 kinase to inhibit its kinase activity. Using biochemical, biophysical and structural mass spectrometry, we identify a direct interaction of Ca2+-CaM with the CHK2 …

Resolving The Mysteries Of Brain Clearance And Immune Surveillance, Jonathan Kipnis, Et Al.

2020-Current year OA Pubs

Recent advances are transforming our understanding of brain fluid dynamics, highlighting cerebrospinal fluid (CSF) flow as a key process in brain waste clearance. While debates persist regarding its anatomical pathways and regulatory mechanisms, certain core principles have become widely accepted. CSF influx occurs primarily along periarterial spaces, solute clearance follows multiple routes, and glymphatic and meningeal lymphatic systems are functionally connected. Brain clearance is influenced by vascular pulsation, neural activity, and sleep. Immune cells at brain-border niches both monitor solute efflux and modulate flow, linking brain clearance to neuroimmune interactions. A deeper understanding of brain clearance could unlock new therapeutic …

Factors Influencing Immediate Post-Angiographic Occlusion Outcomes In Intracranial Aneurysms Treated With The Woven Endobridge Device: A Multi-Center Analysis And Predictive Model From The Worldwideweb Consortium, Muhammed Amir Essibayi, Mohamed Sobhi Jabal, Hasan Jamil, Hamza Adel Salim, Basel Musmar, Nimer Adeeb, Mahmoud Dibas, Nicole M. Cancelliere, Jose Danilo Bengzon Diestro, Oktay Algin, Sherief Ghozy, Sovann V. Lay, Adrien Guenego, Leonardo Renieri, Joseph Carnevale, Guillaume Saliou, Panagiotis Mastorakos, Kareem El Naamani, Arbaz A. Momin, Eimad Shotar, Markus Möhlenbruch, Michael Kral, Charlotte Chung, Mohamed M. Salem, Ivan Lylyk, Paul M. Foreman, Hamza Shaikh, Vedran Župančić, Muhammad U. Hafeez, Joshua Catapano, Muhammad Waqas, Muhammed Said Besler, Yasin Celal Gunes, James D. Rabinov, Julian Maingard, Clemens M. Schirmer, Mariangela Piano, Anna L. Kühn, Caterina Michelozzi, Robert M. Starke, Ameer Hassan, Mark Ogilvie, Anh Nguyen, Jesse Jones, Waleed Brinjikji, Marie T. Nawka, Marios Psychogios, Christian Ulfert, Bryan Pukenas, Jan-Karl Burkhardt, Thien Huynh, Juan Carlos Martinez-Gutierrez, Sunil A. Sheth, Diana Slawski, Rabih Tawk, Benjamin Pulli, Boris Lubicz, Pietro Panni, Ajit S. Puri, Guglielmo Pero, Eytan Raz, Christoph J. Griessenauer, Hamed Asadi, Adnan Siddiqui, Elad I. Levy, Deepak Khatri, Neil Haranhalli, Andrew F. Ducruet, Felipe C. Albuquerque, Robert W. Regenhardt, Christopher J. Stapleton, Peter Kan, Vladimir Kalousek, Pedro Lylyk, Srikanth Boddu, Jared Knopman, Stavropoula I. Tjoumakaris, Hugo H. Cuellar-Saenz, Pascal M. Jabbour, Frédéric Clarençon, Nicola Limbucci, Vitor Mendes Pereira, Aman B. Patel, David J Altschul, Adam A. Dmytriw, Worldwideweb Consortium Collaborators

Jefferson Hospital Staff Papers and Presentations

The Woven EndoBridge (WEB) device treats wide-necked bifurcation aneurysms, but occlusion rates vary. This study aims to identify factors associated with immediate WEB device occlusion. Data from patients treated with WEB devices across 36 sites were analyzed. Machine learning algorithms and ordinal regression models were developed to predict immediate incomplete occlusion for ruptured and unruptured aneurysms. The study included 1565 patients, with 436 ruptured and 1129 unruptured aneurysms. Immediate complete occlusion was achieved in 38.3% of ruptured and 32.8% of unruptured aneurysms. For ruptured aneurysms, the CatBoost classifier achieved an AUROC of 0.69. Key predictors of incomplete occlusion included pretreatment …

Reducing Storage-Related Bias In Reproductive Vitamin D Research: Towards A Stable And Reliable Biomarker Of Ovarian Vitamin D Status, Evelin E Lara-Molina, Jason M. Franasiak, Almudena Devesa-Peiro, Marina López-Nogueroles, Alberto Vázquez, David Amorós, Agustín Ballesteros, Antonio Pellicer, Patricia Sebastian-Leon, Patricia Diaz-Gimeno

SKMC Student Presentations and Publications

Background/Objectives: One of the main reasons for discrepancies in the role of vitamin D in ART could be the measurement of the conventional biomarker 25(OH)D₃. It is known that this value is affected by multiple factors, such as tissue origin, assay variability, classification criteria, and potential storage-related degradation. In this study, we investigate 24,25(OH)₂D₃ as a new biomarker to improve vitamin D assessment in women’s reproductive health, particularly regarding oocyte development. Methods: A prospective cohort study including 35 oocyte donors undergoing controlled ovarian stimulation, who were recruited between October and November 2017, was conducted. Vitamin …

Per Se Driving Under The Influence Of Cannabis Statutes And Blood Delta-9-Tetrahydrocannabinol Concentrations Following Short-Term Cannabis Abstinence, Robert L. Fitzgerald, Anya Umlauf, Raymond T. Suhandynata, David J. Grelotti, Marilyn A. Huestis, Kyle F. Mastropietro, Igor Grant, Thomas D. Marcotte

Institute of Emerging Health Professions Faculty Papers

BACKGROUND: Several US states have per se laws using 2 or 5 ng/mL of delta-9-tetrahydrocannabinol (THC) as cutpoints for driving under the influence of cannabis, while some have zero-tolerance statutes. These cutpoints are considered prima facia evidence of driving impairment.

METHODS: In a cohort of people who regularly use cannabis (N = 190) we measured baseline concentrations of THC after instructing participants to abstain from cannabis for at least 48 hours. Baseline driving performance was evaluated using a driving simulator. We also measured blood THC concentrations serially following a smoking session (placebo or active cannabis).

RESULTS: Forty-three percent of the …

Epigenome-Wide Association Study Of Nuclear Dna Methylation In Relation To Mitochondrial Heteroplasmy, Meng Lai, Kyeezu Kim, Yinan Zheng, Christina A Castellani, Scott M Ratliff, Mengyao Wang, Xue Liu, Jeffrey Haessler, Tianxiao Huan, Kwadwo Bonsu, Charles Newcomb, Kyler Mckessy, Lawrence F Bielak, Wei Zhao, Roby Joehanes, Jiantao Ma, Xiuqing Guo, Joann E Manson, Megan L Grove, Jan Bressler, Kent D Taylor, Tuuli Lappalainen, Silva Kasela, Thomas W Blackwell, Nicole J Lake, Jessica D Faul, Kendra R Ferrier, Stephen C Ekker, Lifang Hou, Charles Kooperberg, Alexander P Reiner, Kai Zhang, Patricia A Peyser, Myriam Fornage, Eric Boerwinkle, Laura M Raffield, April P Carson, Stephen S Rich, Yongmei Liu, Daniel Levy, Jerome I Rotter, Jennifer A Smith, Dan E Arking, Chunyu Liu

Faculty, Staff and Student Publications

We analyze 10,986 participants (mean age 77; 63% women; 54% non-White) across seven U.S. cohorts to study the relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA methylation. We identify 597 CpGs associated with heteroplasmy burden, generally showing lower methylation. These CpGs are enriched in dynamically regulated island shores and depleted in CpG islands, indicating involvement in context-specific rather than constitutive gene regulation. In HEK293T cells, we introduce a truncating mtDNA mutation (MT-COX3, mt.9979) and observe a positive correlation between variant allele fraction and methylation at cg04569152, supporting a direct mtDNA-nDNA epigenetic link. Many heteroplasmy-associated CpGs overlap with known methylation-trait …

Patient-Reported Experience Measures For Person-Centred Care: A Survey For The Development And Psychometric Testing Of A Targeted Measure, The Epcc-14, Ryan Statton, Lena Rosenlund, James Close, Anna Dencker, Helen Lloyd

School of Psychology

Objectives This study aims to develop a robust, targeted measure of patient experiences of person-centred care (PCC), informed by the lived experiences of patients with chronic illness using the psychometric theory of Rasch measurement. Design The Rasch measurement model was used to analyse the psychometric functioning of 57 candidate items and select appropriate items for a targeted measure. Setting Participants were recruited from Prolific.com, having experience of both chronic or long-term illness and first-hand experience of primary or secondary care in the UK healthcare setting and completed a survey containing PCC items and descriptors of healthcare experience. Participants Data from …

Multi-Omic Profiling Provides Insights Into The Heterogeneity, Microenvironmental Features, And Biomarker Landscape Of Small-Cell Lung Cancer, Mingchao Xie, Miljenka Vuko, Shashank Saran, Siyu Liu, Andrew G Chambers, Hana Baakza, Helen K Angell, Felicia Ng, Carl M Gay, Robert J Cardnell, Felix J Segerer, Alma Andoni, Jaime Rodriguez-Canales, Paul M Waring, Markus Schick, J Carl Barrett, Lauren A Byers, Giulia Fabbri

Faculty, Staff and Student Publications

Background: Greater understanding of differential therapeutic sensitivity, specifically to immunotherapy, in small-cell lung cancer (SCLC) is required.

Methods: We explored SCLC heterogeneity through integrated molecular characterization of tumor tissue samples from 159 treatment-naive patients, utilizing genetic, epigenetic, transcriptional, and proteomic profiling, immunohistochemistry staining for multiple biologically relevant markers including transcriptional subtype-defining proteins, and spatial immune profiling using multiplex immunofluorescence.

Results: Multi-omics analysis confirmed high heterogeneity across/within neuroendocrine and non-neuroendocrine subtypes. Methylomics analysis identified four methylome clusters that may enhance subtype prediction, prognosis, and longitudinal monitoring of subtype evolution. Immunohistochemistry analysis showed high MHC-I expression in non-neuroendocrine subtypes, which have greatest …

Individualized Perioperative Blood Pressure Management In Patients Undergoing Major Abdominal Surgery: The Improve-Multi Randomized Clinical Trial, Bernd Saugel, Agnes S Meidert, Frank M Brunkhorst, Robert Bischoff, Joseph Esser, Minca Mattis, Pauline Naue, Katharina Vogel, Alina Bergholz, Moritz Flick, Alina Kröker, Dominik X Müller, Kristen K Thomsen, Christina Vokuhl, Mirja Wegge, Sebastian Bratke, Martin Graeßner, Bettina Jungwirth, Sebastian Schmid, Carla D Grundmann, Jan M Wischermann, Patrick Kellner, Moritz Steinhaus, Linda Grüßer, Sina M Coldewey, Kai Zacharowski, Patrick Meybohm, Marit Habicher, Alexander Zarbock, Amelie Zitzmann, Svenja Letz, Claudia Neumann, Jan Larmann, Thomas Renné, Linda Krause, Eik Vettorazzi, Antonia Zapf, Annemarie Carlstedt, Daniel I Sessler, Karim Kouz

Faculty, Staff and Student Publications

Importance: Intraoperative hypotension is associated with organ injury. However, it remains unknown if targeted blood pressure management during surgery can improve clinical outcomes.

Objective: To evaluate whether individualized vs routine perioperative blood pressure management during major abdominal surgery improves clinical outcomes in patients considered at high risk of postoperative complications.

Design, setting, and participants: This randomized single-blind clinical trial enrolled patients 45 years or older undergoing elective major abdominal surgery with general anesthesia expected to last 90 minutes or longer who had at least 1 additional high-risk criterion between February 26, 2023, and April 25, 2024, at 15 German university …

Factors Influencing Immediate Post-Angiographic Occlusion Outcomes In Intracranial Aneurysms Treated With The Woven Endobridge Device: A Multi-Center Analysis And Predictive Model From The Worldwideweb Consortium, Muhammed Amir Essibayi, Mohamed Sobhi Jabal, Hasan Jamil, Hamza Adel Salim, Basel Musmar, Nimer Adeeb, Mahmoud Dibas, Nicole M Cancelliere, Jose Danilo Bengzon Diestro, Oktay Algin, Sherief Ghozy, Sovann V Lay, Adrien Guenego, Leonardo Renieri, Joseph Carnevale, Guillaume Saliou, Panagiotis Mastorakos, Kareem El Naamani, Arbaz A Momin, Eimad Shotar, Markus Möhlenbruch, Michael Kral, Charlotte Chung, Mohamed M Salem, Ivan Lylyk, Paul M Foreman, Hamza Shaikh, Vedran Župančić, Muhammad U Hafeez, Joshua Catapano, Muhammad Waqas, Muhammed Said Besler, Yasin Celal Gunes, James D Rabinov, Julian Maingard, Clemens M Schirmer, Mariangela Piano, Anna L Kühn, Caterina Michelozzi, Robert M Starke, Ameer Hassan, Mark Ogilvie, Anh Nguyen, Jesse Jones, Waleed Brinjikji, Marie T Nawka, Marios Psychogios, Christian Ulfert, Bryan Pukenas, Jan-Karl Burkhardt, Thien Huynh, Juan Carlos Martinez-Gutierrez, Sunil A Sheth, Diana Slawski, Rabih Tawk, Benjamin Pulli, Boris Lubicz, Pietro Panni, Ajit S Puri, Guglielmo Pero, Eytan Raz, Christoph J Griessenauer, Hamed Asadi, Adnan Siddiqui, Elad I Levy, Deepak Khatri, Neil Haranhalli, Andrew F Ducruet, Felipe C Albuquerque, Robert W Regenhardt, Christopher J Stapleton, Peter Kan, Vladimir Kalousek, Pedro Lylyk, Srikanth Boddu, Jared Knopman, Stavropoula I Tjoumakaris, Hugo H Cuellar-Saenz, Pascal M Jabbour, Frédéric Clarençon, Nicola Limbucci, Vitor Mendes Pereira, Aman B Patel, David J Altschul, Adam A Dmytriw, Worldwideweb Consortium Collaborators

Faculty, Staff and Student Publications

The Woven EndoBridge (WEB) device treats wide-necked bifurcation aneurysms, but occlusion rates vary. This study aims to identify factors associated with immediate WEB device occlusion. Data from patients treated with WEB devices across 36 sites were analyzed. Machine learning algorithms and ordinal regression models were developed to predict immediate incomplete occlusion for ruptured and unruptured aneurysms. The study included 1565 patients, with 436 ruptured and 1129 unruptured aneurysms. Immediate complete occlusion was achieved in 38.3% of ruptured and 32.8% of unruptured aneurysms. For ruptured aneurysms, the CatBoost classifier achieved an AUROC of 0.69. Key predictors of incomplete occlusion included pretreatment …

Hif-2-Dependent Regulation Of Pthrp And Paraneoplastic Hypercalcemia In Aggressive Clear-Cell Renal Cell Carcinoma, Arijit Mal, Bingqing Xie, Zane Gray, Charlotte Small, Susmita G Ramanand, Yunpeng Gao, Vanina Toffessi Tcheuyap, Sashi Debnath, Alana Christie, Jeffrey Miyata, Brooklyn Jackson, Hua Zhong, Boning Gao, Jay Lohrey, Naim M Maalouf, Sangeetha M Reddy, John D Minna, Ivan Pedrosa, Xiankai Sun, Ram S Mani, Payal Kapur, James Brugarolas

Faculty, Staff and Student Publications

Renal cell carcinoma (RCC) patients with hypercalcemia (HC) have worse outcomes. HC often involves PTHrP, and the role of HIF-2 is incompletely understood. Leveraging RCC tumorgraft (TG) models of HC, which were characterized by tumor cell autonomous inflamatory/immune signatures, we show that HIF-2 inhibition with PT2399 frequently normalized calcium, downregulated circulating PTHrP and reduced HIF-2 binding to the PTHLH (PTHrP) promoter. Likely contributing to the selective induction of PTHrP in a subset of HIF-2-dependent tumors, the PTHLH locus was generally more accessible in TG(HC). However, PTHLH chromatin accessibility was grossly unaffected by PT2399, unlike elsewhere (including EPO locus in a …