Digital Commons Network^™

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 …

Retrospective Review Of Metastatic Hormone Receptor-Positive Inflammatory Breast Cancer Patients Reveals Poor Responses To Cyclin Dependent Kinase 4/6 Inhibition, Azadeh Nasrazadani, Rebecca S Tidwell, Megumi Kai, Bora Lim, Vicente Valero, Debu Tripathy, Sadia Saleem, Bisrat G Debeb, Anthony Lucci, Wendy A Woodward, Rachel M Layman

Faculty, Staff and Student Publications

Background: Patients with inflammatory breast cancer (IBC) have aggressive biology and relatively inferior responses to standard-of-care (SOC) therapies. Understanding the efficacy of SOC therapies in IBC is critical to optimize outcomes. Our objective was to assess the progression-free survival (PFS) of metastatic hormone receptor-positive HER2-negative/low (HR+HER2-) IBC patients treated with CDK4/6 inhibitors (CDKIs) and hormonal therapy (HT).

Methods: Data from 58 IBC patients with metastatic HR + /HER2- IBC from a single institution were reviewed. The medians (95% confidence intervals) of overall survival (OS), PFS, and time on treatment (ToT) from the time of CDKI initiation were reported via the …

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 …

Effect Of Same-Day Hiv Treatment Initiation (Sdi) On 1-Year Outcomes In Low-And Middle -Income Countries: Systematic Review And Meta-Analysis Of Randomised Trials, Nikita Sass, Hanna Havrylenko, Felix Gerber, Alain Amstutz, Sydney Rosen, Alana Brennan, Mhairi Maskew, Serena Koenig, Nancy Dorvil, Elvin H Geng, Tracy Glass, Nathan P Ford, Niklaus Daniel Labhardt, Stefan Schandelmaier

2020-Current year OA Pubs

INTRODUCTION: Same-day initiation (SDI) of antiretroviral therapy is recommended for people presenting with HIV who have no contraindications. We reviewed the evidence on SDI interventions in low- and middle-income countries (LMICs).

METHODS: We conducted a systematic review and meta-analysis of randomised controlled trials of SDI in adults diagnosed with HIV in LMICs. We searched MEDLINE, Embase and the Cochrane Library up to December 2024. Primary outcomes were viral suppression and retention in care 6-12 months after enrolment. Based on a qualitative assessment of the complex trial interventions, we considered two subgroups: (1) interventions newly introducing SDI and (2) interventions improving …

The Breakdown Of Neurovascular Barriers: Molecular Mechanisms Of Tight Junction Dysfunction, Sowmya Shree Gopal, Mandeep Kaur, Sophie Lanzkron, Amit K. Srivastava

Department of Medicine Faculty Papers

The central nervous system (CNS) relies on tightly regulated barriers to maintain homeostasis and protect neural tissue from blood-borne toxins, pathogens, and inflammatory mediators. Tight junctions (TJs) are critical components of the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), forming selective paracellular seals that regulate molecular trafficking. These structures comprise transmembrane proteins and cytoplasmic scaffolding proteins, which anchor TJs to the actin cytoskeleton. The spatial organization and function of TJs are dynamically regulated by calcium-dependent signaling, phosphorylation events, and G-protein-mediated pathways, which govern their assembly, disassembly, and response to physiological and pathological stimuli. The integrity of TJ complexes is …

Consensus-Based Expert Recommendations For Diagnosis And Clinical Management Of Vanishing White Matter., Romy J. Van Voorst, Daphne H. Schoenmakers, Joshua L. Bonkowsky, Adeline Vanderver, Ingeborg Krägeloh-Mann, Geneviève Bernard, Enrico Bertini, Ali Fatemi, Paulo V. Sgobbi, Nicole I. Wolf, Samuel Groeschel, Davide Tonduti, Caroline Sevin, Jennifer L. Orthmann-Murphy, Ludger Schöls, Ettore Salsano, Bernard Brais, Nicole Jaffe, Kasper W. Ter Horst, Sabine E. Hannema, Katherine G. Hayes, Jochen Meyburg, Marc Van Heerde, Anne Marie Sbrocchi, Rosalina Van Spaendonk, Isabelle Thiffault, Geesje H. Hofsteenge, Carolina Sudmeier-Broek, Corrie Timmer, Donna Skwirut, Allyson Buck, Bret Hollberg, Ron Chapleau, Hanka Dekker, Susan G. Campbell, Truus E M Abbink, Prisca S. Leferink, Marjo S. Van Der Knaap

Manuscripts, Articles, Book Chapters and Other Papers

Vanishing white matter (VWM) is a rare disorder, characterized by degeneration of CNS white matter, clinically often exacerbated by stressors such as fever and minor head trauma. VWM is caused by biallelic pathogenic variants in the EIF2B1-5 genes, causing reduced activity of eukaryotic initiation of translation factor 2B, resulting in dysregulation of the integrated stress response (ISR). New scientific insights and increased clinical trials in experimental therapies highlight the need for clinical guidelines to improve and standardize care for patients with VWM worldwide. Standardized care is important for therapy development, as it lessens clinical variability of trial participants at study …

Circulating Tumor Dna Refines Risk Stratification Of Neoadjuvant Therapy-Resistant Breast Tumors, Mark Jesus M Magbanua, Nayelis A Manon, Denise M Wolf, Samuel Rivero-Hinojosa, Ziad Ahmed, Rosalyn W Sayaman, Antony Tin, Derrick Renner, Ekaterina Kalashnikova, Lamorna Brown-Swigart, Gillian L Hirst, Christina Yau, Wen Li, Claudine Isaacs, Rebecca A Shatsky, Amy S Clark, Alexandra Zimmer, Amy L Delson, Angel Rodriguez, Minetta C Liu, Paula R Pohlmann, Laura J Esserman, Hope S Rugo, Angela Demichele, Laura Van 'T Veer

Faculty, Staff and Student Publications

Early-stage breast cancers resistant to neoadjuvant therapy (NAT), characterized by high residual cancer burden (RCB) after treatment, have an increased risk of metastatic recurrence. Here, we show that circulating tumor DNA (ctDNA) detected using a tumor-informed test (1) can improve risk stratification of patients with NAT-resistant tumors (RCB-II/RCB-III) and (2) predict response to NAT. Stratification using ctDNA status at pretreatment or post-NAT and ctDNA dynamics identified NAT-resistant tumors with a significantly decreased risk of metastatic recurrence. ctDNA clearance as early as week 3 across receptor subtypes predicted favorable responses to NAT, including immunotherapies. Interestingly, less than a fifth of patients …

Single Cell Spatial Profiling Of The Matrisome Identifies Region-Specific Adhesion And Signaling Networks In Glioblastoma, Arpan De, Santiago A Forero, Ali Pirani, John E Morales, Marisol De La Fuente-Granada, Sumod Sebastian, Jason T Huse, Leomar Y Ballester, Jeffrey S Weinberg, Frederick F Lang, Kadir C Akdemir, Joseph H Mccarty

Faculty, Staff and Student Publications

The human brain contains a milieu of extracellular matrix (ECM) components that promote normal development and physiology. ECM signaling pathways are often dysregulated in brain pathologies including the malignant cancer glioblastoma (GBM). Here, we used single-cell spatial transcriptomic platforms to map the expression of nearly 400 ECM genes in matching non-cancerous brain and GBM samples. At least four different GBM cell populations have been identified that show unique ECM expression profiles and spatial enrichment in distinct intratumor regions. Spatial mapping demonstrates largely non-overlapping expression signatures of ECM components in GBM stromal cell types, particularly in vascular endothelial cells and microglia/macrophages. …

Glycoside Hydrolase-Mediated Glucomannan Catabolism In Segatella Copri, A Target Of Microbiota-Directed Foods For Malnourished Children, Cyrus Zhou, Matthew C Hibberd, Evan M Lee, Suzanne Henrissat, Marie A Crane, Jiye Cheng, Michael J Barratt, Jeffrey I Gordon, Et Al.

2020-Current year OA Pubs

Evidence is emerging that perturbed postnatal gut microbiota development is causally related to childhood undernutrition. Clinical trials in undernourished Bangladeshi children found that a polysaccharide-rich, microbiota-directed complementary food (MDCF-2) designed to repair this perturbation produced superior ponderal and linear growth compared to a standard ready-to-use supplementary food. Subsequent analyses disclosed several candidate bioactive polysaccharides in the MDCF and their bacterial targets, notably strains of

International Consensus Guidelines For The Conduct And Reporting Of Car T-Cell Clinical Trials In Aml, Swati Naik, Richard Aplenc, Susanne H C Baumeister, Marco Becilli, Anand S Bhagwat, Challice L Bonifant, Lihua E Budde, Christopher D Chien, Kevin J Curran, Anthony F Daniyan, Alexandra Dreyzin, Rebecca A Gardner, Sara Ghorashian, Stephen Gottschalk, Laquisa C Hill, M Eric Kohler, Adam Lamble, Franco Locatelli, Maksim Mamonkin, Bilal Omer, Jae H Park, Concetta Quintarelli, Benedetta Rambaldi, Rebecca M Richards, David A Sallman, Tim Sauer, Nirali N Shah, Marion Subklewe, Corinne Summers, Sarah K Tasian, Naomi Taylor, Sarah Tettamanti, Michael R Verneris, M Paulina Velasquez, Saar I Gill

Faculty, Staff and Students Publications

Early clinical experience with the use of chimeric antigen receptor (CAR) T-cell therapies for patients with acute myeloid leukemia (AML) has been beset by high rates of toxicities and low rates of response. We convened an international workshop with the goal of bringing investigators in the field of AML-directed CAR T-cell therapy together to facilitate discussion of challenges and to brainstorm potential solutions. Based on discussions at the workshop, it was evident that (1) treating and targeting AML with CAR T cells is associated with unique clinical challenges, and (2) variability in clinical trial design, definitions of toxicities, correlative data …

Implementing The Nyu Electronic Patient Visit Assessment (Epva), Janet H Van Cleave, Abraham A Brody, Dena Schulman-Green, Kenneth S Hu, Zujun Li, Stephen B Johnson, Vincent J Major, Christopher E Lominska, Jessica R Bauman, Alexander N Hanania, Ghia V Tatlonghari, Marcely Tsikis, Brian L Egleston

Faculty, Staff and Students Publications

Background: Aggressive treatment with multimodal therapies such as surgery, chemotherapy, and radiation therapy has improved survival in head and neck cancer (HNC) but at a human cost of a substantial symptom burden and impact on quality of life. We developed the NYU Electronic Patient Visit Assessment (ePVA)© for HNC as a digital patient-reported symptom monitoring system that enables early symptom detection and real-time interventions at the point of care. With this study protocol, we aim to test the effectiveness of the ePVA in improving HNC outcomes in real-world settings and to identify implementation strategies optimizing its effectiveness.

Methods: We will …

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 …

Artem-Is For Erp: Agreed Reporting Template For Eeg Methodology-International Standard For Event-Related Potential Experiments, Giorgio Ganis

School of Psychology

The choices we make during the recording, preprocessing and analysis of event-related potentials (ERP) data can affect study outcomes. As such, it is critical that they are transparently reported to allow for reproducibility. Yet, systematic reviews of reporting practices in the field have shown that journal articles often do not meet this goal and that existing reporting guidelines have not resulted in a sufficient improvement in reporting transparency. An easier workflow for transparently documenting pipelines used in regular journal articles is needed. The ARTEM-IS (Agreed Reporting Template for EEG Methodology—International Standard) initiative is working towards addressing this issue by building …

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 …

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 …

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 …

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, …