Digital Commons Network^™

Identification And Characterization Of Cannabichromene's Major Metabolite Following Incubation With Human Liver Microsomes, Alexandra M Ward, Touraj Shokati, Jost Klawitter, Jelena Klawitter, Vu Nguyen, Laura Kozell, Atheir I Abbas, David Jones, Uwe Christians

Faculty, Staff and Student Publications

Cannabichromene (CBC) is a minor cannabinoid within the array of over 120 cannabinoids identified in the Cannabis sativa plant. While CBC does not comprise a significant portion of whole plant material, it is available to the public in a purified and highly concentrated form. As minor cannabinoids become more popular due to their potential therapeutic properties, it becomes crucial to elucidate their metabolism in humans. Therefore, the goal of this was study to identify the major CBC phase I-oxidized metabolite generated in vitro following incubation with human liver microsomes. The novel metabolite structure was identified as 2′-hydroxycannabicitran using gas chromatography–mass …

Durable Objective Response To Lurbinectedin In Small Cell Bladder Cancer With Tp53 Mutation: A Molecular-Directed Strategy, Mohammad Jad Moussa, Jaanki Khandelwal, Nathaniel R Wilson, Sagar A Naik, Vivek Subbiah, Matthew T Campbell, Pavlos Msaouel, Parminder Singh, Omar Alhalabi

Faculty, Staff and Student Publications

Small cell bladder cancer (SCBC) is a rare and aggressive disease, often treated with platinum/etoposide-based chemotherapy. Key molecular drivers include the inactivation of onco-suppressor genes (TP53, RB1) and amplifications in proto-oncogenes (MYC). We report a patient with SCBC who achieved an objective and prolonged response to lurbinectedin, which has been approved for metastatic small cell lung cancer, after developing disease progression on cisplatin/etoposide and nivolumab/ipilimumab. A genomic analysis of a metastatic biopsy prior to lurbinectedin initiation revealed a TP53 mutation and amplification of the cell cycle regulators E2F3 and MYCL. A repeat biopsy following …

Development Of Biochemical And Cellular Probes To Study Ripk1 Target Engagement, Xin Yu, Hanfeng Lin, Feng Li, Jin Wang, Dong Lu

Faculty, Staff and Students Publications

RIPK1 inhibitors have emerged as promising candidates for treating diverse diseases, including inflammatory diseases, autoimmune disorders, Alzheimer’s disease, and cancer. However, the previously reported binding assays have limited sensitivity and stability, impeding high-throughput screening and robust characterization of the RIPK1 inhibitors. To address this challenge, we introduced two probes, T2-BDP-FL and T3-BDP-FL, derived from distinct RIPK1 inhibitors with different binding modes to establish time-resolved fluorescence resonance energy transfer (TR-FRET) displacement assays. Employing our TR-FRET displacement assays, we quantified the biochemical binding affinities of a series of RIPK1 inhibitors with diverse structural and binding modes for human RIPK1. Consistent results were …

Chagas Disease In Immunocompromised Patients, Eva H Clark, Louisa A Messenger, Jeffrey D Whitman, Caryn Bern

Faculty, Staff and Students Publications

As Chagas disease remains prevalent in the Americas, it is important that healthcare professionals and researchers are aware of the screening, diagnosis, monitoring, and treatment recommendations for the populations of patients they care for and study. Management of Trypanosoma cruzi infection in immunocompromised hosts is challenging, particularly because, regardless of antitrypanosomal treatment status, immunocompromised patients with Chagas disease are at risk for T. cruzi reactivation, which can be lethal. Evidence-based practices to prevent and manage T. cruzi reactivation vary depending on the type of immunocompromise. Here, we review available data describing Chagas disease epidemiology, testing, and management practices for various …

Rest-Dependent Downregulation Of Von Hippel-Lindau Tumor Suppressor Promotes Autophagy In Shh-Medulloblastoma, Ashutosh Singh, Donghang Cheng, Jyothishmathi Swaminathan, Yanwen Yang, Yan Zheng, Nancy Gordon, Vidya Gopalakrishnan

Faculty, Staff and Student Publications

The RE1 silencing transcription factor (REST) is a driver of sonic hedgehog (SHH) medulloblastoma genesis. Our previous studies showed that REST enhances cell proliferation, metastasis and vascular growth and blocks neuronal differentiation to drive progression of SHH medulloblastoma tumors. Here, we demonstrate that REST promotes autophagy, a pathway that is found to be significantly enriched in human medulloblastoma tumors relative to normal cerebella. In SHH medulloblastoma tumor xenografts, REST elevation is strongly correlated with increased expression of the hypoxia-inducible factor 1-alpha (HIF1α)-a positive regulator of autophagy, and with reduced expression of the von Hippel-Lindau (VHL) tumor suppressor protein - a …

Digital Twin Mathematical Models Suggest Individualized Hemorrhagic Shock Resuscitation Strategies, Jeremy W Cannon, Danielle S Gruen, Ruben Zamora, Noah Brostoff, Kelly Hurst, John H Harn, Fayten El-Dehaibi, Zhi Geng, Rami Namas, Jason L Sperry, John B Holcomb, Bryan A Cotton, Jason J Nam, Samantha Underwood, Martin A Schreiber, Kevin K Chung, Andriy I Batchinsky, Leopoldo C Cancio, Andrew J Benjamin, Erin E Fox, Steven C Chang, Andrew P Cap, Yoram Vodovotz

Faculty, Staff and Student Publications

Background: Optimizing resuscitation to reduce inflammation and organ dysfunction following human trauma-associated hemorrhagic shock is a major clinical hurdle. This is limited by the short duration of pre-clinical studies and the sparsity of early data in the clinical setting.

Methods: We sought to bridge this gap by linking preclinical data in a porcine model with clinical data from patients from the Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study via a three-compartment ordinary differential equation model of inflammation and coagulation.

Results: The mathematical model accurately predicts physiologic, inflammatory, and laboratory measures in both the porcine model and patients, as well …

Digital Twin Mathematical Models Suggest Individualized Hemorrhagic Shock Resuscitation Strategies, Jeremy W Cannon, Danielle S Gruen, Ruben Zamora, Noah Brostoff, Kelly Hurst, John H Harn, Fayten El-Dehaibi, Zhi Geng, Rami Namas, Jason L Sperry, John B Holcomb, Bryan A Cotton, Jason J Nam, Samantha Underwood, Martin A Schreiber, Kevin K Chung, Andriy I Batchinsky, Leopoldo C Cancio, Andrew J Benjamin, Erin E Fox, Steven C Chang, Andrew P Cap, Yoram Vodovotz

Faculty, Staff and Student Publications

BACKGROUND: Optimizing resuscitation to reduce inflammation and organ dysfunction following human trauma-associated hemorrhagic shock is a major clinical hurdle. This is limited by the short duration of pre-clinical studies and the sparsity of early data in the clinical setting.

METHODS: We sought to bridge this gap by linking preclinical data in a porcine model with clinical data from patients from the Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study via a three-compartment ordinary differential equation model of inflammation and coagulation.

RESULTS: The mathematical model accurately predicts physiologic, inflammatory, and laboratory measures in both the porcine model and patients, as well …

Germ Cell Tumor Of The Testis: Lethal Subtypes Of A Curable Cancer, Jamaal C Jackson, Darren Sanchez, Andrew C Johns, Matthew T Campbell, Ahmet M Aydin, Neriman Gokden, Sanjay Maraboyina, Jason L Muesse, John F Ward, Louis L Pisters, Niki M Zacharias, Charles C Guo, Shi-Ming Tu

Faculty, Staff and Student Publications

Germ cell tumor of the testis (GCT) is a curable cancer even when it is widely metastatic; however, outcomes can differ based on tumor histology. Chemo-resistance in certain phenotypes, such as teratoma and yolk sac tumor, contributes to poor clinical outcomes in some patients with GCT. Despite this resistance to S-YSTemic therapy, many of these tumor subtypes remain amenable to surgical resection and possible cure. In this study, we report on a series of seven patients highlighting two chemo-resistant subtypes of nonseminomatous germ cell tumor (NSGCT), sarcomatoid yolk sac tumor (S-YST), and epithelioid trophoblastic tumor (ETT) for which early resection …

Small Rna Signatures Of Acute Ischemic Stroke In L1cam Positive Extracellular Vesicles, Bharti Manwani, Nivetha Brathaban, Abiya Baqai, Yashee Munshi, Hilda W Ahnstedt, Mengqi Zhang, Kajsa Arkelius, Ted Llera, Edilberto Amorim, Fanny M Elahi, Neel S Singhal

Faculty, Staff and Student Publications

L1CAM-positive extracellular vesicles (L1EV) are an emerging biomarker that may better reflect ongoing neuronal damage than other blood-based biomarkers. The physiological roles and regulation of L1EVs and their small RNA cargoes following stroke is unknown. We sought to characterize L1EV small RNAs following stroke and assess L1EV RNA signatures for diagnosing stroke using weighted gene co-expression network analysis and random forest (RF) machine learning algorithms. Interestingly, small RNA sequencing of plasma L1EVs from patients with stroke and control patients (n = 28) identified micro(mi)RNAs known to be enriched in the brain. Weighted gene co-expression network analysis (WGCNA) revealed small RNA …

Structural Analysis Of The Female Reptile Reproductive System By Micro-Computed Tomography And Optical Coherence Tomography†, Bonnie K Kircher, Michaela A Mccown, Deirdre M Scully, Richard R Behringer, Irina V Larina

Faculty, Staff and Student Publications

Volumetric data provide unprecedented structural insight to the reproductive tract and add vital anatomical context to the relationships between organs. The morphology of the female reproductive tract in non-avian reptiles varies between species, corresponding to a broad range of reproductive modes and providing valuable insight to comparative investigations of reproductive anatomy. However, reproductive studies in reptilian models, such as the brown anole studied here, have historically relied on histological methods to understand the anatomy. While these methods are highly effective for characterizing the cell types present in each organ, histological methods lose the 3D relationships between images and leave the …

Machine Learning In Time-Lapse Imaging To Differentiate Embryos From Young Vs Old Mice†, Liubin Yang, Carolina Leynes, Ashley Pawelka, Isabel Lorenzo, Andrew Chou, Brendan Lee, Jason D Heaney

Faculty, Staff and Students Publications

Time-lapse microscopy for embryos is a non-invasive technology used to characterize early embryo development. This study employs time-lapse microscopy and machine learning to elucidate changes in embryonic growth kinetics with maternal aging. We analyzed morphokinetic parameters of embryos from young and aged C57BL6/NJ mice via continuous imaging. Our findings show that aged embryos accelerated through cleavage stages (from 5-cells) to morula compared to younger counterparts, with no significant differences observed in later stages of blastulation. Unsupervised machine learning identified two distinct clusters comprising of embryos from aged or young donors. Moreover, in supervised learning, the extreme gradient boosting algorithm successfully …

Meningioma Transcriptomic Landscape Demonstrates Novel Subtypes With Regional Associated Biology And Patient Outcome, H Nayanga Thirimanne, Damian Almiron-Bonnin, Nicholas Nuechterlein, Sonali Arora, Matt Jensen, Carolina A Parada, Chengxiang Qiu, Frank Szulzewsky, Collin W English, William C Chen, Philipp Sievers, Farshad Nassiri, Justin Z Wang, Tiemo J Klisch, Kenneth D Aldape, Akash J Patel, Patrick J Cimino, Gelareh Zadeh, Felix Sahm, David R Raleigh, Jay Shendure, Manuel Ferreira, Eric C Holland

Faculty, Staff and Students Publications

Meningiomas, although mostly benign, can be recurrent and fatal. World Health Organization (WHO) grading of the tumor does not always identify high-risk meningioma, and better characterizations of their aggressive biology are needed. To approach this problem, we combined 13 bulk RNA sequencing (RNA-seq) datasets to create a dimension-reduced reference landscape of 1,298 meningiomas. The clinical and genomic metadata effectively correlated with landscape regions, which led to the identification of meningioma subtypes with specific biological signatures. The time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape, where the nearest …

An Essential Gene Signature Of Breast Cancer Metastasis Reveals Targetable Pathways, Yiqun Zhang, Fengju Chen, Marija Balic, Chad J Creighton

Faculty, Staff and Students Publications

BACKGROUND: The differential gene expression profile of metastatic versus primary breast tumors represents an avenue for discovering new or underappreciated pathways underscoring processes of metastasis. However, as tumor biopsy samples are a mixture of cancer and non-cancer cells, most differentially expressed genes in metastases would represent confounders involving sample biopsy site rather than cancer cell biology.

METHODS: By paired analysis, we defined a top set of differentially expressed genes in breast cancer metastasis versus primary tumors using an RNA-sequencing dataset of 152 patients from The Breast International Group Aiming to Understand the Molecular Aberrations dataset (BIG-AURORA). To filter the genes …

An Inducible Genetic Tool To Track And Manipulate Specific Microglial States Reveals Their Plasticity And Roles In Remyelination, Kia M Barclay, Nora Abduljawad, Zuolin Cheng, Min Woo Kim, Lu Zhou, Jin Yang, Justin Rustenhoven, Jose A Mazzitelli, Leon C D Smyth, Dvita Kapadia, Simone Brioschi, Wandy Beatty, Jinchao Hou, Naresha Saligrama, Marco Colonna, Guoqiang Yu, Jonathan Kipnis, Qingyun Li

The Brown Foundation: Institute of Molecular Medicine

Recent single-cell RNA sequencing studies have revealed distinct microglial states in development and disease. These include proliferative region-associated microglia (PAM) in developing white matter and disease-associated microglia (DAM) prevalent in various neurodegenerative conditions. PAM and DAM share a similar core gene signature. However, the extent of the dynamism and plasticity of these microglial states, as well as their functional significance, remains elusive, partly due to the lack of specific tools. Here, we generated an inducible Cre driver line, Clec7a-CreERT2, that targets PAM and DAM in the brain parenchyma. Utilizing this tool, we profiled labeled cells during development and in several …

Slow Proliferation Of Bap1-Deficient Uveal Melanoma Cells Is Associated With Reduced S6 Signaling And Resistance To Nutrient Stress, Vivian Chua, Melisa Lopez-Anton, Mizue Terai, Ryota Tanaka, Usman Baqai, Timothy J Purwin, Jelan I Haj, Francis J Waltrich, Isabella Trachtenberg, Kristine Luo, Rohith Tudi, Angela Jeon, Anna Han, Inna Chervoneva, Michael A Davies, Julio A Aguirre-Ghiso, Takami Sato, Andrew E Aplin

Faculty, Staff and Student Publications

Uveal melanoma (UM) is the deadliest form of eye cancer in adults. Inactivating mutations and/or loss of expression of the gene encoding BRCA1-associated protein 1 (BAP1) in UM tumors are associated with an increased risk of metastasis. To investigate the mechanisms underlying this risk, we explored the functional consequences of BAP1 deficiency. UM cell lines expressing mutant BAP1 grew more slowly than those expressing wild-type BAP1 in culture and in vivo. The ability of BAP1 reconstitution to restore cell proliferation in BAP1-deficient cells required its deubiquitylase activity. Proteomic analysis showed that BAP1-deficient cells had decreased phosphorylation of ribosomal S6 and …

Role Of Ethanolamine Utilization And Bacterial Microcompartment Formation In Listeria Monocytogenes Intracellular Infection, Ayan Chatterjee, Karan Gautam Kaval, Danielle A Garsin

Faculty, Staff and Student Publications

Ethanolamine (EA) affects the colonization and pathogenicity of certain human bacterial pathogens in the gastrointestinal tract. However, EA can also affect the intracellular survival and replication of host cell invasive bacteria such as Listeria monocytogenes (LMO) and Salmonella enterica serovar Typhimurium (S. Typhimurium). The EA utilization (eut) genes can be categorized as regulatory, enzymatic, or structural, and previous work in LMO showed that loss of genes encoding functions for the enzymatic breakdown of EA inhibited LMO intracellular replication. In this work, we sought to further characterize the role of EA utilization during LMO infection of host …

Collaborative Modeling To Compare Different Breast Cancer Screening Strategies: A Decision Analysis For The Us Preventive Services Task Force, Amy Trentham-Dietz, Christina Hunter Chapman, Jinani Jayasekera, Kathryn P Lowry, Brandy M Heckman-Stoddard, John M Hampton, Jennifer L Caswell-Jin, Ronald E Gangnon, Ying Lu, Hui Huang, Sarah Stein, Liyang Sun, Eugenio J Gil Quessep, Yuanliang Yang, Yifan Lu, Juhee Song, Diego F Muñoz, Yisheng Li, Allison W Kurian, Karla Kerlikowske, Ellen S O'Meara, Brian L Sprague, Anna N A Tosteson, Eric J Feuer, Donald Berry, Sylvia K Plevritis, Xuelin Huang, Harry J De Koning, Nicolien T Van Ravesteyn, Sandra J Lee, Oguzhan Alagoz, Clyde B Schechter, Natasha K Stout, Diana L Miglioretti, Jeanne S Mandelblatt

Faculty, Staff and Student Publications

IMPORTANCE: The effects of breast cancer incidence changes and advances in screening and treatment on outcomes of different screening strategies are not well known.

OBJECTIVE: To estimate outcomes of various mammography screening strategies.

DESIGN, SETTING, AND POPULATION: Comparison of outcomes using 6 Cancer Intervention and Surveillance Modeling Network (CISNET) models and national data on breast cancer incidence, mammography performance, treatment effects, and other-cause mortality in US women without previous cancer diagnoses.

EXPOSURES: Thirty-six screening strategies with varying start ages (40, 45, 50 years) and stop ages (74, 79 years) with digital mammography or digital breast tomosynthesis (DBT) annually, biennially, or …

Rigor And Reproducibility In Human Brain Organoid Research: Where We Are And Where We Need To Go, Soraya O Sandoval, Gerarda Cappuccio, Karina Kruth, Sivan Osenberg, Saleh M Khalil, Natasha M Méndez-Albelo, Krishnan Padmanabhan, Daifeng Wang, Mark J Niciu, Anita Bhattacharyya, Jason L Stein, André M M Sousa, Elisa A Waxman, Elizabeth D Buttermore, Dosh Whye, Carissa L Sirois, Cross-Iddrc Human Stem Cell Consortium, Aislinn Williams, Mirjana Maletic-Savatic, Xinyu Zhao

Faculty, Staff and Students Publications

Human brain organoid models have emerged as a promising tool for studying human brain development and function. These models preserve human genetics and recapitulate some aspects of human brain development, while facilitating manipulation in an in vitro setting. Despite their potential to transform biology and medicine, concerns persist about their fidelity. To fully harness their potential, it is imperative to establish reliable analytic methods, ensuring rigor and reproducibility. Here, we review current analytical platforms used to characterize human forebrain cortical organoids, highlight challenges, and propose recommendations for future studies to achieve greater precision and uniformity across laboratories.

Author Correction: The Frequency Of Pathogenic Variation In The All Of Us Cohort Reveals Ancestry-Driven Disparities, Eric Venner, Karynne Patterson, Divya Kalra, Marsha M Wheeler, Yi-Ju Chen, Sara E Kalla, Bo Yuan, Jason H Karnes, Kimberly Walker, Joshua D Smith, Sean Mcgee, Aparna Radhakrishnan, Andrew Haddad, Philip E Empey, Qiaoyan Wang, Lee Lichtenstein, Diana Toledo, Gail Jarvik, Anjene Musick, Richard A Gibbs, All Of Us Research Program Investigators

Faculty, Staff and Students Publications

Correction to: Communications Biology 10.1038/s42003-023-05708-y, published online 19 February 2024

The data availability statement was incorrectly given as “All sequencing data used in this study are available on the All of Us Researcher Workbench in the v7 release.” but should have been “All sequencing data used in this study are available on the All of Us Researcher Workbench in the v6 release”. The original Article has been corrected.

Echocardiogram By Apical-Subcostal Protocol In Prone Position During Invasive Mechanical Ventilation In Cardiovascular Intensive Care Unit, César Del Castillo, Fernando Verdugo, Franco Appiani, Francisca Yáñez, Camila Bontá, Carlos Torres-Herrera, Angela Garcia, Zorba Blázquez-Bermejo, Javier Castrodeza, Daniel Requena, Andreina Rodríguez, Arquimedes Silvio, Agustín Gatica, Arnulfo Begazo, Mario Alfaro

Faculty, Staff and Students Publications

AIMS: To evaluate the feasibility of a transthoracic echocardiogram using an apical-subcostal protocol in invasive mechanical ventilation (IMV) and prone position.

METHODS: Prospective study of adults who required a prone position during IMV. A pillow was placed only under the left hemithorax in the prone position to elevate and ease the apical and subcostal windows. A critical care cardiologist (prone group) acquired and evaluated the images using the apical-subcostal protocol. Besides, we used ambulatory echocardiograms performed as a comparative group (supine group).

RESULTS: 86 patients were included, 43 in the prone and 43 in the supine. In the prone group, …

Folate As A Potential Treatment For Lethal Ventricular Arrhythmias In Tango2-Deficiency Disorder, Weiyi Xu, Yingqiong Cao, Sara B Stephens, Maria Jose Arredondo, Yifan Chen, William Perez, Liang Sun, Andy C Yu, Jean J Kim, Seema R Lalani, Na Li, Frank T Horrigan, Francisco Altamirano, Xander Ht Wehrens, Christina Y Miyake, Lilei Zhang

Faculty, Staff and Students Publications

TANGO2-deficiency disorder (TDD) is an autosomal-recessive genetic disease caused by biallelic loss-of-function variants in the TANGO2 gene. TDD-associated cardiac arrhythmias are recalcitrant to standard antiarrhythmic medications and constitute the leading cause of death. Disease modeling for TDD has been primarily carried out using human dermal fibroblast and, more recently, in Drosophila by multiple research groups. No human cardiomyocyte system has been reported, which greatly hinders the investigation and understanding of TDD-associated arrhythmias. Here, we established potentially novel patient-derived induced pluripotent stem cell differentiated cardiomyocyte (iPSC-CM) models that recapitulate key electrophysiological abnormalities in TDD. These electrophysiological abnormalities were rescued in iPSC-CMs …

The Emerging Biomarkers In Chronic Obstructive Pulmonary Disease: A Narrative Review, Kaitlin M Phillips, Philip F Lavere, Nicola A Hanania, Muhammad Adrish

Faculty, Staff and Students Publications

The burden of chronic obstructive pulmonary disease (COPD) is increasing, especially for women in low-to-middle income countries. Biomarkers provide ever-increasing diagnostic precision for COPD and show promise for primary, secondary, and tertiary disease prevention. This review describes emerging applications for biomarkers in COPD, especially as they align with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) emphasis on prevention, early diagnosis, and response to therapy. These biomarkers include blood eosinophils; IgE; C-reactive protein; fibrinogen; procalcitonin; interleukins 6, 8, and 33; tumor necrosis factor alpha; and soluble receptor for advanced glycated products (sRAGE). They have been used in various ways …

Driving Pressure Decoded: Precision Strategies In Adult Respiratory Distress Syndrome Management, Muhammad Adrish, Sai Doppalapudi, Dmitry Lvovsky

Faculty, Staff and Students Publications

Mechanical ventilation (MV) is an important strategy for improving the survival of patients with respiratory failure. However, MV is associated with aggravation of lung injury, with ventilator-induced lung injury (VILI) becoming a major concern. Thus, ventilation protection strategies have been developed to minimize complications from MV, with the goal of relieving excessive breathing workload, improving gas exchange, and minimizing VILI. By opting for lower tidal volumes, clinicians seek to strike a balance between providing adequate ventilation to support gas exchange and preventing overdistension of the alveoli, which can contribute to lung injury. Additionally, other factors play a role in optimizing …

Artificial Intelligence-Based Epigenomic, Transcriptomic And Histologic Signatures Of Tobacco Use In Oral Squamous Cell Carcinoma, Chi T Viet, Kesava R Asam, Gary Yu, Emma C Dyer, Sara Kochanny, Carissa M Thomas, Nicholas F Callahan, Anthony B Morlandt, Allen C Cheng, Ashish A Patel, Dylan F Roden, Simon Young, James Melville, Jonathan Shum, Paul C Walker, Khanh K Nguyen, Stephanie N Kidd, Steve C Lee, Gretchen S Folk, Dan T Viet, Anupama Grandhi, Jeremy Deisch, Yi Ye, Fatemeh Momen-Heravi, Alexander T Pearson, Bradley E Aouizerat

Faculty, Staff and Student Publications

Oral squamous cell carcinoma (OSCC) biomarker studies rarely employ multi-omic biomarker strategies and pertinent clinicopathologic characteristics to predict mortality. In this study we determine for the first time a combined epigenetic, gene expression, and histology signature that differentiates between patients with different tobacco use history (heavy tobacco use with ≥10 pack years vs. no tobacco use). Using The Cancer Genome Atlas (TCGA) cohort (n = 257) and an internal cohort (n = 40), we identify 3 epigenetic markers (GPR15, GNG12, GDNF) and 13 expression markers (IGHA2, SCG5, RPL3L, NTRK1, CD96, BMP6, TFPI2, EFEMP2, RYR3, DMTN, GPD2, BAALC, and FMO3), which …

Vertebral Hu Value And The Pectoral Muscle Index Based On Chest Ct Can Be Used To Opportunistically Screen For Osteoporosis, Xiong-Yi Wang, Sheng Pan, Wei-Feng Liu, Yi-Ke Wang, Si-Min Yun, You-Jia Xu

Faculty, Staff and Student Publications

BACKGROUND: Existing studies have shown that computed tomography (CT) attenuation and skeletal muscle tissue are strongly associated with osteoporosis; however, few studies have examined whether vertebral HU values and the pectoral muscle index (PMI) measured at the level of the 4th thoracic vertebra (T4) are strongly associated with bone mineral density (BMD). In this study, we demonstrate that vertebral HU values and the PMI based on chest CT can be used to opportunistically screen for osteoporosis and reduce fracture risk through prompt treatment.

METHODS: We retrospectively evaluated 1000 patients who underwent chest CT and DXA scans from August 2020-2022. The …

Impact Of Risk-Based Therapy On Late Morbidity And Mortality In Neuroblastoma Survivors: A Report From The Childhood Cancer Survivor Study, Danielle Novetsky Friedman, Pamela J Goodman, Wendy M Leisenring, Lisa R Diller, Susan L Cohn, Rebecca M Howell, Susan A Smith, Emily S Tonorezos, Suzanne L Wolden, Joseph P Neglia, Kirsten K Ness, Todd M Gibson, Paul C Nathan, Lucie M Turcotte, Brent R Weil, Leslie L Robison, Kevin C Oeffinger, Gregory T Armstrong, Charles A Sklar, Tara O Henderson

Faculty, Staff and Student Publications

Background: Early efforts at risk-adapted therapy for neuroblastoma are predicted to result in differential late effects; the magnitude of these differences has not been well described.

Methods: Late mortality, subsequent malignant neoplasms (SMNs), and severe/life-threatening chronic health conditions (CHCs), graded according to CTCAE v4.03, were assessed among 5-year Childhood Cancer Survivor Study (CCSS) survivors of neuroblastoma diagnosed 1987-1999. Using age, stage at diagnosis, and treatment, survivors were classified into risk groups (low [n = 425]; intermediate [n = 252]; high [n = 245]). Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) of SMNs were compared with matched population controls. …

Defining The Kras- And Erk-Dependent Transcriptome In Kras-Mutant Cancers, Jeffrey A Klomp, Jennifer E Klomp, Clint A Stalnecker, Kirsten L Bryant, A Cole Edwards, Kristina Drizyte-Miller, Priya S Hibshman, J Nathaniel Diehl, Ye S Lee, Alexis J Morales, Khalilah E Taylor, Sen Peng, Nhan L Tran, Laura E Herring, Alex W Prevatte, Natalie K Barker, Laura D Hover, Jill Hallin, Alexey Sorokin, Preeti Marie Kanikarla, Saikat Chowdhury, Oluwadara Coker, Hey Min Lee, Craig M Goodwin, Prson Gautam, Peter Olson, James G Christensen, John P Shen, Scott Kopetz, Lee M Graves, Kian-Huat Lim, Andrea Wang-Gillam, Krister Wennerberg, Adrienne D Cox, Channing J Der

Faculty, Staff and Student Publications

How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and ERK-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges significantly from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome and other components of the cell cycle machinery as …

Placental Co-Transcriptional Activator Vestigial-Like 1 (Vgll1) Drives Tumorigenesis Via Increasing Transcription Of Proliferation And Invasion Genes, Heather M Sonnemann, Barbara Pazdrak, Barbara Nassif, Yimo Sun, Lama Elzohary, Amjad H Talukder, Arjun S Katailiha, Krishna Bhat, Gregory Lizée

Faculty, Staff and Student Publications

INTRODUCTION: Vestigial-like 1 (VGLL1) is a co-transcriptional activator that binds to TEA domain-containing transcription factors (TEADs). Its expression is upregulated in a variety of aggressive cancer types, including pancreatic and basal-like breast cancer, and increased transcription of VGLL1 is strongly correlated with poor prognosis and decreased overall patient survival. In normal tissues, VGLL1 is most highly expressed within placental trophoblast cells, which share the common attributes of rapid cellular proliferation and invasion with tumor cells. The impact of VGLL1 in cancer has not been fully elucidated and no VGLL1-targeted therapy currently exists.

METHODS: The aim of this study was to …

Seroprevalence Of Anti-Sars-Cov-2 Igg Antibodies In Healthcare Personnel In El Salvador Prior To Vaccination Campaigns, José Elías Aguilar Ramírez, Adrianna Maliga, Allison Stewart, Allison Lino, José Eduardo Oliva, Xochitl Sandoval, Emily Zielinski-Gutierrez, Rafael Chacon-Fuentes, Parminder S Suchdev, Susana Zelaya, Mario Sánchez, Delmy Lisseth Recinos, Beatriz López, Ella Hawes, Julie Liu, Shannon E Ronca, Sarah M Gunter, Kristy O Murray, Rhina Domínguez

Faculty, Staff and Students Publications

COVID-19, caused by the SARS-CoV-2 virus, is a highly pathogenic emerging infectious disease. Healthcare personnel (HCP) are presumably at higher risk of acquiring emerging infections because of occupational exposure. The prevalence of COVID-19 in HCP is unknown, particularly in low- to middle-income countries like El Salvador. The goal of this study was to determine the seroprevalence of anti-SARS-CoV-2 antibodies among HCP in El Salvador just prior to vaccine rollout in March 2021. We evaluated 2176 participants from a nationally representative sample of national healthcare institutions. We found 40.4% (n = 880) of the study participants were seropositive for anti-spike …

Phase 1, Randomized, Rater And Participant Blinded Placebo-Controlled Study Of The Safety, Reactogenicity, Tolerability And Immunogenicity Of H1n1 Influenza Vaccine Delivered By Vx-103 (A Mimix Microneedle Patch [Map] System) In Healthy Adult, Naveen Garg, Guy Tellier, Noah Vale, Jon Kluge, Jonathan L Portman, Anna Markowska, Lynda Tussey

Faculty, Staff and Student Publications

BACKGROUND: The MIMIX platform is a novel microneedle array patch (MAP) characterized by slowly dissolving microneedle tips that deploy into the dermis following patch application. We describe safety, reactogenicity, tolerability and immunogenicity for MIMIX MAP vaccination against influenza.

METHODOLOGY: The trial was a Phase 1, exploratory, first-in-human, parallel randomized, rater, participant, study analyst-blinded, placebo-controlled study in Canada. Forty-five healthy participants (18 to 39 years of age, inclusive) were randomized in a 1:1:1 ratio to receive either 15 μg or 7.5 μg of an H1N1 influenza vaccine, or placebo delivered via MIMIX MAP to the volar forearm. A statistician used a …