Digital Commons Network^™

Molecular Profiles Of Serum-Derived Extracellular Vesicles In High-Grade Serous Ovarian Cancer, Li Zhao, Sara Corvigno, Shaolin Ma, Joseph Celestino, Nicole D Fleming, Richard A Hajek, Adrian Lankenau Ahumada, Nicholas B Jennings, Erika J Thompson, Hongli Tang, Shannon N Westin, Amir A Jazaeri, Jianhua Zhang, P Andrew Futreal, Anil K Sood, Sanghoon Lee

Faculty, Staff and Student Publications

Patients with high-grade serous ovarian cancer (HGSC) who have no visible residual disease (R0) after primary surgery have the best clinical outcomes, followed by patients who undergo neoadjuvant chemotherapy (NACT) and have a response enabling interval cytoreductive surgery. Clinically useful biomarkers for predicting these outcomes are still lacking. Extracellular vesicles (EVs) have been recognized as liquid biopsy-based biomarkers for early cancer detection and disease surveillance in other disease settings. In this study, we performed extensive molecular characterization of serum-derived EVs and correlated the findings with therapeutic outcomes in patients with HGSC. Using EV-DNA whole-genome sequencing and EV-RNA sequencing, we identified …

Genome-Wide Association Study In Minority Children With Asthma Implicates Dnah5 In Bronchodilator Responsiveness, Jaehyun Joo, Angel C. Y Mak, Shujie Xiao, Patrick M. Sleiman, Donglei Hu, Scott Huntsman, Celeste Eng, Mengyuan Kan, Avantika R. Diwakar, Jessica A. Lasky-Su, Scott T. Weiss, Joanne E. Sordillo, Ann C. Wu, Michelle Cloutier, Glorisa Canino, Erick Forno, Juan C. Celedón, Max A. Seibold, Hakon Hakonarson, Keoki L. Williams, Esteban G. Burchard, Blanca E. Himes

Center for Individualized and Genomic Medicine Research Articles

Variability in response to short-acting β(2)-agonists (e.g., albuterol) among patients with asthma from diverse racial/ethnic groups may contribute to asthma disparities. We sought to identify genetic variants associated with bronchodilator response (BDR) to identify potential mechanisms of drug response and risk factors for worse asthma outcomes. Genome-wide association studies of bronchodilator response (BDR) were performed using TOPMed Whole Genome Sequencing data of the Asthma Translational Genomic Collaboration (ATGC), which corresponded to 1136 Puerto Rican, 656 Mexican and 4337 African American patients with asthma. With the population-specific GWAS results, a trans-ethnic meta-analysis was performed to identify BDR-associated variants shared across the …

Regulated Dicing Of Pre-Mir-144 Via Reshaping Of Its Terminal Loop., Renfu Shang, Dmitry A Kretov, Scott I Adamson, Thomas Treiber, Nora Treiber, Jeffrey Vedanayagam, Jeffrey H Chuang, Gunter Meister, Daniel Cifuentes, Eric C Lai

Faculty Research 2022

Although the route to generate microRNAs (miRNAs) is often depicted as a linear series of sequential and constitutive cleavages, we now appreciate multiple alternative pathways as well as diverse strategies to modulate their processing and function. Here, we identify an unusually profound regulatory role of conserved loop sequences in vertebrate pre-mir-144, which are essential for its cleavage by the Dicer RNase III enzyme in human and zebrafish models. Our data indicate that pre-mir-144 dicing is positively regulated via its terminal loop, and involves the ILF3 complex (NF90 and its partner NF45/ILF2). We provide further evidence that this regulatory switch involves …

Integrated Dna Copy Number And Expression Profiling Identifies Igf1r As A Prognostic Biomarker In Pediatric Osteosarcoma., Aaron M Taylor, Jiayi M Sun, Alexander Yu, Horatiu Voicu, Jianhe Shen, Donald A Barkauskas, Timothy J Triche, Julie M Gastier-Foster, Tsz-Kwong Man, Ching C Lau

Faculty Research 2022

Osteosarcoma is a primary malignant bone tumor arising from bone-forming mesenchymal cells in children and adolescents. Despite efforts to understand the biology of the disease and identify novel therapeutics, the survival of osteosarcoma patients remains dismal. We have concurrently profiled the copy number and gene expression of 226 osteosarcoma samples as part of the Strategic Partnering to Evaluate Cancer Signatures (SPECS) initiative. Our results demonstrate the heterogeneous landscape of osteosarcoma in younger populations by showing the presence of genome-wide copy number abnormalities occurring both recurrently among samples and in a high frequency. Insulin growth factor receptor 1 (IGF1R) is a …

Integrated Dna Copy Number And Expression Profiling Identifies Igf1r As A Prognostic Biomarker In Pediatric Osteosarcoma, Aaron M Taylor, Jiayi M Sun, Alexander Yu, Horatiu Voicu, Jianhe Shen, Donald A Barkauskas, Timothy J Triche, Julie M Gastier-Foster, Tsz-Kwong Man, Ching C Lau

Center for Medical Ethics and Health Policy Staff Publications

Osteosarcoma is a primary malignant bone tumor arising from bone-forming mesenchymal cells in children and adolescents. Despite efforts to understand the biology of the disease and identify novel therapeutics, the survival of osteosarcoma patients remains dismal. We have concurrently profiled the copy number and gene expression of 226 osteosarcoma samples as part of the Strategic Partnering to Evaluate Cancer Signatures (SPECS) initiative. Our results demonstrate the heterogeneous landscape of osteosarcoma in younger populations by showing the presence of genome-wide copy number abnormalities occurring both recurrently among samples and in a high frequency. Insulin growth factor receptor 1 (IGF1R) is a …

Advanced-Stage Melanoma At Presentation Following The Peak Of The Pandemic: A Covid-19 Cancer Canary In A Coal Mine, Ryan Lamm, Md, Walker Lyons, Md, Winnie So, Rn, Alliric I. Willis, Md, Facs, Msph

Department of Surgery Faculty Papers

Background: For melanoma patients, timely identification and tumor thickness are directly correlated with outcomes. COVID-19 impacted both patients' ability and desire to see physicians. We sought to identify whether the pandemic correlated with changes in melanoma thickness at presentation and subsequent treatment timeline.

Methods: Retrospective chart review was performed on patients who underwent surgery for melanoma in an academic center surgical oncology practice from May 2019 to September 2021. Patients were split into two cohorts: "pre-pandemic" from May 2019 to May 2020 and "pandemic," after May 2020, representing when these patients received their initial diagnostic biopsy. Demographic and melanoma-specific variables …

Proteomic Biomarkers Of The Apnea Hypopnea Index And Obstructive Sleep Apnea: Insights Into The Pathophysiology Of Presence, Severity, And Treatment Response, Katie L J Cederberg, Yo-El S Ju, Et Al

2020-Current year OA Pubs

Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (

Graded Variation In T1w/T2w Ratio During Adolescence: Measurement, Caveats, And Implications For Development Of Cortical Myelin, Graham L Baum, John C Flournoy, Matthew F Glasser, Michael P Harms, Patrick Mair, Ashley F P Sanders, Deanna M Barch, Randy L Buckner, Susan Bookheimer, Mirella Dapretto, Stephen Smith, Kathleen M Thomas, Essa Yacoub, David C Van Essen, Leah H Somerville

2020-Current year OA Pubs

Adolescence is characterized by the maturation of cortical microstructure and connectivity supporting complex cognition and behavior. Axonal myelination influences brain connectivity during development by enhancing neural signaling speed and inhibiting plasticity. However, the maturational timing of cortical myelination during human adolescence remains poorly understood. Here, we take advantage of recent advances in high-resolution cortical T1w/T2w mapping methods, including principled correction of B1+ transmit field effects, using data from the Human Connectome Project in Development (HCP-D;

Kathryn V. Holmes: A Career Of Contributions To The Coronavirus Field, Aurelio Bonavia, Samuel R Dominguez, Gabriela Dveksler, Sara Gagneten, Megan Howard, Scott Jeffers, Zhaohui Qian, Mary Kathryn Smith, Larissa B Thackray, Dina B Tresnan, David E Wentworth, David R Wessner, Richard K Williams, Tanya A Miura

2020-Current year OA Pubs

Over the past two years, scientific research has moved at an unprecedented rate in response to the COVID-19 pandemic. The rapid development of effective vaccines and therapeutics would not have been possible without extensive background knowledge on coronaviruses developed over decades by researchers, including Kathryn (Kay) Holmes. Kay's research team discovered the first coronavirus receptors for mouse hepatitis virus and human coronavirus 229E and contributed a wealth of information on coronaviral spike glycoproteins and receptor interactions that are critical determinants of host and tissue specificity. She collaborated with several research laboratories to contribute knowledge in additional areas, including coronaviral pathogenesis, …

Effect Of Race On Prediction Of Brain Amyloidosis By Plasma Aβ42/Aβ40, Phosphorylated Tau, And Neurofilament Light, Suzanne E Schindler, Rachel L Henson, Yan Li, Benjamin Saef, Krista L Moulder, David Bradford, Anne M Fagan, Brian A Gordon, Tammie L S Benzinger, Joyce Balls-Berry, Randall J Bateman, Chengjie Xiong, John C Morris, Et Al

2020-Current year OA Pubs

BACKGROUND AND OBJECTIVES: To evaluate whether plasma biomarkers of amyloid (Aβ42/Aβ40), tau (p-tau181 and p-tau231), and neuroaxonal injury (neurofilament light chain [NfL]) detect brain amyloidosis consistently across racial groups.

METHODS: Individuals enrolled in studies of memory and aging who self-identified as African American (AA) were matched 1:1 to self-identified non-Hispanic White (NHW) individuals by age,

RESULTS: There were 76 matched pairs of AA and NHW participants (n = 152 total). For both AA and NHW groups, the median age was 68.4 years, 42% were

DISCUSSION: Models predicting brain amyloidosis using a high-performance plasma Aβ42/Aβ40 assay may provide an accurate and …

Adipose Methylome Integrative-Omic Analyses Reveal Genetic And Dietary Metabolic Health Drivers And Insulin Resistance Classifiers., Colette Christiansen, Max Tomlinson, Melissa Eliot, Emma Nilsson, Ricardo Costeira, Yujing Xia, Sergio Villicaña, Olatz Mompeo, Philippa Wells, Juan Castillo-Fernandez, Louis Potier, Marie-Claude Vohl, Andre Tchernof, Julia El-Sayed Moustafa, Cristina Menni, Claire J. Steves, Karl Kelsey, Charlotte Ling, Elin Grundberg, Kerrin S. Small, Jordana T. Bell

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: There is considerable evidence for the importance of the DNA methylome in metabolic health, for example, a robust methylation signature has been associated with body mass index (BMI). However, visceral fat (VF) mass accumulation is a greater risk factor for metabolic disease than BMI alone. In this study, we dissect the subcutaneous adipose tissue (SAT) methylome signature relevant to metabolic health by focusing on VF as the major risk factor of metabolic disease. We integrate results with genetic, blood methylation, SAT gene expression, blood metabolomic, dietary intake and metabolic phenotype data to assess and quantify genetic and environmental drivers …

Therapeutic Targeting Of Macrophage Plasticity Remodels The Tumor-Immune Microenvironment, Hee-Jin Jang, Hyun-Sung Lee, Wendong Yu, Maheshwari Ramineni, Cynthia Y Truong, Daniela Ramos, Taylor Splawn, Jong Min Choi, Sung Yun Jung, Ju-Seog Lee, Daniel Y Wang, Joel M Sederstrom, Massimo Pietropaolo, Farrah Kheradmand, Christopher I Amos, Thomas M Wheeler, R Taylor Ripley, Bryan M Burt

Center for Medical Ethics and Health Policy Staff Publications

Although the majority of patients with advanced lung adenocarcinoma (LUAD) are eligible to receive immune checkpoint blockade, approximately 80% of these tumors are resistant to this therapeutic approach. Insights at the single-cell level into mechanisms that drive LUAD tumorigenesis and the relationship of LUAD histologic heterogeneity to response to immune checkpoint blockade could help identify biomarkers and potential combinational approaches to improve immunotherapy efficacy. Here we used a genetically engineered mouse model that replicates the development of human LUAD through a spectrum of pre-invasive to invasive adenocarcinoma histologic subtypes. A systems onco-immunology approach of integrating the analytical power and unique, …

A Method For Bridging Population-Specific Genotypes To Detect Gene Modules Associated With Alzheimer's Disease, Yulin Dai, Peilin Jia, Zhongming Zhao, Assaf Gottlieb

Faculty, Staff and Student Publications

BACKGROUND: Genome-wide association studies have successfully identified variants associated with multiple conditions. However, generalizing discoveries across diverse populations remains challenging due to large variations in genetic composition. Methods that perform gene expression imputation have attempted to address the transferability of gene discoveries across populations, but with limited success.

METHODS: Here, we introduce a pipeline that combines gene expression imputation with gene module discovery, including a dense gene module search and a gene set variation analysis, to address the transferability issue. Our method feeds association probabilities of imputed gene expression with a selected phenotype into tissue-specific gene-module discovery over protein interaction …

Cranial Base Synchondrosis: Chondrocytes At The Hub, Shawn A Hallett, Wanida Ono, Renny T Franceschi, Noriaki Ono

Faculty, Staff and Student Publications

The cranial base is formed by endochondral ossification and functions as a driver of anteroposterior cranial elongation and overall craniofacial growth. The cranial base contains the synchondroses that are composed of opposite-facing layers of resting, proliferating and hypertrophic chondrocytes with unique developmental origins, both in the neural crest and mesoderm. In humans, premature ossification of the synchondroses causes midfacial hypoplasia, which commonly presents in patients with syndromic craniosynostoses and skeletal Class III malocclusion. Major signaling pathways and transcription factors that regulate the long bone growth plate-PTHrP-Ihh, FGF, Wnt, BMP signaling and Runx2-are also involved in the cranial base synchondrosis. Here, …

Echocardiographic Predictors Of Symptomatic Cardiotoxicity Among Patients Undergoing Chemotherapy: A Systematic Review And Meta-Analysis, Muhammad Umer Siddiqui, Youssef Yaacoub, Heidi-Anne Hanson, Joey Junarta, Ahmed K Pasha, Mahek Shah

Division of Internal Medicine Faculty Papers & Presentations

BACKGROUND: Chemotherapeutic agents have been associated with cardiotoxicity; thus, they require close monitoring. Several echocardiographic variables have been investigated as early predictors of symptomatic cardiotoxicity in patients undergoing chemotherapy.

OBJECTIVE: To identify if global longitudinal strain (GLS) is a better predictor of symptomatic cardiotoxicity compared to left ventricular ejection fraction (LVEF) in patients receiving chemotherapy.

METHODS: MEDLINE, Scopus, and Cochrane Central Register of Controlled Trials were searched from inception through December 2020. Adults who developed symptomatic cardiotoxicity (New York Heart Association [NYHA] Class III-IV heart failure, cardiac arrest, or cardiac death) after undergoing chemotherapy with pre- and postchemotherapy echocardiographic measures …

Impairing Proliferation Of Glioblastoma Multiforme With Cd44+ Selective Conjugated Polymer Nanoparticles, Dorota Lubanska, Sami Alrashed, Gage T. Mason, Fatima Nadeem, Angela Awada, Mitchell Dipasquale, Alexandra Sorge, Aleena Malik, Monika Kojic, Mohamed A. R Soliman, Ana C. De Carvalho, Abdalla Shamisa, Swati Kulkarni, Drew Marquardt, Lisa A. Porter, Simon Rondeau-Gagné

Neurosurgery Articles

Glioblastoma is one of the most aggressive types of cancer with success of therapy being hampered by the existence of treatment resistant populations of stem-like Tumour Initiating Cells (TICs) and poor blood-brain barrier drug penetration. Therapies capable of effectively targeting the TIC population are in high demand. Here, we synthesize spherical diketopyrrolopyrrole-based Conjugated Polymer Nanoparticles (CPNs) with an average diameter of 109 nm. CPNs were designed to include fluorescein-conjugated Hyaluronic Acid (HA), a ligand for the CD44 receptor present on one population of TICs. We demonstrate blood-brain barrier permeability of this system and concentration and cell cycle phase-dependent selective uptake …

Cd11b Suppresses Tlr Activation Of Nonclassical Monocytes To Reduce Primary Graft Dysfunction After Lung Transplantation, Melissa Querrey, Stephen Chiu, Emilia Lecuona, Qiang Wu, Haiying Sun, Megan Anderson, Megan Kelly, Sowmya Ravi, Alexander V. Misharin, Daniel Kreisel, Ankit Bharat, G. R. Scott Budinger

2020-Current year OA Pubs

Primary graft dysfunction (PGD) is the leading cause of postoperative mortality in lung transplant recipients and the most important risk factor for development of chronic lung allograft dysfunction. The mechanistic basis for the variability in the incidence and severity of PGD between lung transplant recipients is not known. Using a murine orthotopic vascularized lung transplant model, we found that redundant activation of Toll-like receptors 2 and 4 (TLR2 and -4) on nonclassical monocytes activates MyD88, inducing the release of the neutrophil attractant chemokine CXCL2. Deletion of Itgam (encodes CD11b) in nonclassical monocytes enhanced their production of CXCL2 and worsened PGD, …

Long-Term Outcomes For Ibrutinib-Rituximab And Chemoimmunotherapy In Cll: Updated Results Of The E1912 Trial, Tait D Shanafelt, Amanda F Cashen, Et Al.

2020-Current year OA Pubs

Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib-rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR. With a median follow-up of 5.8 years, median progression-free survival (PFS) is superior for IR (hazard ratio [HR], 0.37; P < .001). IR improved PFS relative to FCR in patients with both immunoglobulin heavy chain variable region (IGHV) gene mutated CLL (HR: 0.27; P < .001) and IGHV unmutated CLL (HR: 0.27; P < .001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events (AEs)/complications, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. This trial was registered at www.clinicaltrials.gov as #NCT02048813.

Gut Bacterial Isoamylamine Promotes Age-Related Cognitive Dysfunction By Promoting Microglial Cell Death, Yun Teng, Jingyao Mu, Fangyi Xu, Xiangcheng Zhang, Mukesh K Sriwastva, Qiaohong M Liu, Xiaohong Li, Chao Lei, Kumaran Sundaram, Xin Hu, Lifeng Zhang, Juw Won Park, Jae Yeon Hwang, Eric C Rouchka, Xiang Zhang, Jun Yan, Michael L Merchant, Huang-Ge Zhang

Faculty, Staff and Student Publications

The intestinal microbiome releases a plethora of small molecules. Here, we show that the Ruminococcaceae metabolite isoamylamine (IAA) is enriched in aged mice and elderly people, whereas Ruminococcaceae phages, belonging to the Myoviridae family, are reduced. Young mice orally administered IAA show cognitive decline, whereas Myoviridae phage administration reduces IAA levels. Mechanistically, IAA promotes apoptosis of microglial cells by recruiting the transcriptional regulator p53 to the S100A8 promoter region. Specifically, IAA recognizes and binds the S100A8 promoter region to facilitate the unwinding of its self-complementary hairpin structure, thereby subsequently enabling p53 to access the S100A8 promoter and enhance S100A8 expression. …

Renin-Angiotensin System In Huntington's Disease: Evidence From Animal Models And Human Patients, Lucas M Kangussu, Natalia P Rocha, Priscila A C Valadão, Thatiane C G Machado, Kívia B Soares, Julliane V Joviano-Santos, Leigh B Latham, Gabriela D Colpo, Ana Flávia Almeida-Santos, Erin Furr Stimming, Ana Cristina Simões E Silva, Antônio L Teixeira, Aline Silva Miranda, Cristina Guatimosim

Faculty, Staff and Student Publications

The Renin-Angiotensin System (RAS) is expressed in the central nervous system and has important functions that go beyond blood pressure regulation. Clinical and experimental studies have suggested that alterations in the brain RAS contribute to the development and progression of neurodegenerative diseases. However, there is limited information regarding the involvement of RAS components in Huntington's disease (HD). Herein, we used the HD murine model, (BACHD), as well as samples from patients with HD to investigate the role of both the classical and alternative axes of RAS in HD pathophysiology. BACHD mice displayed worse motor performance in different behavioral tests alongside …

Integrated Persevere And Endothelial Biomarker Risk Model Predicts Death And Persistent Mods In Pediatric Septic Shock: A Secondary Analysis Of A Prospective Observational Study., Mihir R. Atreya, Natalie Z. Cvijanovich, Julie C. Fitzgerald, Scott L. Weiss, Michael T. Bigham, Parag N. Jain, Adam J. Schwarz, Riad Lutfi, Jeffrey Nowak, Geoffrey L. Allen, Neal J. Thomas, Jocelyn R. Grunwell, Torrey Baines, Michael Quasney, Bereketeab Haileselassie, Christopher J. Lindsell, Matthew N. Alder, Hector R. Wong

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Multiple organ dysfunction syndrome (MODS) is a critical driver of sepsis morbidity and mortality in children. Early identification of those at risk of death and persistent organ dysfunctions is necessary to enrich patients for future trials of sepsis therapeutics. Here, we sought to integrate endothelial and PERSEVERE biomarkers to estimate the composite risk of death or organ dysfunctions on day 7 of septic shock.

METHODS: We measured endothelial dysfunction markers from day 1 serum among those with existing PERSEVERE data. TreeNet® classification model was derived incorporating 22 clinical and biological variables to estimate risk. Based on relative variable importance, …

Multi-Modal Molecular Programs Regulate Melanoma Cell State, Miles C Andrews, Junna Oba, Chang-Jiun Wu, Haifeng Zhu, Tatiana Karpinets, Caitlin A Creasy, Marie-Andrée Forget, Xiaoxing Yu, Xingzhi Song, Xizeng Mao, A Gordon Robertson, Gabriele Romano, Peng Li, Elizabeth M Burton, Yiling Lu, Robert Szczepaniak Sloane, Khalida M Wani, Kunal Rai, Alexander J Lazar, Lauren E Haydu, Matias A Bustos, Jianjun Shen, Yueping Chen, Margaret B Morgan, Jennifer A Wargo, Lawrence N Kwong, Cara L Haymaker, Elizabeth A Grimm, Patrick Hwu, Dave S B Hoon, Jianhua Zhang, Jeffrey E Gershenwald, Michael A Davies, P Andrew Futreal, Chantale Bernatchez, Scott E Woodman

Faculty, Staff and Student Publications

Melanoma cells display distinct intrinsic phenotypic states. Here, we seek to characterize the molecular regulation of these states using multi-omic analyses of whole exome, transcriptome, microRNA, long non-coding RNA and DNA methylation data together with reverse-phase protein array data on a panel of 68 highly annotated early passage melanoma cell lines. We demonstrate that clearly defined cancer cell intrinsic transcriptomic programs are maintained in melanoma cells ex vivo and remain highly conserved within melanoma tumors, are associated with distinct immune features within tumors, and differentially correlate with checkpoint inhibitor and adoptive T cell therapy efficacy. Through integrative analyses we demonstrate …

Prmt5 Activates Akt Via Methylation To Promote Tumor Metastasis., Lei Huang, Xiao-Ou Zhang, Esteban J Rozen, Xiaomei Sun, Benjamin Sallis, Odette Verdejo-Torres, Kim Wigglesworth, Daniel Moon, Tingting Huang, John P Cavaretta, Gang Wang, Lei Zhang, Jason M Shohet, Mary M. Lee, Qiong Wu

Department of Pediatrics Faculty Papers

Protein arginine methyltransferase 5 (PRMT5) is the primary methyltransferase generating symmetric-dimethyl-arginine marks on histone and non-histone proteins. PRMT5 dysregulation is implicated in multiple oncogenic processes. Here, we report that PRMT5-mediated methylation of protein kinase B (AKT) is required for its subsequent phosphorylation at Thr308 and Ser473. Moreover, pharmacologic or genetic inhibition of PRMT5 abolishes AKT1 arginine 15 methylation, thereby preventing AKT1 translocation to the plasma membrane and subsequent recruitment of its upstream activating kinases PDK1 and mTOR2. We show that PRMT5/AKT signaling controls the expression of the epithelial-mesenchymal-transition transcription factors ZEB1, SNAIL, and TWIST1. PRMT5 inhibition significantly attenuates primary tumor …

In Vivo Determination Of The Human Corneal Elastic Modulus Using Vibrational Optical Coherence Tomography, Marcos A. Crespo, Hiram J. Jimenez, Tanmay Deshmukh, Jose S. Pulido, Ahmed Saeed Saad, Frederick H Silver, Dominick A Benedetto, Christopher J Rapuano, Zeba Syed

Wills Eye Hospital Papers

Purpose: To determine the in vivo elastic modulus of the human cornea using vibrational optical coherence tomography (VOCT).

Methods: Vibrational analysis coupled with optical coherence tomography (OCT) was used to obtain the resonant frequency (RF) and elastic modulus of corneal structural components. VOCT corneal thickness values were measured using OCT images and correlated with corneal thickness determined with Pentacam (Oculus, Wetzlar, Germany). Moduli were obtained at two locations: central cornea (CC) and inferior cornea (IC). Measurements were obtained with and without anesthetic eye drops to assess their effect on the modulus measurements.

Results: VOCT thickness values correlated positively (R2 = …

Microbial Liberation Of N-Methylserotonin From Orange Fiber In Gnotobiotic Mice And Humans, Nathan D Han, Daniel Webber, Stacey Marion, Michael J Barratt, Andrew C Heath, Et Al.

2020-Current year OA Pubs

Plant fibers in byproduct streams produced by non-harsh food processing methods represent biorepositories of diverse, naturally occurring, and physiologically active biomolecules. To demonstrate one approach for their characterization, mass spectrometry of intestinal contents from gnotobiotic mice, plus in vitro studies, revealed liberation of N-methylserotonin from orange fibers by human gut microbiota members including Bacteroides ovatus. Functional genomic analyses of B. ovatus strains grown under permissive and non-permissive N-methylserotonin "mining" conditions revealed polysaccharide utilization loci that target pectins whose expression correlate with strain-specific liberation of this compound. N-methylserotonin, orally administered to germ-free mice, reduced adiposity, altered liver glycogenesis, shortened gut transit …

Dissecting The Treatment-Naive Ecosystem Of Human Melanoma Brain Metastasis, Jana Biermann, Johannes C Melms, Amit Dipak Amin, Yiping Wang, Lindsay A Caprio, Alcida Karz, Somnath Tagore, Irving Barrera, Miguel A Ibarra-Arellano, Massimo Andreatta, Benjamin T Fullerton, Kristjan H Gretarsson, Varun Sahu, Vaibhav S Mangipudy, Trang T T Nguyen, Ajay Nair, Meri Rogava, Patricia Ho, Peter D Koch, Matei Banu, Nelson Humala, Aayushi Mahajan, Zachary H Walsh, Shivem B Shah, Daniel H Vaccaro, Blake Caldwell, Michael Mu, Florian Wünnemann, Margot Chazotte, Simon Berhe, Adrienne M Luoma, Joseph Driver, Matthew Ingham, Shaheer A Khan, Suthee Rapisuwon, Craig L Slingluff, Thomas Eigentler, Martin Röcken, Richard Carvajal, Michael B Atkins, Michael A Davies, Albert Agustinus, Samuel F Bakhoum, Elham Azizi, Markus Siegelin, Chao Lu, Santiago J Carmona, Hanina Hibshoosh, Antoni Ribas, Peter Canoll, Jeffrey N Bruce, Wenya Linda Bi, Praveen Agrawal, Denis Schapiro, Eva Hernando, Evan Z Macosko, Fei Chen, Gary K Schwartz, Benjamin Izar

Faculty, Staff and Student Publications

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant …

Tp53 Copy Number And Protein Expression Inform Mutation Status Across Risk Categories In Acute Myeloid Leukemia, Mehrnoosh Tashakori, Tapan Kadia, Sanam Loghavi, Naval Daver, Rashmi Kanagal-Shamanna, Sherry Pierce, Dawen Sui, Peng Wei, Farnoosh Khodakarami, Zhenya Tang, Mark Routbort, Carol A Bivins, Elias J Jabbour, L Jeffrey Medeiros, Kapil Bhalla, Hagop M Kantarjian, Farhad Ravandi, Joseph D Khoury

Faculty, Staff and Student Publications

Mutant TP53 is an adverse risk factor in acute myeloid leukemia (AML), but large-scale integrated genomic-proteomic analyses of TP53 alterations in patients with AML remain limited. We analyzed TP53 mutational status, copy number (CN), and protein expression data in AML (N = 528) and provide a compilation of mutation sites and types across disease subgroups among treated and untreated patients. Our analysis shows differential hotspots in subsets of AML and uncovers novel pathogenic variants involving TP53 splice sites. In addition, we identified TP53 CN loss in 70.2% of TP53-mutated AML cases, which have more deleterious TP53 mutations, as well as …

Long-Term Follow-Up For The Development Of Subsequent Malignancies In Patients Treated With Genetically Modified Iecs, David H M Steffin, Ibrahim N Muhsen, Laquisa C Hill, Carlos A Ramos, Nabil Ahmed, Meenakshi Hegde, Tao Wang, Mengfen Wu, Stephen Gottschalk, Sarah B Whittle, Premal D Lulla, Maksim Mamonkin, Bilal Omer, Rayne H Rouce, Andras Heczey, Leonid S Metelitsa, Bambi J Grilley, Catherine Robertson, Virginia Torrano, Natalia Lapteva, Adrian P Gee, Cliona M Rooney, Malcolm K Brenner, Helen E Heslop

Faculty, Staff and Students Publications

Subsequent malignancies are well-documented complications in long-term follow-up of cancer patients. Recently, genetically modified immune effector (IE) cells have shown benefit in hematologic malignancies and are being evaluated in clinical trials for solid tumors. Although the short-term complications of IE cells are well described, there is limited literature summarizing long-term follow-up, including subsequent malignancies. We retrospectively reviewed data from 340 patients treated across 27 investigator-initiated pediatric and adult clinical trials at our center. All patients received IE cells genetically modified with γ-retroviral vectors to treat relapsed and/or refractory hematologic or solid malignancies. In a cumulative 1027 years of long-term follow-up, …

A Spatiotemporal Map Of Reading Aloud, Oscar Woolnough, Cristian Donos, Aidan Curtis, Patrick S Rollo, Zachary J Roccaforte, Stanislas Dehaene, Simon Fischer-Baum, Nitin Tandon

Faculty, Staff and Student Publications

Reading words aloud is a fundamental aspect of literacy. The rapid rate at which multiple distributed neural substrates are engaged in this process can only be probed via techniques with high spatiotemporal resolution. We probed this with direct intracranial recordings covering most of the left hemisphere in 46 humans (26 male, 20 female) as they read aloud regular, exception and pseudo-words. We used this to create a spatiotemporal map of word processing and to derive how broadband γ activity varies with multiple word attributes critical to reading speed: lexicality, word frequency, and orthographic neighborhood. We found that lexicality is encoded …

Comprehensive Short And Long Read Sequencing Analysis For The Gaucher And Parkinson's Disease-Associated Gba Gene., Marco Toffoli, Xiao Chen, Fritz J. Sedlazeck, Chiao Yin Lee, Stephen Mullin, Abigail Higgins, Sofia Koletsi, Monica Emili Garcia-Segura, Esther Sammler, Sonja W. Scholz, Anthony H.V. Schapira, Michael A. Eberle, Christos Proukakis

Peninsula Medical School

GBA variants carriers are at increased risk of Parkinson's disease (PD) and Lewy body dementia (LBD). The presence of pseudogene GBAP1 predisposes to structural variants, complicating genetic analysis. We present two methods to resolve recombinant alleles and other variants in GBA: Gauchian, a tool for short-read, whole-genome sequencing data analysis, and Oxford Nanopore sequencing after PCR enrichment. Both methods were concordant for 42 samples carrying a range of recombinants and GBAP1-related mutations, and Gauchian outperformed the GATK Best Practices pipeline. Applying Gauchian to sequencing of over 10,000 individuals shows that copy number variants (CNVs) spanning GBAP1 are relatively common in …