Biomedical Informatics Commons^™

Sptssa Variants Alter Sphingolipid Synthesis And Cause A Complex Hereditary Spastic Paraplegia, Siddharth Srivastava, Hagar Mor Shaked, Kenneth Gable, Sita D Gupta, Xueyang Pan, Niranjanakumari Somashekarappa, Gongshe Han, Payam Mohassel, Marc Gotkine, Elizabeth Doney, Paula Goldenberg, Queenie K G Tan, Yi Gong, Benjamin Kleinstiver, Brian Wishart, Heidi Cope, Claudia Brito Pires, Hannah Stutzman, Rebecca C Spillmann, Undiagnosed Disease Network, Reza Sadjadi, Orly Elpeleg, Chia-Hsueh Lee, Hugo J Bellen, Simon Edvardson, Florian Eichler, Teresa M Dunn

Faculty, Staff and Students Publications

Sphingolipids are a diverse family of lipids with critical structural and signalling functions in the mammalian nervous system, where they are abundant in myelin membranes. Serine palmitoyltransferase, the enzyme that catalyses the rate-limiting reaction of sphingolipid synthesis, is composed of multiple subunits including an activating subunit, SPTSSA. Sphingolipids are both essential and cytotoxic and their synthesis must therefore be tightly regulated. Key to the homeostatic regulation are the ORMDL proteins that are bound to serine palmitoyltransferase and mediate feedback inhibition of enzymatic activity when sphingolipid levels become excessive. Exome sequencing identified potential disease-causing variants in SPTSSA in three children presenting …

The "Great Debate" At Melanoma Bridge 2022, Naples, December 1st-3rd, 2022, Paolo A Ascierto, Christian Blank, Alexander M Eggermont, Claus Garbe, Jeffrey E Gershenwald, Omid Hamid, Axel Hauschild, Jason J Luke, Janice M Mehnert, Jeffrey A Sosman, Hussein A Tawbi, Mario Mandalà, Alessandro Testori, Corrado Caracò, Iman Osman, Igor Puzanov

Faculty, Staff and Student Publications

The Great Debate session at the 2022 Melanoma Bridge congress (December 1-3) featured counterpoint views from leading experts on five contemporary topics of debate in the management of melanoma. The debates considered the choice of anti-lymphocyte-activation gene (LAG)-3 therapy or ipilimumab in combination with anti-programmed death (PD)-1 therapy, whether anti-PD-1 monotherapy is still acceptable as a comparator arm in clinical trials, whether adjuvant treatment of melanoma is still a useful treatment option, the role of adjuvant therapy in stage II melanoma, what role surgery will continue to have in the treatment of melanoma. As is customary in the Melanoma Bridge …

Interrogating Bromodomain Inhibitor Resistance In Kmt2a-Rearranged Leukemia Through Combinatorial Crispr Screens, Shaela Wright, Jianzhong Hu, Hong Wang, Judith Hyle, Yang Zhang, Guoqing Du, Marina Y Konopleva, Steven M Kornblau, Mohamed Nadhir Djekidel, Wojciech Rosikiewicz, Beisi Xu, Rui Lu, Jun J Yang, Chunliang Li

Faculty, Staff and Student Publications

Bromo- and extra-terminal domain inhibitors (BETi) have exhibited therapeutic activities in many cancers. However, the mechanisms controlling BETi response and resistance are not well understood. We conducted genome-wide loss-of-function CRISPR screens using BETi-treated KMT2A-rearranged (KMT2A-r) cell lines. We revealed that Speckle-type POZ protein (SPOP) gene (Speckle Type BTB/POZ Protein) deficiency caused significant BETi resistance, which was further validated in cell lines and xenograft models. Proteomics analysis and a kinase-vulnerability CRISPR screen indicated that cells treated with BETi are sensitive to GSK3 perturbation. Pharmaceutical inhibition of GSK3 reversed the BETi-resistance phenotype. Based on this observation, a combination therapy regimen inhibiting both …

Stranger Things: New Roles And Opportunities For Androgen Receptor In Oncology Beyond Prostate Cancer, Javier Leo, Eleonora Dondossola, Kaitlin J Basham, Nathaniel R Wilson, Omar Alhalabi, Jianjun Gao, Katherine C Kurnit, Michael G White, Jennifer L Mcquade, Shannon N Westin, Elizabeth A Wellberg, Daniel E Frigo

Faculty, Staff and Student Publications

The androgen receptor (AR) is one of the oldest therapeutic targets in oncology and continues to dominate the treatment landscape for advanced prostate cancer, where nearly all treatment regimens include some form of AR modulation. In this regard, AR remains the central driver of prostate cancer cell biology. Emerging preclinical and clinical data implicate key roles for AR in additional cancer types, thereby expanding the importance of this drug target beyond prostate cancer. In this mini-review, new roles for AR in other cancer types are discussed as well as their potential for treatment with AR-targeted agents. Our understanding of these …

Ether Phospholipids Are Required For Mitochondrial Reactive Oxygen Species Homeostasis, Ziheng Chen, I-Lin Ho, Melinda Soeung, Er-Yen Yen, Jintan Liu, Liang Yan, Johnathon L Rose, Sanjana Srinivasan, Shan Jiang, Q Edward Chang, Ningping Feng, Jason P Gay, Qi Wang, Jing Wang, Philip L Lorenzi, Lucas J Veillon, Bo Wei, John N Weinstein, Angela K Deem, Sisi Gao, Giannicola Genovese, Andrea Viale, Wantong Yao, Costas A Lyssiotis, Joseph R Marszalek, Giulio F Draetta, Haoqiang Ying

Faculty, Staff and Student Publications

Mitochondria are hubs where bioenergetics, redox homeostasis, and anabolic metabolism pathways integrate through a tightly coordinated flux of metabolites. The contributions of mitochondrial metabolism to tumor growth and therapy resistance are evident, but drugs targeting mitochondrial metabolism have repeatedly failed in the clinic. Our study in pancreatic ductal adenocarcinoma (PDAC) finds that cellular and mitochondrial lipid composition influence cancer cell sensitivity to pharmacological inhibition of electron transport chain complex I. Profiling of patient-derived PDAC models revealed that monounsaturated fatty acids (MUFAs) and MUFA-linked ether phospholipids play a critical role in maintaining ROS homeostasis. We show that ether phospholipids support mitochondrial …

Cancer Cell-Extrinsic Roles For The Androgen Receptor In Prostate Cancer, Andrew W Hahn, Bilal A Siddiqui, Javier Leo, Eleonora Dondossola, Kaitlin J Basham, Cindy K Miranti, Daniel E Frigo

Faculty, Staff and Student Publications

Given the central role of the androgen receptor (AR) in prostate cancer cell biology, AR-targeted therapies have been the backbone of prostate cancer treatment for over 50 years. New data indicate that AR is expressed in additional cell types within the tumor microenvironment. Moreover, targeting AR for the treatment of prostate cancer has established side effects such as bone complications and an increased risk of developing cardiometabolic disease, indicating broader roles for AR. With the advent of novel technologies, such as single-cell approaches and advances in preclinical modeling, AR has been identified to have clinically significant functions in other cell …

Deep-Learning-Based Hepatic Ploidy Quantification Using H&E Histopathology Images, Zhuoyu Wen, Yu-Hsuan Lin, Shidan Wang, Naoto Fujiwara, Ruichen Rong, Kevin W Jin, Donghan M Yang, Bo Yao, Shengjie Yang, Tao Wang, Yang Xie, Yujin Hoshida, Hao Zhu, Guanghua Xiao

Faculty, Staff and Student Publications

Polyploidy, the duplication of the entire genome within a single cell, is a significant characteristic of cells in many tissues, including the liver. The quantification of hepatic ploidy typically relies on flow cytometry and immunofluorescence (IF) imaging, which are not widely available in clinical settings due to high financial and time costs. To improve accessibility for clinical samples, we developed a computational algorithm to quantify hepatic ploidy using hematoxylin-eosin (H&E) histopathology images, which are commonly obtained during routine clinical practice. Our algorithm uses a deep learning model to first segment and classify different types of cell nuclei in H&E images. …

Anthracycline-Containing And Taxane-Containing Chemotherapy For Early-Stage Operable Breast Cancer: A Patient-Level Meta-Analysis Of 100 000 Women From 86 Randomised Trials, Early Breast Cancer Trialists’ Collaborative Group (Ebctcg)

Faculty, Staff and Student Publications

BACKGROUND: Anthracycline-taxane chemotherapy for early-stage breast cancer substantially improves survival compared with no chemotherapy. However, concerns about short-term and long-term side-effects of anthracyclines have led to increased use of taxane chemotherapy without anthracycline, which could compromise efficacy. We aimed to better characterise the benefits and risks of including anthracycline, and the comparative benefits of different anthracycline-taxane regimens.

METHODS: We did an individual patient-level meta-analysis of randomised trials comparing taxane regimens with versus without anthracycline, and updated our previous meta-analysis of anthracycline regimens with versus without taxane, as well as analysing 44 trials in six related comparisons. We searched databases, including …

Ethnic-Specific Predictors Of Neurotoxicity Among Patients With Pediatric Acute Lymphoblastic Leukemia After High-Dose Methotrexate, Rachel D Harris, Melanie Brooke Bernhardt, Mark C Zobeck, Olga A Taylor, Maria Monica Gramatges, Eric S Schafer, Philip J Lupo, Karen R Rabin, Michael E Scheurer, Austin L Brown

Faculty, Staff and Students Publications

High-dose methotrexate (HD-MTX; 5,000 mg/m2) is an important component of curative therapy in many treatment regimens for high-risk pediatric acute lymphoblastic leukemia (ALL). However, methotrexate therapy can result in dose-limiting neurotoxicity which may disproportionately affect Latino children. Thus, we evaluated risk factors for neurotoxicity in an ethnically diverse population of 351 patients (58.1% Latino) who received 1,183 HD-MTX infusions. Overall, thirty-five patients (10%) experienced neurotoxicity, 71% of whom were Latino. After adjusting for clinical risk factors, we found that serum creatinine elevations ≥50% of baseline were associated with a 3-fold increased odds (OR = 3.32, 95% CI: 0.98-11.21, p=0.05) for …

The Potential Regulation Of A-To-I Rna Editing On Genes In Parkinson's Disease, Sijia Wu, Qiuping Xue, Xinyu Qin, Xiaoming Wu, Pora Kim, Jacqueline Chyr, Xiaobo Zhou, Liyu Huang

Faculty, Staff and Student Publications

Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration and an abnormal accumulation of α-synuclein aggregates. A number of genetic factors have been shown to increase the risk of PD. Exploring the underlying molecular mechanisms that mediate PD's transcriptomic diversity can help us understand neurodegenerative pathogenesis. In this study, we identified 9897 A-to-I RNA editing events associated with 6286 genes across 372 PD patients. Of them, 72 RNA editing events altered miRNA binding sites and this may directly affect miRNA regulations of their host genes. However, RNA editing effects on the miRNA regulation of genes are more complex. They can (1) …

Molecular Disparity Of Hla-Dpb1 Is Associated With The Development Of Subsequent Solid Cancer After Allogeneic Hematopoietic Stem Cell Transplantation, Jun Zou, Piyanuch Kongtim, Betül Oran, Samer A Srour, Uri Greenbaum, Yudith Carmazzi, Gabriela Rondon, Stefan O Ciurea, Qing Ma, Elizabeth J Shpall, Richard E Champlin, Kai Cao

Faculty, Staff and Student Publications

Background: An increased incidence of subsequent solid cancers (SSCs) has been reported in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and SSC is associated with inferior mortality and morbidity. Previous studies showed that the incidence of SSC is significantly higher in those who underwent allo-HSCT from HLA-mismatched donors, suggesting that persistent alloimmunity may predispose patients to SSCs. It was recently reported that, in a cohort of patients who received allo-HSCT from an unrelated donor matched at HLA-A, -B, -C, -DRB1/3/4/5, and -DQB1 loci, HLA-DPB1 alloimmunity determined by high mismatched eplets (MEs) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) …

Serinc5 Restricts Hiv Membrane Fusion By Altering Lipid Order And Heterogeneity In The Viral Membrane, Amanda E Ward, Daria Sokovikova, Melvin Neal Waxham, Frederick A Heberle, Ilya Levental, Kandice R Levental, Volker Kiessling, Judith M White, Lukas K Tamm

Faculty, Staff and Student Publications

The host restriction factor, Serinc5, incorporates into budding HIV particles and inhibits their infection by an incompletely understood mechanism. We have previously reported that Serinc5 but not its paralogue, Serinc2, blocks HIV cell entry by membrane fusion, specifically by inhibiting fusion pore formation and dilation. A body of work suggests that Serinc5 may alter the conformation and clustering of the HIV fusion protein, Env. To contribute an additional perspective to the developing model of Serinc5 restriction, we assessed Serinc2 and Serinc5's effects on HIV pseudoviral membranes. By measuring pseudoviral membrane thickness via cryo-electron microscopy and order via the fluorescent dye, …

Bayesian Adaptive Model Selection Design For Optimal Biological Dose Finding In Phase I/Ii Clinical Trials, Ruitao Lin, Guosheng Yin, Haolun Shi

Faculty, Staff and Student Publications

Identification of the optimal dose presents a major challenge in drug development with molecularly targeted agents, immunotherapy, as well as chimeric antigen receptor T-cell treatments. By casting dose finding as a Bayesian model selection problem, we propose an adaptive design by simultaneously incorporating the toxicity and efficacy outcomes to select the optimal biological dose (OBD) in phase I/II clinical trials. Without imposing any parametric assumption or shape constraint on the underlying dose-response curves, we specify curve-free models for both the toxicity and efficacy endpoints to determine the OBD. By integrating the observed data across all dose levels, the proposed design …

The Abscopal Effect In Patients With Cancer Receiving Immunotherapy, Blessie Elizabeth Nelson, Jacob J Adashek, Steven H Lin, Vivek Subbiah

Faculty, Staff and Student Publications

Interest in the abscopal effect has been rekindled over the past decade with the advent of immunotherapy. Although purportedly elusive, this phenomenon is being increasingly reported. Venturing further using a multimodality approach with an array of systemic agents and unconventional modalities is direly needed. In this perspective, we describe the fundamentals of abscopal responses (ARs), explore combinations with systemic therapies that hold promise in eliciting ARs, and reconnoiter unconventional modalities that may induce ARs. Finally, we scrutinize prospective agents and modalities that exhibit preclinical ability to elicit ARs and discuss prognostic biomarkers, their limitations, and pathways of abscopal resistance for …

Feature Selection For Support Vector Regression Using A Genetic Algorithm, Shannon B Mckearnan, David M Vock, G Elisabeta Marai, Guadalupe Canahuate, Clifton D Fuller, Julian Wolfson

Faculty, Staff and Student Publications

Support vector regression (SVR) is particularly beneficial when the outcome and predictors are nonlinearly related. However, when many covariates are available, the method's flexibility can lead to overfitting and an overall loss in predictive accuracy. To overcome this drawback, we develop a feature selection method for SVR based on a genetic algorithm that iteratively searches across potential subsets of covariates to find those that yield the best performance according to a user-defined fitness function. We evaluate the performance of our feature selection method for SVR, comparing it to alternate methods including LASSO and random forest, in a simulation study. We …

Mmp9 Clears The Way For Metastatic Cell Penetration Across The Blood-Brain Barrier, Joseph H Mccarty

Faculty, Staff and Student Publications

Although brain metastases are 10-fold more prevalent than primary brain cancers, relatively little is understood about the genes and pathways that promote metastatic cell entry, growth, and survival in the brain. Hence, determining how metastatic tumors colonize the brain and thrive within the neural microenvironment is a topic of both fundamental importance and direct clinical relevance. In this issue, a report by Karreman and colleagues explores pathways that are exploited by metastatic tumor cells to arrest in the circulation, cross the endothelial blood-brain barrier (BBB), and thrive in the brain microenvironment. The authors used elegant imaging tools including intravital fluorescence …

Mechanisms Of Response And Resistance To Combined Decitabine And Ipilimumab For Advanced Myeloid Disease, Livius Penter, Yang Liu, Jacquelyn O Wolff, Lin Yang, Len Taing, Aashna Jhaveri, Jackson Southard, Manishkumar Patel, Nicole M Cullen, Kathleen L Pfaff, Nicoletta Cieri, Giacomo Oliveira, Seunghee Kim-Schulze, Srinika Ranasinghe, Rebecca Leonard, Taylor Robertson, Elizabeth A Morgan, Helen X Chen, Minkyung H Song, Magdalena Thurin, Shuqiang Li, Scott J Rodig, Carrie Cibulskis, Stacey Gabriel, Pavan Bachireddy, Jerome Ritz, Howard Streicher, Donna S Neuberg, F Stephen Hodi, Matthew S Davids, Sacha Gnjatic, Kenneth J Livak, Jennifer Altreuter, Franziska Michor, Robert J Soiffer, Jacqueline S Garcia, Catherine J Wu

Faculty, Staff and Student Publications

The challenge of eradicating leukemia in patients with acute myelogenous leukemia (AML) after initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either after allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304 961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were …

A Reduced Pancreatic Polypeptide Response Is Associated With New-Onset Pancreatogenic Diabetes Versus Type 2 Diabetes, Phil A Hart, Yogish C Kudva, Dhiraj Yadav, Dana K Andersen, Yisheng Li, Frederico G S Toledo, Fuchenchu Wang, Melena D Bellin, David Bradley, Randall E Brand, Kenneth Cusi, William Fisher, Kieren Mather, Walter G Park, Zeb Saeed, Robert V Considine, Sarah C Graham, Jo Ann Rinaudo, Jose Serrano, Mark O Goodarzi

Faculty, Staff and Student Publications

PURPOSE: Pancreatogenic diabetes refers to diabetes mellitus (DM) that develops in the setting of a disease of the exocrine pancreas, including pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). We sought to evaluate whether a blunted nutrient response of pancreatic polypeptide (PP) can differentiate these DM subtypes from type 2 DM (T2DM).

METHODS: Subjects with new-onset DM (<3 >years' duration) in the setting of PDAC (PDAC-DM, n = 28), CP (CP-DM, n = 38), or T2DM (n = 99) completed a standardized mixed meal tolerance test, then serum PP concentrations were subsequently measured at a central laboratory. Two-way comparisons of …

Pancreatic Cancer: Advances And Challenges, Christopher J Halbrook, Costas A Lyssiotis, Marina Pasca Di Magliano, Anirban Maitra

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Significant efforts have largely defined major genetic factors driving PDAC pathogenesis and progression. Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche. In this review, we highlight the foundational studies that have driven our understanding of these processes. We further discuss the recent technological advances that continue to expand our understanding of PDAC complexity. We posit that the clinical translation of these research endeavors will enhance the currently dismal survival rate of this recalcitrant …

Immune Checkpoint Therapy-Current Perspectives And Future Directions, Padmanee Sharma, Sangeeta Goswami, Deblina Raychaudhuri, Bilal A Siddiqui, Pratishtha Singh, Ashwat Nagarajan, Jielin Liu, Sumit K Subudhi, Candice Poon, Kristal L Gant, Shelley M Herbrich, Swetha Anandhan, Shajedul Islam, Moran Amit, Gayathri Anandappa, James P Allison

Faculty, Staff and Student Publications

Immune checkpoint therapy (ICT) has dramatically altered clinical outcomes for cancer patients and conferred durable clinical benefits, including cure in a subset of patients. Varying response rates across tumor types and the need for predictive biomarkers to optimize patient selection to maximize efficacy and minimize toxicities prompted efforts to unravel immune and non-immune factors regulating the responses to ICT. This review highlights the biology of anti-tumor immunity underlying response and resistance to ICT, discusses efforts to address the current challenges with ICT, and outlines strategies to guide the development of subsequent clinical trials and combinatorial efforts with ICT.

The Role Of Extracellular Vesicles In Cancer, Raghu Kalluri, Kathleen M Mcandrews

Faculty, Staff and Student Publications

Intercellular communication is a key feature of cancer progression and metastasis. Extracellular vesicles (EVs) are generated by all cells, including cancer cells, and recent studies have identified EVs as key mediators of cell-cell communication via packaging and transfer of bioactive constituents to impact the biology and function of cancer cells and cells of the tumor microenvironment. Here, we review recent advances in understanding the functional contribution of EVs to cancer progression and metastasis, as cancer biomarkers, and the development of cancer therapeutics.

Targeting Of Epigenetic Co-Dependencies Enhances Anti-Aml Efficacy Of Menin Inhibitor In Aml With Mll1-R Or Mutant Npm1, Warren Fiskus, Christopher P Mill, Christine Birdwell, John A Davis, Kaberi Das, Steffen Boettcher, Tapan M Kadia, Courtney D Dinardo, Koichi Takahashi, Sanam Loghavi, Michael J Soth, Tim Heffernan, Gerard M Mcgeehan, Xinjia Ruan, Xiaoping Su, Christopher R Vakoc, Naval Daver, Kapil N Bhalla

Faculty, Staff and Student Publications

Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A …

Low And Differential Polygenic Score Generalizability Among African Populations Due Largely To Genetic Diversity, Lerato Majara, Allan Kalungi, Nastassja Koen, Kristin Tsuo, Ying Wang, Rahul Gupta, Lethukuthula L Nkambule, Heather Zar, Dan J Stein, Eugene Kinyanda, Elizabeth G Atkinson, Alicia R Martin

Faculty, Staff and Students Publications

African populations are vastly underrepresented in genetic studies but have the most genetic variation and face wide-ranging environmental exposures globally. Because systematic evaluations of genetic prediction had not yet been conducted in ancestries that span African diversity, we calculated polygenic risk scores (PRSs) in simulations across Africa and in empirical data from South Africa, Uganda, and the United Kingdom to better understand the generalizability of genetic studies. PRS accuracy improves with ancestry-matched discovery cohorts more than from ancestry-mismatched studies. Within ancestrally and ethnically diverse South African individuals, we find that PRS accuracy is low for all traits but varies across …

Cancer Neuroscience: State Of The Field, Emerging Directions, Frank Winkler, Humsa S Venkatesh, Moran Amit, Tracy Batchelor, Ihsan Ekin Demir, Benjamin Deneen, David H Gutmann, Shawn Hervey-Jumper, Thomas Kuner, Donald Mabbott, Michael Platten, Asya Rolls, Erica K Sloan, Timothy C Wang, Wolfgang Wick, Varun Venkataramani, Michelle Monje

Faculty, Staff and Student Publications

The nervous system governs both ontogeny and oncology. Regulating organogenesis during development, maintaining homeostasis, and promoting plasticity throughout life, the nervous system plays parallel roles in the regulation of cancers. Foundational discoveries have elucidated direct paracrine and electrochemical communication between neurons and cancer cells, as well as indirect interactions through neural effects on the immune system and stromal cells in the tumor microenvironment in a wide range of malignancies. Nervous system-cancer interactions can regulate oncogenesis, growth, invasion and metastatic spread, treatment resistance, stimulation of tumor-promoting inflammation, and impairment of anti-cancer immunity. Progress in cancer neuroscience may create an important new …

Development Of A Corticosteroid-Immunosuppressed Mouse Model To Study The Pathogenesis And Therapy Of Influenza-Associated Pulmonary Aspergillosis, Sebastian Wurster, Jezreel Pantaleón García, Nathaniel D Albert, Ying Jiang, Keerthi Bhoda, Vikram V Kulkarni, Yongxing Wang, Thomas J Walsh, Scott Evans, Dimitrios P Kontoyiannis

Faculty, Staff and Student Publications

Influenza-associated pulmonary aspergillosis (IAPA) is a feared complication in patients with influenza tracheobronchitis, especially those receiving corticosteroids. Herein, we established a novel IAPA mouse model with low-inoculum Aspergillus infection and compared outcomes in mice with and without cortisone acetate (CA) immunosuppression. CA was an independent predictor of increased morbidity/mortality in mice with IAPA. Early antifungal treatment with liposomal amphotericin B was pivotal to improve IAPA outcomes in CA-immunosuppressed mice, even after prior antiviral therapy with oseltamivir. In summary, our model recapitulates key clinical features of IAPA and provides a robust preclinical platform to study the pathogenesis and treatment of IAPA.

Physio-Psycho-Social Interaction Mechanism In Dyadic Health Of Young And Middle-Aged Stroke Survivors And Their Spousal Caregivers: A Longitudinal Observational Study Protocol, Dandan Xiang, Zhen-Xiang Zhang, Song Ge, Wen Na Wang, Bei-Lei Lin, Su-Yan Chen, Er-Feng Guo, Peng-Bo Zhang, Zhi-Wei Liu, Hui Li, Yong-Xia Mei

Faculty, Staff and Student Publications

Introduction: In recent years, stroke has become more common among young people. Stroke not only has a profound impact on patients' health but also incurs stress and health threats to their caregivers, especially spousal caregivers. Moreover, the health of stroke survivors and their caregivers is interdependent. To our knowledge, no study has explored dyadic health of young and middle-aged stroke survivors and their spousal caregivers from physiological, psychological and social perspectives. Therefore, this proposed study aims to explore the mechanism of how physiological, psychological and social factors affect dyadic health of young and middle-aged stroke survivors and their spousal caregivers. …

Quantitative Proteomic Screening Uncovers Candidate Diagnostic And Monitoring Serum Biomarkers Of Ankylosing Spondylitis, Mark Hwang, Shervin Assassi, Jim Zheng, Jessica Castillo, Reyna Chavez, Kamala Vanarsa, Chandra Mohan, John Reveille

Faculty, Staff and Student Publications

BACKGROUND: We sought to discover serum biomarkers of ankylosing spondylitis (AS) for diagnosis and monitoring disease activity.

METHODS: We studied biologic-treatment-naïve AS and healthy control (HC) patients' sera. Eighty samples matched by age, gender, and race (1:1:1 ratio) for AS patients with active disease, inactive disease, and HC were analyzed with SOMAscan™, an aptamer-based discovery platform. T-tests tests were performed for high/low-disease activity AS patients versus HCs (diagnosis) and high versus low disease activity (Monitoring) in a 2:1 and 1:1 ratio, respectively, to identify differentially expressed proteins (DEPs). We used the Cytoscape Molecular Complex Detection (MCODE) plugin to find clusters …

Risk Of Early Death In Adolescents And Young Adults With Cancer: A Population-Based Study, Amy M Berkman, Clark R Andersen, Michelle A T Hildebrandt, J A Livingston, Adam L Green, Vidya Puthenpura, Susan K Peterson, Joel Milam, Kimberly A Miller, David R Freyer, Michael E Roth

Faculty, Staff and Student Publications

BACKGROUND: Advancements in treatment and supportive care have led to improved survival for adolescents and young adults (AYAs) with cancer; however, a subset of those diagnosed remain at risk for early death (within 2 months of diagnosis). Factors that place AYAs at increased risk of early death have not been well studied.

METHODS: The Surveillance, Epidemiology, and End Results registry was used to assess risk of early death in AYAs with hematologic malignancies, central nervous system tumors, and solid tumors. Associations between age at diagnosis, sex, race, ethnicity, socioeconomic status, insurance status, rurality, and early death were assessed.

RESULTS: A …

Upper Age Limits For Us Male Human Papillomavirus Vaccination For Oropharyngeal Cancer Prevention: A Microsimulation-Based Modeling Study, Rebecca Landy, Gregory Haber, Barry I Graubard, Nicole G Campos, Stephen Sy, Jane J Kim, Emily A Burger, Li C Cheung, Hormuzd A Katki, Maura L Gillison, Anil K Chaturvedi

Faculty, Staff and Student Publications

BACKGROUND: Human papillomavirus (HVP)-positive oropharyngeal cancer is the most common HPV-associated cancer in the United States. The age at acquisition of oral HPV infections that cause oropharyngeal cancer (causal infections) is unknown; consequently, the benefit of vaccination of US men aged 27-45 years remains uncertain.

METHODS: We developed a microsimulation-based, individual-level, state-transition model of oral HPV16 and HPV16-positive oropharyngeal cancer among heterosexual US men aged 15-84 years, calibrated to population-level data. We estimated the benefit of vaccination of men aged 27-45 years for prevention of oropharyngeal cancer, accounting for direct- and indirect effects (ie, herd effects) of male and female …

Molecular Mechanisms Of Ferroptosis And Updates Of Ferroptosis Studies In Cancers And Leukemia, Hiroki Akiyama, Bing Z Carter, Michael Andreeff, Jo Ishizawa

Faculty, Staff and Student Publications

Ferroptosis is a mode of cell death regulated by iron-dependent lipid peroxidation. Growing evidence suggests ferroptosis induction as a novel anti-cancer modality that could potentially overcome therapy resistance in cancers. The molecular mechanisms involved in the regulation of ferroptosis are complex and highly dependent on context. Therefore, a comprehensive understanding of its execution and protection machinery in each tumor type is necessary for the implementation of this unique cell death mode to target individual cancers. Since most of the current evidence for ferroptosis regulation mechanisms is based on solid cancer studies, the knowledge of ferroptosis with regard to leukemia is …