Digital Commons Network^™

Mbnl Loss Of Function In Smooth Muscle As A Model For Myotonic Dystrophy Associated Gastrointestinal Dysmotility, Janel A M Peterson, Jesus A Frias, Andrew N Miller, Krishnakant G Soni, Yi Zhang, Zheng Xia, John W Day, Geoffrey A Preidis, Thomas A Cooper

Faculty, Staff and Students Publications

Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy and severely affects multiple organ systems, including the brain, heart, skeletal muscle, and gastrointestinal (GI) tract. Despite 80% of individuals with DM1 experiencing GI dysfunction that affects their daily life, the mechanisms of GI dysmotility in DM1 remain an understudied aspect of the disease. DM1 is caused by a CTG repeat expansion in the DMPK gene that, when expressed as an expanded CUG repeat RNA, sequesters and reduces the activity of the muscleblind-like (MBNL) RNA-binding protein family. We developed a mouse line with conditional, smooth muscle-specific knockout of …

Spinach (Spinacia Oleracea L) Flavonoids Are Hydrolyzed During Digestion And Their Bioaccessibility Is Under Stronger Genetic Control Than Raw Material Content, Michael P Dzakovich, Alvin L Tak, Elaine A Le, Rachel P Dang, Benjamin W Redan, Geoffrey A Dubrow

Children’s Nutrition Research Center Staff Publications

Spinach (

Diagnosis Of Platelet Dysfunction In Children: Clinical Predictors And Test Methods, Bhavya S. Doshi, Eric N. Thompson, Walter Faig, Abigail Wax, Amrom E. Obstfeld, Michele P. Lambert

Student Papers, Posters & Projects

Evaluation for platelet function disorders (PFD) in children is complicated by their limited exposure to hemostatic challenges, large volumes needed for light transmission aggregometry (LTA) testing, and limited data on the performance characteristics of whole-blood methods such as whole-blood impedance lumiaggregometry (WBILA). The objective of this study was to determine the clinical variables associated with the diagnosis of a PFD. A single-center, retrospective, cohort study of children evaluated for PFD was conducted. Medical charts were abstracted for demographics, medications, testing indications, bleeding sites and severity, and laboratory results. Univariate odds ratios (OR) and multivariable modeling were conducted for association of …

Impact Of Postoperative Intraocular Pressure Spikes On Outcomes Following Goniotomy: A Comparative Study Of Surgical Techniques, Wesam S. Shalaby, Steven L. Chang, Julia Yu, Teresa Horan, Sagar Shah, Shahin Hallaj, Marlene Moster, Reza Razeghinejad, Daniel Lee, Michael Pro, Aakriti Shukla, Ping Huang, Jonathan S. Myers, Tina Xia, Dilru Amarasekera

Wills Eye Hospital Papers

AIM AND BACKGROUND:To compare postoperative intraocular pressure (IOP) spikes and 1-year surgical success among goniotomy procedures: Kahook Dual Blade (KDB), OMNI, bent ab interno needle goniotomy (BANG), and gonioscopy-assisted transluminal trabeculotomy (GATT).

MATERIALS AND METHODS: This single-center, retrospective chart review included glaucoma patients ≥18 years, who underwent goniotomy from January 2021 to December 2022 with ≥3 months of follow-up. Primary outcomes were IOP spikes (≥10 mm Hg increase within 3 months) and 12-month surgical success (≥20% IOP and/or ≥1 medication reduction without further surgery). Secondary outcomes included IOP and medication changes.

RESULTS: Among 247 eyes (107 KDB, 63 OMNI, 77 …

Protocol For Isolation Of Lipid Droplets And Mitochondria From Acute Myeloid Leukemia Cells For Lipidomic Analysis, Ran Zhao, Liang Zhang, Shuxin Dong, Kazuharu Kamachi, Saurabh Kumar Gupta, Hiroki Akiyama, Jalen Nguyen, G Lavender Hackman, Michael Andreeff, Alessia Lodi, Jo Ishizawa

Faculty, Staff and Student Publications

Lipid droplets (LDs) are dynamic organelles critical for lipid and energy homeostasis. LD dysregulation is implicated in various diseases, including acute myeloid leukemia (AML), which exhibits aberrant lipid metabolism and chemoresistance. Here, we describe an effective protocol for the co-isolation of LDs and mitochondria from lipid-deficient cell types, e.g., AML cells. We detail procedures for the isolation, quality verification, and results from mass spectrometry-based lipidomic analysis. This protocol enables the functional study of organellar lipidomic regulation in AML.

Itpr1 Autoantibody-Associated Autoimmunity As A Cause Of Newly Emerging Cognitive Decline Mimicking Alzheimer's Disease: Case Report And Brief Review Of The Literature, Nicolas Kunath, Hermod Arne Bollandsås Ramfjord, Elisabeth Volden Kvisvik, Marton Konyves-Kolonics, Gøril Rolfseng Grøntvedt, Irina I Serysheva, Lars Komorowski, Brigitte Wildemann, Sven Jarius

Faculty, Staff and Student Publications

Background: Since its first description in 2014, anti-inositol 1,4,5-trisphosphate receptor type 1 (ITPR1, also termed IP3R1) autoimmunity has been recognized as causing a clinically heterogeneous spectrum of symptoms. While first described in patients with autoimmune cerebellar ataxia, this facultative paraneoplastic disease has been associated also with peripheral neuropathy, dysautonomia, sleep disorders, neuropsychiatric/psychotic symptoms, and cognitive decline.

Methods: Retrospective case study.

Results: We report the case of a 58-year-old patient who was admitted with acute confusion, rapidly progressive cognitive decline, and hallucinations. A history of mild cognitive impairment over several years and low cerebrospinal fluid (CSF) amyloid beta-42 and elevated CSF …

Extracellular Matrix-Mycaf Signatures Correlate With Resistance To Neoadjuvant Apd-L1 Immune Checkpoint Inhibition With Durvalumab + Metformin In Hpv+ Hnscc, Pablo Llerena, Hani Samarah, Kathryn Nunes, Zhao Lin, Kelly Bridgham, Sruti Tekumalla, Amiti Jain, Larry A. Harshyne, Sanket Kumar Shukla, Ioannis Vathiotis, Madalina Tuluc, Stacey Gargano, John R. Eisenbrey, Scott W Keith, David Cognetti, Voichita Bar-Ad, Adam J. Luginbuhl, Rita S. Axelrod, Rajanikanth Vadigepalli, Hushan Yang, Diana Whitaker-Menezes, Megan Roche, My G. Mahoney, Athanassios Argiris, Charalambos C. Solomides, Jennifer Johnson, Md, Mouadh Barbirou, Amanda Miller, Andrew P. South, Ramkrishna Mitra, Alban J Linnenbach, Ubaldo E. Martinez-Outshoorn, Joseph Curry

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

PURPOSE: Immune checkpoint inhibitors (ICI) have demonstrated clinical benefit in head and neck squamous cell carcinoma (HNSCC); however, single-agent efficacy is limited, leaving significant unmet needs. Metformin may synergize with ICIs, offering promise to improve response rates. We leveraged multiomic data from a randomized, presurgical neoadjuvant trial (NCT03618654) evaluating a single infusion of the anti-PD-L1 ICI durvalumab with or without daily, standard dose metformin in previously untreated, nondiabetic patients with HNSCC to understand predictors of response and the effect of combination therapy.

PATIENTS AND METHODS: Clinical, pathologic, and correlative data were analyzed to investigate response and resistance mechanisms. We present …

Low-Dimensional Signatures Of Neuronal Activity Associated With Long-Term Operant Conditioning In Aplysia, Sara Vanaki, Nicholas O Gonzalez, Curtis L Neveu, Yuto Momohara, Behnaam Aazhang, John H Byrne

Faculty, Staff and Student Publications

Operant conditioning is a form of learning in which a behavior is reinforced by reward. Operant conditioning has multiple temporal domains, ranging from short-term, lasting a few minutes, to long-term, persisting for at least 24 h. The extent to which short- and long-term operant conditioning memories rely on shared or separate neural mechanisms is poorly understood. Voltage-sensitive dye (VSD) imaging has been used previously to record the activity of a large number of neurons simultaneously in the buccal ganglion to measure changes in neuronal activity during short-term operant conditioning. We examined neuronal activity using VSD 24 h after operant conditioning …

Violence Between Residents In Nursing Homes Is An Enduring Problem. The Agencies, Nursing Homes, And Residents Are Playing Hot Potato With The Responsibility, Cindy Marchionda, Rafael Escalara Montoto

Capstones

Resident-to-resident aggression in nursing homes is a persistent issue, far more common than the general public realizes. While many of these violent situations can be managed, some tragically escalate to fatal outcomes, leaving families mourning the loss of their loved ones at the hands of a facility that was meant to provide safety and care during their final years. Experts agree that this issue is largely driven by chronic understaffing and insufficient training for employees on how to manage patients with dementia and aggression issues.

Radiogenomic Profiling Of Prostate Tumors Prior To External Beam Radiotherapy Converges On A Transcriptomic Signature Of Tgf-Β Activity Driving Tumor Recurrence, Anson T. Ku, Uma Shankavaram, Shana Y. Trostel, Hong Zhang, Sumeyra Kartal, Houssein A. Sater, Stephanie A. Harmon, Nicole V. Carrabba, Yang Liu, Hyunnam Ryu, James A. Proudfoot, Boon Hao Hong, Bradford J. Wood, Peter A. Pinto, Peter L. Choyke, Mack Roach, Howard M. Sandler, Stephanie L. Pugh, Kenneth L. Zeitzer, Lucas C. Mendez, Nirav S. Kapadia, William A. Hall, Anand B. Desai, Radka S. Stoyanova, Alan Pollack, Elai Davicioni, Melvin L. K. Chua, Baris Turkbey, Adam G. Sowalsky, Deborah E. Citrin

Einstein Health Papers

PURPOSE: Clinical risk grouping based on PSA, tumor grade, and disease extent guides treatment intensity for localized prostate cancer. However, many patients with intermediate- or high-risk disease treated with external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) still develop biochemical recurrence (BCR). Early identification of patients at high risk for BCR could enable personalized treatment strategies.

EXPERIMENTAL DESIGN: We prospectively enrolled 29 patients with intermediate- or high-risk prostate cancer undergoing EBRT and ADT. Pretreatment biopsies (n = 60) underwent whole-transcriptome microarray and whole-exome sequencing. Patients received multiparametric MRI at baseline and 6 months after treatment, with a median follow-up …

Tumor Mirna Signatures Associate With Outcomes Of Patients With Stage Ii/Iii Melanoma, Jennifer M Wiggins, Qiao Zhang, Yian Zhang, Fatemeh Vand-Rajabpour, Douglas Hanniford, Linchen He, Yuting Lu, Jessica M Kenney, Keimya D Sadeghi, Diana Argibay, Irene Orlow, Klaus J Busam, Cecilia Lezcano, Tim K Lee, Li Luo, Ivan P Gorlov, Christopher Amos, Marc S Ernstoff, Venkatraman E Seshan, Anne E Cust, James Wilmott, Richard A Scolyer, Graham J Mann, Allison Reiner, Caroline E Kostrzewa, Eduardo Nagore, Pauline Funchain, Jennifer Ko, Sharon N Edmiston, Kathleen Conway, Paul B Googe, David W Ollila, Jeffrey E Lee, Judy R Rees, Cheryl L Thompson, Meg Gerstenblith, Marcus Bosenberg, Bonnie E Gould Rothberg, Iman Osman, Yvonne Saenger, Adam Z Reynolds, Tawny Boyce, Sheri Holmen, Shaofeng Yan, Elise Brunsgaard, Paul Bogner, Pei Fen Kuan, Nancy E Thomas, Colin B Begg, Ronglai Shen, Marianne Berwick, Yongzhao Shao, David Polsky, Eva Hernando

Faculty, Staff and Students Publications

Purpose: Patients with stage II and resected stage III melanomas have variable clinical outcomes, providing evidence of underlying biological differences in tumors and/or the patients themselves, beyond stage. The approval of adjuvant immunotherapy for stage IIB/C and resected stage III/IV disease (and adjuvant targeted therapy for resected stage III disease) has created a pressing need to develop biomarkers to accurately distinguish patients at low risk versus high risk for recurrence and death from melanoma. miRNAs are promising biomarkers because of their stability in tissues and fluids and their demonstrated functional and prognostic roles in melanoma. We hypothesized that miRNA expression …

Benchmarking Of Duplex Sequencing Approaches To Reveal Somatic Mutation Landscapes, Yang Zhang, Vinayak V Viswanadham, Michail Andreopoulos, Dominik Glodzik, Ruolin Liu, Lovelace J Luquette, Se-Young Jo, Azeet Narayan, Muchun Niu, Lisa Anderson, Joseph A Brew, Hsu Chao, Carrie Cibulskis, Guanlan Dong, Uday S Evani, William C Feng, Marta Grońska-Pęski, Adrienne Helland, Nazia Hilal, Nisrine T Jabara, Hu Jin, Ning Li, Monica D Manam, Shayna L Mallett, Alexi Runnels, Constantijn Scharlee, Carter Smith, Smaht Duplex Sequencing Focus Group, Diane Shao, Christopher A Walsh, Viktor A Adalsteinsson, Eunjung Alice Lee, Peter J Park, Kristin G Ardlie, Soren Germer, Richard A Gibbs, Sangita Choudhury, Harsha V Doddapaneni, Gilad D Evrony, Chenghang Zong, Tim H H Coorens

Faculty, Staff and Students Publications

Detecting somatic mutations in normal tissues is challenging due to sequencing errors and the low allele fractions of post-zygotic variants. Duplex sequencing greatly reduces errors and can detect mutations at any allele fraction, but systematic, cross-platform comparisons are lacking. We present a comprehensive benchmarking of six duplex sequencing technologies used by the SMaHT Network: CODEC, CompDuplex-seq, HiDEF-seq, NanoSeq, ppmSeq, and VISTA-seq. We evaluated their performance using cord blood DNA, a tumor-normal cell line mixture, and homogenates from six human tissues. Each method shows distinct profiles in genomic footprint, sensitivity, and cost. Despite differences in library construction and sequencing platforms, estimates …

Mrna Vaccines Encoding Variant Forms Of Sm-Tsp-2 Confer Protective Immunity Against Schistosoma Mansoni, Athos Silva De Oliveira, Sevan Alwan, Philip T Loverde, Ramiz Shaheed, Pranav Mandyam, Rakesh Adhikari, Peter Hotez, Maria Elena Bottazzi, Jeroen Pollet

Faculty, Staff and Students Publications

This study explored the development and evaluation of mRNA vaccine candidates targeting Schistosoma mansoni tetraspanin-2 (Sm-TSP-2). We designed constructs encoding either full-length Sm-TSP-2, or its large extracellular loop (EC2) domain in secretory, membrane-anchored, or cytosolic forms. In a murine model, the secreted and membrane-anchored versions of Sm-TSP-2-EC2 induced the highest antigen-specific antibody titers. These two construct designs, along with full-length Sm-TSP-2 mRNA, also significantly reduced adult worm and egg burden compared to controls. The membrane-anchored Sm-TSP-2-EC2 mRNA was the most effective, lowering worm and egg burdens by 66.7% and 66.9%, respectively. Protective responses induced by the mRNA vaccines were comparable …

Facts And Hopes Of Chimeric Antigen Receptor-Redirected Nk T Cells, Amy N Courtney, Xin Zhou, Gengwen Tian, Ying Wang, Leonid S Metelitsa, Gianpietro Dotti

Faculty, Staff and Students Publications

Chimeric antigen receptor (CAR)-engineered invariant NK T cells (CAR-NKT) are a novel cell platform for cancer immunotherapy. Unlike conventional T cells, NKTs are characterized by innate antitumor properties, minimal alloreactivity, and a unique ability to modulate the tumor microenvironment. This article provides a comprehensive overview of preclinical and early clinical studies evaluating CAR-NKTs in both autologous and allogeneic clinical settings. We discuss the contributions of CAR signaling domains, cytokine coexpression, and other functional measures that correlate with CAR-NKT persistence, function, and metabolic fitness. We also discuss the critical role of immunocompetent animal models in elucidating the interactions of CAR-NKTs with …

Mitochondrial Complex Ii Orchestrates Divergent Effects In Cd4+ And Cd8+ T Cells, Keisuke Seike, Shih-Chun A Chu, Yuichi Sumii, Takashi Ikeda, Meng-Chih Wu, Laure Maneix, Dongchang Zhao, Yaping Sun, Marcin Cieslik, Pavan Reddy

Faculty, Staff and Students Publications

Mitochondrial metabolism orchestrates T cell functions, yet the role of specific mitochondrial components in distinct T cell subsets remains poorly understood. Here, we explored the role of mitochondrial complex II (MC II), the only complex from the electron transport chain (ETC) that plays a role in both ETC and metabolism, in regulating T cell functions. Surprisingly, MC II exerts divergent effects on CD4+ and CD8+ T cell activation and function. Using T cell-specific MC II subunit, succinate dehydrogenase A-deficient (SDHA-deficient) mice, we integrated single-cell RNA-seq and metabolic profiling, with in vitro and in vivo T cell functional assays to illuminate …

Transdiagnostic Links Of Reward Processing In Obsessive-Compulsive Disorder And Depression, Kevin M Wagner, Matti Cervin, Jessica S C Cheng, Jasmine Arriaga, Vanessa Zavala Cruz, Dayan Berrones, Josselyn S Muñoz, Renee M Frederick, Jacey L Anderberg, Belinda E Núñez Bracho, Victor R Adorno, Leonardo F Fontenelle, Andrew D Wiese, Latin American Trans-Ancestry Initiative For Ocd Genomics (Latino), Brazilian Obsessive-Compulsive Spectrum Disorder Working Group (Gttoc), James J Crowley, Eric A Storch

Faculty, Staff and Students Publications

Objectives: Transdiagnostic models aim to uncover shared mechanisms across mental disorders. Reward responsiveness (the ability to experience pleasure from rewarding stimuli) is a plausible, yet underexplored, transdiagnostic mechanism linking obsessive-compulsive disorder (OCD) and depression. This study used network analysis to (1) examine how key reward responsiveness domains are interlinked in individuals with OCD and (2) explore how each domain is uniquely associated with OCD and depression.

Methods: A total of 1345 individuals with a history of OCD symptoms (ages 18-88, 71 % women) from Latino communities in the United States (including Puerto Rico) and nine Latin American countries completed validated …

Vasoactive Drug Use In Children With Community Acquired Septic Shock In Australia And New Zealand, Elliot Long, Stephen Hearps, Amanda Williams, Ben Gelbart, Warwick Butt, Thomas Rozen, Sarah Mcnab, Meredith Borland, Simon Erickson, Shefali Jani, Marino Festa, Eunicia Tan, Natalie Phillips, Sainath Raman, Amit Kochar, Subodh Ganu, Simon Craig, Anna Lithgow, Arjun Rao, Emma Whyte, Stuart Dalziel, Shane George, Fran Balamuth, Scott Weiss, Nathan Kuppermann, Franz Babl

Department of Medicine Faculty Papers

BACKGROUND: Vasoactive agents are a critical supportive therapy for children with sepsis. We describe the choice and use patterns of vasoactive agents in children with sepsis.

METHODS: Prospective observational study conducted in 11 hospitals in Australia and New Zealand through the Paediatric Research in Emergency Departments International Collaborative (PREDICT) Network from April 2021 to December 2023. Children aged 0-< 18 years with suspected sepsis were included. Children admitted to hospital and treated with parenteral antibiotics and either 1) a provisional diagnosis of sepsis, and/or 2) treatment for suspected sepsis (fluid bolus to treat poor perfusion). The frequency and sequence of use of vasoactive agents, and contributors to the choice of initial vasoactive were collected.

FINDINGS: 6232 children with suspected sepsis were included; median age of 2.1 years (IQR 0.3-7.1 years), in-hospital mortality of 60 (1.0%), in whom a subset of 306 (4.9%) met Phoenix sepsis criteria. Vasoactive agents were used in 179 (2.9%) children overall …

The Hidden Toll: Atrophy Of Key Central Nervous System Relays In African American Women With Multiple Sclerosis, Nabeela Nathoo, Nur Neyal, Jiye Son, Christopher G Schwarz, Elizabeth J Atkinson, Holly A Morrison, June Kendall Thomas, John D Port, Kejal Kantarci, Orhun H Kantarci, Burcu Zeydan

Faculty, Staff and Students Publications

Background: African American persons with MS (AApwMS) have more aggressive clinical and imaging outcomes than White American pwMS (WApwMS), including lower brain and spinal cord (SC) volumes. However, imaging studies are lacking considering the effects of sex, race, and ethnicity together.

Objective: Compare MS clinical and imaging features among AApwMS and WApwMS, incorporating the modifying effects of sex, race, and ethnicity.

Methods: Clinical variables and MRI were obtained for AApwMS and WApwMS.

Results: Thirty-five MRIs in 28 AApwMS (61 % female) and 255 MRIs in 91 WApwMS (68 % female) were evaluated. AApwMS had a shorter MS disease duration (median …

A Long Non-Coding Rna Leat1 Mediates The Hormone Responsiveness Of Efnb2 During Male Urogenital Development, Deidre Mattiske, Pascal Bernard, Paul E Gradie, Richard R Behringer, Paul A Overbeek, Rachel J O'Neill, Tiffany Phillips, Melanie Stewart, Neil Youngson, Gerard Tarulli, Andrew J Pask

Faculty, Staff and Students Publications

The novel long non-coding RNA (lncRNA) Leat1 is extraordinarily conserved in both its location (syntenic with EfnB2, an essential gene in anogenital patterning) and sequence. Here we show that Leat1 is upregulated following the production of testosterone from the developing testis in mice and interacts with EfnB2, positively regulating its expression. Leat1 expression is suppressed by estrogen, which in turn suppresses the expression of EfnB2. Moreover, the loss of Leat1 leads to reduced EfnB2, resulting in a severe hypospadias phenotype. The human LEAT1 gene is also co-expressed with EFNB2 in the developing human penis, suggesting a conserved function for this …

Treating Atrial Fibrillation: Cryoballoon Vs. Radiofrequency Ablation, Nile A. Latowsky, Jordan E. Andre

Physician Assistant Capstones, 2020-current

Objective: Assess the effectiveness of pulmonary vein isolation (PVI) by cryoballoon ablation (CBA) compared to the current gold standard of care, radiofrequency ablation (RFA), for the treatment of paroxysmal and persistent atrial fibrillation in a symptomatic population. Design: Literature review. Methods: Searches were done in PubMed and Cochrane Library, utilizing the terms atrial fibrillation, cryoballoon ablation, and radiofrequency. In PubMed, the following limits and terms were used: published in the last 10 years, humans, randomized controlled trial, and English. Results: Search results revealed four studies meeting the inclusion/exclusion criteria. Conclusion: Cryoballoon ablation (CBA) is as efficacious in treating atrial fibrillation …

Patient-Derived Ovarian Cancer Models Provide Insight Into Cancer Cell-Intrinsic And Immune Cell-Dependent Effects On Therapeutic Response, Parisa Nikeghbal

Biomedical Sciences ETDs

Ovarian cancer is the most lethal gynecologic malignancy, largely due to late diagnosis and resistance to chemotherapy. This dissertation applies patient-derived organoids (PDOs), xenograft-derived organoids (PDXOs), and humanized xenografts (huPDX) to investigate therapeutic responses and immune interactions. Organoids were shown to retain critical features of the original malignancy. Across platinum-sensitive, -resistant, and -refractory cases, both PDOs and PDXOs exhibited drug sensitivities that aligned with patients’ clinical classifications. Building on this foundation, a drug screen revealed novel strategies. Auranofin restored platinum sensitivity in Notch3-active models, afatinib broadly reduced viability, and adavosertib–gemcitabine and sorafenib–topotecan combinations produced synergy. Extending this work, immune interactions …

Recreating Fiber Recruitment With Fiber Recruitment Using Additive Manufacturing, Natalia D. Mciver

Biomedical Engineering ETDs

Injured ligaments are often repaired with tendon grafts which may over or under constrain the joint; there is a need for an artificial graft option with the mechanical properties of a native ligament. Crimped fibers within ligaments allow for recruitment which means the viscoelastic properties of stress relaxation and creep are not inversely related. A feasibility study using ACLs and large-scale crimp models to study viscoelasticity, led to an in-depth analysis of the scapholunate interosseous ligament. Using the Modified Kelvin spring-dashpot model, for describing viscoelasticity with a variable stiffness property (time dependent fiber recruitment), we defined the relationship between creep …

Krasg12d Mutation Promotes Pancreatic Tumorigenesis By Suppressing Sirtuin Three Via The Guanine Nucleotide Exchange Factor Rcc1, Taoyi Mai, Mengwen Wang, Ya Qiu, Wenhua Lu, Hongyu Wu, Shuna Chen, Paul J Chiao, Peng Huang

Faculty, Staff and Student Publications

KRASG12D mutation is a prevalent gain-of-function mutation that drives pancreatic cancer tumorigenesis, but the underlying mechanisms that promote KRAS-induced cell proliferation and tumor formation remain elusive. To uncover the molecular pathways that facilitate KRASG12D-driven malignant transformation, we measured the transcriptomic alterations at various time points after induction of KRASG12D expression in human pancreatic normal epithelial cells. KEGG pathway enrichment of the differentially expressed genes (DEGs) showed that the major DEGs were located in pathways that regulate nicotinate/nicotinamide metabolism, TNF signaling, and microRNAs associated with cancer. Among these molecular alterations, the NAD-dependent deacetylase gene SIRT3 was significantly down-regulated by KRASG12D. Conversely, …

Protein-Nucleic Acid Language Model-Assisted Design Of Precise And Compact Adenine Base Editor, Jingxuan Ren, Jiawei Yao, Qiuyu Cao, Yinuo Li, Yang Li, Ziyi Zhang, Xiyu Ge, Shengfang Wang, Yang Zhang, Xiaogang Wang, Xiaohui Zhang

Faculty, Staff and Students Publications

Adenine base editors (ABEs) are powerful tools for gene therapy. However, efficient version of ABEs (e.g. ABE8e) always induce excessive bystander and off-target editing events and are large in size, hindering their potential in clinical disease treatment. Here, we develop a pre-trained Protein-Nucleic Acid Constrained Language Model to design ABE8e with high activity, reduced editing window and decreased size. By further engineering, the smallest ABE8e- PNLM-pcABE- with a 27% size reduction, exhibits high activity, precise 3-nt editing window, and reduced off-target events near background level in HEK293T cells. Compared to ABE8e, PNLM-pcABE has up to 133.5-fold precision improvement in pathogenic …

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 …

Measurable Imaging-Based Changes In Enhancement Of Intrahepatic Cholangiocarcinoma After Radiotherapy Reflect Physical Mechanisms Of Response, Brian De, Prashant Dogra, Mohamed Zaid, Dalia Elganainy, Kevin Sun, Ahmed M Amer, Charles Wang, Michael K Rooney, Enoch Chang, Hyunseon C Kang, Zhihui Wang, Priya Bhosale, Bruno C Odisio, Timothy E Newhook, Ching-Wei D Tzeng, Hop S Tran Cao, Yun S Chun, Jean-Nicholas Vauthey, Sunyoung S Lee, Ahmed Kaseb, Kanwal Raghav, Milind Javle, Bruce D Minsky, Sonal S Noticewala, Emma B Holliday, Grace L Smith, Albert C Koong, Prajnan Das, Vittorio Cristini, Ethan B Ludmir, Eugene J Koay

Faculty, Staff and Student Publications

Escalated doses of radiotherapy associate with improved local control and overall survival (OS) in intrahepatic cholangiocarcinoma (iCCA), but personalization remains limited because conventional size-based CT criteria correlate poorly with outcomes. We hypothesized that quantitative enhancement measurements would better predict clinical outcomes and guide individualized RT optimization. In a retrospective cohort of 154 patients, we analyzed pre- and post-RT CT scans using quantitative European Association for Study of Liver (qEASL) to derive viable tumor volumes, comparing enhancement-based metrics with size-based RECIST and linking them to outcomes via survival and mathematical modeling. Change in enhancement volume was strongly associated with OS after …

Improving Dka Protocol Adherence In The Emergency Department, Anjolaoluwa Lawani

Master's Projects and Capstones

Problem There was inconsistency in implementation of the DKA protocol by nurses in the emergency department at the Hospital A. Only 58% of the nurses reported feeling comfortable following the DK protocol, and 84% of the nurses described the DKA order set as confusing. Context Hospital A is a large magnet-recognition hospital system in the Bay Area. The emergency department at Hospital A averages about 12 DKA patients per quarter. Intervention Education sessions were held during pre-shift cuddles across day and night shifts to clarify the DKA protocol and answer any questions or nurses may have. Measures Baseline surveys and …

Correction: Amino Acid Transporter Lat1 (Slc7a5) Promotes Metabolic Rewiring In Tnbc Progression Through The L-Trp/Qprt/Nad+ Pathway, Margot Y. Fedoroff, Lei Zhao, Shaomin Wang, Leili Saeednejad Zanjani, Alok Bhushan, Haifeng Yang, Karen M. Bussard, Stephen C Peiper, Jun He

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Correction: J Exp Clin Cancer Res 44, 190 (2025) Following publication of the original article [1], the authors found that Dr. Leila Saeednejad Zanjani was not included in the final author list despite her contributions. The details are provided below: Current authors: Margot Y. Fedoroff1†, Lei Zhao1†, Shaomin Wang1, Alok Bhushan2, Haifeng Yang1, Karen M. Bussard3, Stephen C. Peiper1 and Jun He1*. Updated author list: Margot Y. Fedoroff1†, Lei Zhao1†, Shaomin Wang1, Leili Saeednejad Zanjani1, Alok Bhushan2, Haifeng Yang1, Karen M Bussard3, Stephen C Peiper1, Jun He1*. The correction does not compromise the validity of the conclusions and the overall …

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 …

Stromal Fibroblastic Mutant Trp53 Promotes Mammary Tumor Development Via Enhanced Secretion Of Paracrine Factors, Bin Liu, Shunbin Xiong, Abie Williams-Villalobo, Gilda Chau, Yuan Qi, Hehua Chen, Carenza Johnson, Dhruv Chachad, Joy Mcdaniel, Xiaoping Su, Adel K El-Naggar, Guillermina Lozano, Yun Zhang

Faculty, Staff and Student Publications

Mutations in the tumor suppressor gene TP53 have been identified in breast cancer-associated fibroblasts and are associated with poor patient prognosis. However, the functional impact of fibroblastic mutant p53 on breast cancer development remains unclear. To investigate this, we compared female mice harboring HER2-driven mammary tumors with a fibroblast-specific Trp53 mutation (NP) to those with wild-type fibroblastic Trp53 (N). NP mice exhibited significantly shorter median tumor-free survival than N mice. RNA sequencing of NP and N tumors and mammary glands revealed numerous differentially expressed genes (DEGs) between tumors and the corresponding glands in both genotypes. Notably, the NP tumors showed …