Medicine and Health Sciences Commons^™

What Regenerative Agriculture Can Teach Medical Students About Human Health, David Ebbott, Dimitrios Papanagnou

Department of Emergency Medicine Faculty Papers

No abstract provided.

Zinc Treatment Reverses And Anti-Zn-Regulated Mirs Suppress Esophageal Carcinomas In Vivo, Louise Fong, Kay Huebner, Ruiyan Jing, Karl Smalley, Christopher R Brydges, Oliver Fiehn, John Farber, Carlo M Croce

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Esophageal squamous cell carcinoma (ESCC) is a deadly disease with few prevention or treatment options. ESCC development in humans and rodents is associated with Zn deficiency (ZD), inflammation, and overexpression of oncogenic microRNAs: miR-31 and miR-21. In a ZD-promoted ESCC rat model with upregulation of these miRs, systemic antimiR-31 suppresses the miR-31-EGLN3/STK40-NF-κB-controlled inflammatory pathway and ESCC. In this model, systemic delivery of Zn-regulated antimiR-31, followed by antimiR-21, restored expression of tumor-suppressor proteins targeted by these specific miRs: STK40/EGLN3 (miR-31), PDCD4 (miR-21), suppressing inflammation, promoting apoptosis, and inhibiting ESCC development. Moreover, ESCC-bearing Zn-deficient (ZD) rats receiving Zn medication showed a 47% …

Sleep Problems In Old Age: Metabotropic Glutamate Receptor To The Rescue, Sho Inami, Dinis J.S. Afonso, Kyunghee Koh

Farber Institute for Neuroscience Faculty Papers

No abstract provided.

Impact Of Early Relapse Within 24 Months After First-Line Systemic Therapy (Pod24) On Outcomes In Patients With Marginal Zone Lymphoma: A Us Multisite Study, Narendranath Epperla, Rina Li Welkie, Pallawi Torka, Geoffrey Shouse, Reem Karmali, Lauren Shea, Andrea Anampa-Guzmán, Timothy S Oh, Heather Reaves, Montreh Tavakkoli, Kathryn Lindsey, Irl Brian Greenwell, Emily Hansinger, Colin Thomas, Sayan Mullick Chowdhury, Kaitlin Annunzio, Beth Christian, Stefan K Barta, Praveen Ramakrishnan Geethakumari, Nancy L Bartlett, Alex F Herrera, Natalie S Grover, Adam J Olszewski

Department of Medicine Faculty Papers

Progression of disease within 24 months (POD24) from diagnosis in marginal zone lymphoma (MZL) was shown to portend poor outcomes in prior studies. However, many patients with MZL do not require immediate therapy, and the time from diagnosis-to-treatment interval can be highly variable with no universal criteria to initiate systemic therapy. Hence, we sought to evaluate the prognostic relevance of early relapse or progression within 24 months from systemic therapy initiation in a large US cohort. The primary objective was to evaluate the overall survival (OS) in the two groups. The secondary objective included the evaluation of factors predictive of …

A Rare Metastatic Mesenteric Malignant Pecoma With Tsc2 Mutation Treated With Palliative Surgical Resection And Nab-Sirolimus: A Case Report, Luke Meredith, Timothy Chao, Avinoam Nevler, Atrayee Basu Mallick, Rajan Singla, Peter Mccue, Wilbur Bowne, Wei Jiang, Md, Phd

Kimmel Cancer Center Faculty Papers

BACKGROUND: Malignant perivascular epithelioid cell tumors (PEComas) are exceedingly rare malignant mesenchymal neoplasms with characteristic morphological and immunohistochemical (IHC) patterns. However, some malignant PEComas are poorly differentiated with atypical histopathological features, making a definitive diagnosis difficult. PEComas are most commonly found in females and often show either TSC1 or TSC2 alterations, which result in the activation of the mTOR pathway, or TFE3 fusions. Given these molecular characteristics, mTOR inhibitors have recently been approved by the FDA in the treatment of malignant PEComas, particularly in those with TSC1/2 alterations. Therefore, molecular analyses may be helpful for both the diagnostic workup of …

Spatiotemporally Dynamic Electric Fields For Brain Cancer Treatment: An In Vitro Investigation, Erin Iredale, Abdulla Elsaleh, Hu Xu, Paul Christiaans, Andrew Deweyert, John Ronald, Susanne Schmid, Matthew O Hebb, Terry M Peters, Eugene Wong

Anatomy and Cell Biology Publications

Objective. The treatment of glioblastoma (GBM) using low intensity electric fields (∼1 V cm^-1) is being investigated using multiple implanted bioelectrodes, which was termed intratumoral modulation therapy (IMT). Previous IMT studies theoretically optimized treatment parameters to maximize coverage with rotating fields, which required experimental investigation. In this study, we employed computer simulations to generate spatiotemporally dynamic electric fields, designed and purpose-built an IMT device for in vitro experiments, and evaluated the human GBM cellular responses to these fields. Approach. After measuring the electrical conductivity of the in vitro culturing medium, we designed experiments to evaluate the …

Dpc29 Promotes Post-Initiation Mitochondrial Translation In Saccharomyces Cerevisiae, Kyle A. Hubble, Michael F. Henry

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Mitochondrial ribosomes synthesize essential components of the oxidative phosphorylation (OXPHOS) system in a tightly regulated process. In the yeast Saccharomyces cerevisiae, mitochondrial mRNAs require specific translational activators, which orchestrate protein synthesis by recognition of their target gene's 5'-untranslated region (UTR). Most of these yeast genes lack orthologues in mammals, and only one such gene-specific translational activator has been proposed in humans-TACO1. The mechanism by which TACO1 acts is unclear because mammalian mitochondrial mRNAs do not have significant 5'-UTRs, and therefore must promote translation by alternative mechanisms. In this study, we examined the role of the TACO1 orthologue in yeast. We …

Modulation Of Rna Splicing Enhances Response To Bcl2 Inhibition In Leukemia., Eric Wang, Jose Mario Bello Pineda, Won Jun Kim, Sisi Chen, Jessie Bourcier, Maximilian Stahl, Simon J Hogg, Jan Phillipp Bewersdorf, Cuijuan Han, Michael E Singer, Daniel Cui, Caroline E Erickson, Steven M Tittley, Alexander V Penson, Katherine Knorr, Robert F Stanley, Jahan Rahman, Gnana Krishnamoorthy, James A Fagin, Emily Creger, Elizabeth Mcmillan, Chi-Ching Mak, Matthew Jarvis, Carine Bossard, Darrin M Beaupre, Robert K Bradley, Omar Abdel-Wahab

Faculty Research 2022

Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR-Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncover a selective dependency on RNA splicing factors whose loss preferentially enhances response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augments response to venetoclax in leukemia yet is completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition leads to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. …

Identification Of Proteins Involved In Cell Membrane Permeabilization By Nanosecond Electric Pulses (Nsep), Giedre Silkuniene, Uma Mangalanathan, Alessandra Rossi, Peter A. Mollica, Andrei G. Pakhomov, Olga N. Pakhomova

Bioelectrics Publications

The study was aimed at identifying endogenous proteins which assist or impede the permeabilized state in the cell membrane disrupted by nsEP (20 or 40 pulses, 300 ns width, 7 kV/cm). We employed a LentiArray CRISPR library to generate knockouts (KOs) of 316 genes encoding for membrane proteins in U937 human monocytes stably expressing Cas9 nuclease. The extent of membrane permeabilization by nsEP was measured by the uptake of Yo-Pro-1 (YP) dye and compared to sham-exposed KOs and control cells transduced with a non-targeting (scrambled) gRNA. Only two KOs, for SCNN1A and CLCA1 genes, showed a statistically significant reduction in …

Multi-Ancestry Genome-Wide Association Analyses Improve Resolution Of Genes And Pathways Influencing Lung Function And Chronic Obstructive Pulmonary Disease Risk, Nick Shrine, Abril G. Izquierdo, Jing Chen, Richard Packer, Robert J. Hall, Anna L. Guyatt, Chiara Batini, Rebecca J. Thompson, Chandan Puvuluri, Vidhi Malik, Brian D. Hobbs, Matthew Moll, Wonji Kim, Ruth Tal-Singer, Per Bakke, Katherine A. Fawcett, Catherine John, Kayesha Coley, Noemi Nicole Piga, Sinjini Sikdar, Martin D. Tobin, Et Al.

Mathematics & Statistics Faculty Publications

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of …

A Single-Cell Atlas Of Bovine Skeletal Muscle Reveals Mechanisms Regulating Intramuscular Adipogenesis And Fibrogenesis, Leshan Wang, Peidong Gao, Chaoyag Li, Qianglin Liu, Zeyang Yao, Yuxia Li, Xujia Zhang, Jiangwen Sun, Constantine Simintiras, Matthew Welborn, Kenneth Mcmillin, Stephanie Oprescu, Shihuan Kuang, Xing Fu

Computer Science Faculty Publications

Background: Intramuscular fat (IMF) and intramuscular connective tissue (IMC) are often seen in human myopathies and are central to beef quality. The mechanisms regulating their accumulation remain poorly understood. Here, we explored the possibility of using beef cattle as a novel model for mechanistic studies of intramuscular adipogenesis and fibrogenesis.

Methods: Skeletal muscle single-cell RNAseq was performed on three cattle breeds, including Wagyu (high IMF), Brahman (abundant IMC but scarce IMF), and Wagyu/Brahman cross. Sophisticated bioinformatics analyses, including clustering analysis, gene set enrichment analyses, gene regulatory network construction, RNA velocity, pseudotime analysis, and cell-cell communication analysis, were performed to elucidate …

Exposure To Pcb126 During The Nursing Period Reversibly Impacts Early-Life Glucose Tolerance, Brittany B. Rice, Keegan W. Sammons, Sara Y. Ngo Tenlep, Madeline T. Weltzer, Leryn J. Reynolds, Cetewayo S. Rashid, Hollie I. Swanson, Kevin J. Pearson

Human Movement Sciences Faculty Publications

Polychlorinated biphenyls (PCBs) are persistent environmental organic pollutants known to have detrimental health effects. Using a mouse model, we previously demonstrated that PCB126 exposure before and during pregnancy and throughout the perinatal period adversely affected offspring glucose tolerance and/or body composition profiles. The purpose of this study was to investigate the glucose tolerance and body composition of offspring born to dams exposed to PCB126 during the nursing period only. Female ICR mice were bred, and half of the dams were exposed to either vehicle (safflower oil) or 1 µmole PCB126 per kg of body weight via oral gavage on postnatal …

Short-Term Removal Of Exercise Impairs Glycemic Control In Older Adults: A Randomized Trial, Leryn J. Reynolds, Troy M. Williams, Joel E. Harden, Hannah M. Twiddy, Monica L. Kearney

Human Movement Sciences Faculty Publications

Postprandial glycemia (PPG) predicts cardiovascular disease, and short-term physical inactivity increases PPG in young, active adults. Whether this occurs in older, active adults who may be more prone to bouts of inactivity is unknown. This study determined if postprandial interstitial glucose (PPIG) was impaired in active older adults following the removal of exercise for 3 days (NOEX) compared to active young adults. In this randomized, crossover study, 11 older (69.1 ± 1.9 years) and 9 young (32.8 ± 1.8 years) habitually active (≥90 min/week of exercise) adults completed 3-days of NOEX and 3-days of normal habitual exercise (EX), separated by …

Developmental Pharmacokinetics Of Indomethacin In Preterm Neonates: Severely Decreased Drug Clearance In The First Week Of Life., Wojciech Krzyzanski, Bradley Stockard, Andrea Gaedigk, Allison Scott, Whitney M. Nolte, Kim T. Gibson, J Steven Leeder, Tamorah Lewis

Manuscripts, Articles, Book Chapters and Other Papers

Indomethacin is used commonly in preterm neonates for the prevention of intracranial hemorrhage and closure of an abnormally open cardiac vessel. Due to biomedical advances, the infants who receive this drug in the neonatal intensive care unit setting have become younger, smaller, and less mature (more preterm) at the time of treatment. To develop a pharmacokinetics (PK) model to aid future dosing, we designed a prospective cohort study to characterize indomethacin PK in a dynamically changing patient population. A population PK base model was created using NONMEM, and a covariate model was developed in a primary development cohort and subsequently …

Large-Scale Crispri And Transcriptomics Of Staphylococcus Epidermidis Identify Genetic Factors Implicated In Lifestyle Versatility., Michelle Spoto, Johanna P. Riera Puma, Elizabeth Fleming, Changhui Guan, Yvette Ondouah Nzutchi, Dean Kim, Julia Oh

Faculty Research 2022

Staphylococcus epidermidis is a ubiquitous human commensal skin bacterium that is also one of the most prevalent nosocomial pathogens. The genetic factors underlying this remarkable lifestyle plasticity are incompletely understood, mainly due to the difficulties of genetic manipulation, precluding high-throughput functional profiling of this species. To probe the versatility of S. epidermidis to survive across a diversity of environmental conditions, we developed a large-scale CRISPR interference (CRISPRi) screen complemented by transcriptional profiling (RNA sequencing) across 24 diverse conditions and piloted a droplet-based CRISPRi approach to enhance throughput and sensitivity. We identified putative essential genes, importantly revealing amino acid metabolism as …

Multiplex Immunofluorescence-Guided Laser Capture Microdissection For Spatial Transcriptomics Of Metastatic Melanoma Tissues., Jan Martinek, Te-Chia Wu, Lili Sun, Jianan Lin, Kyung In Kim, Florentina Marches, Paul Robson, Joshy George, Karolina Palucka

Faculty Research 2022

We describe a pipeline for optimized and streamlined multiplexed immunofluorescence-guided laser capture microdissection allowing the harvest of individual cells based on their phenotype and tissue localization for transcriptomic analysis with next-generation RNA sequencing. Here, we analyze transcriptomes of CD3+ T cells, CD14+ monocytes/macrophages, and melanoma cells in non-dissociated metastatic melanoma tissue. While this protocol is described for melanoma tissues, we successfully applied it to human tonsil, skin, and breast cancer tissues as well as mouse lung tissues. For complete details on the use and execution of this protocol, please refer to Martinek et al. (2022).

Extrachromosomal Dna (Ecdna): An Origin Of Tumor Heterogeneity, Genomic Remodeling, And Drug Resistance., Lauren T Pecorino, Roel G W Verhaak, Anton Henssen, Paul S Mischel

Faculty Research 2022

The genome of cancer cells contains circular extrachromosomal DNA (ecDNA) elements not found in normal cells. Analysis of clinical samples reveal they are common in most cancers and their presence indicates poor prognosis. They often contain enhancers and driver oncogenes that are highly expressed. The circular ecDNA topology leads to an open chromatin conformation and generates new gene regulatory interactions, including with distal enhancers. The absence of centromeres leads to random distribution of ecDNAs during cell division and genes encoded on them are transmitted in a non-mendelian manner. ecDNA can integrate into and exit from chromosomal DNA. The numbers of …

Natural Coevolution Of Tumor And Immunoenvironment In Glioblastoma., Lingxiang Wu, Wei Wu, Junxia Zhang, Zheng Zhao, Liangyu Li, Mengyan Zhu, Min Wu, Fan Wu, Fengqi Zhou, Yuxin Du, Rui-Chao Chai, Wei Zhang, Xiaoguang Qiu, Quanzhong Liu, Ziyu Wang, Jie Li, Kening Li, Apeng Chen, Yinan Jiang, Xiangwei Xiao, Han Zou, Rashmi Srivastava, Tingting Zhang, Yun Cai, Yuan Liang, Bin Huang, Ruohan Zhang, Fan Lin, Lang Hu, Xiuxing Wang, Xu Qian, Sali Lv, Baoli Hu, Siyuan Zheng, Zhibin Hu, Hongbing Shen, Yongping You, Roel G W Verhaak, Tao Jiang, Qianghu Wang

Faculty Research 2022

Isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) has a dismal prognosis. A better understanding of tumor evolution holds the key to developing more effective treatment. Here we study GBM's natural evolutionary trajectory by using rare multifocal samples. We sequenced 61,062 single cells from eight multifocal IDH wild-type primary GBMs and defined a natural evolution signature (NES) of the tumor. We show that the NES significantly associates with the activation of transcription factors that regulate brain development, including MYBL2 and FOSL2. Hypoxia is involved in inducing NES transition potentially via activation of the HIF1A-FOSL2 axis. High-NES tumor cells could recruit and polarize …

Phenotype-Aware Prioritisation Of Rare Mendelian Disease Variants., Catherine Kelly, Anita Szabo, Nikolas Pontikos, Gavin Arno, Peter N Robinson, Jules O B Jacobsen, Damian Smedley, Valentina Cipriani

Faculty Research 2022

A molecular diagnosis from the analysis of sequencing data in rare Mendelian diseases has a huge impact on the management of patients and their families. Numerous patient phenotype-aware variant prioritisation (VP) tools have been developed to help automate this process, and shorten the diagnostic odyssey, but performance statistics on real patient data are limited. Here we identify, assess, and compare the performance of all up-to-date, freely available, and programmatically accessible tools using a whole-exome, retinal disease dataset from 134 individuals with a molecular diagnosis. All tools were able to identify around two-thirds of the genetic diagnoses as the top-ranked candidate, …

A Reference Human Induced Pluripotent Stem Cell Line For Large-Scale Collaborative Studies., Caroline B Pantazis, Andrian Yang, Erika Lara, Justin A Mcdonough, Cornelis Blauwendraat, Lirong Peng, Hideyuki Oguro, Jitendra Kanaujiya, Jizhong Zou, David Sebesta, Gretchen Pratt, Erin Cross, Jeffrey Blockwick, Philip Buxton, Lauren Kinner-Bibeau, Constance Medura, Christopher Tompkins, Stephen Hughes, Marianita Santiana, Faraz Faghri, Mike A Nalls, Daniel Vitale, Shannon Ballard, Yue A Qi, Daniel M Ramos, Kailyn M Anderson, Julia Stadler, Priyanka Narayan, Jason Papademetriou, Luke Reilly, Matthew P Nelson, Sanya Aggarwal, Leah U Rosen, Peter Kirwan, Venkat Pisupati, Steven L Coon, Sonja W Scholz, Theresa Priebe, Miriam Öttl, Jian Dong, Marieke Meijer, Lara J M Janssen, Vanessa S Lourenco, Rik Van Der Kant, Dennis Crusius, Dominik Paquet, Ana-Caroline Raulin, Guojun Bu, Aaron Held, Brian J Wainger, Rebecca M C Gabriele, Jackie M Casey, Selina Wray, Dad Abu-Bonsrah, Clare L Parish, Melinda S Beccari, Don W Cleveland, Emmy Li, Indigo V L Rose, Martin Kampmann, Carles Calatayud Aristoy, Patrik Verstreken, Laurin Heinrich, Max Y Chen, Birgitt Schüle, Dan Dou, Erika L F Holzbaur, Maria Clara Zanellati, Richa Basundra, Mohanish Deshmukh, Sarah Cohen, Richa Khanna, Malavika Raman, Zachary S Nevin, Madeline Matia, Jonas Van Lent, Vincent Timmerman, Bruce R Conklin, Katherine Johnson Chase, Ke Zhang, Salome Funes, Daryl A Bosco, Lena Erlebach, Marc Welzer, Deborah Kronenberg-Versteeg, Guochang Lyu, Ernest Arenas, Elena Coccia, Lily Sarrafha, Tim Ahfeldt, John C Marioni, William C Skarnes, Mark R Cookson, Michael E Ward, Florian T Merkle

Faculty Research 2022

Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between lines makes it challenging to replicate key findings and integrate data across research groups. To address this issue, we sub-cloned candidate human iPSC lines and deeply characterized their genetic properties using whole genome sequencing, their genomic stability upon CRISPR-Cas9-based gene editing, and their phenotypic properties including differentiation to commonly used cell types. These studies identified KOLF2.1J as an all-around well-performing iPSC line. We then shared KOLF2.1J with groups around the world who tested its performance in head-to-head comparisons …

Early Experience With Targeted Therapy As A First-Line Adjuvant Treatment For Pediatric Low-Grade Glioma., Nathan K Leclair, William Lambert, Kimberley Roche, Eileen Gillan, Joanna J Gell, Ching C Lau, Gregory Wrubel, Joshua Knopf, Shirali Amin, Megan Anderson, Jonathan E Martin, Markus J Bookland, David S Hersh

Faculty Research 2022

OBJECTIVE: Pediatric low-grade gliomas (pLGGs) frequently exhibit dysregulation of the mitogen-activated protein kinase (MAPK) pathway. Targeted therapies, including mutant BRAF inhibitors (dabrafenib) and MEK inhibitors (trametinib), have shown promise in patients in whom conventional chemotherapy has failed. However, few studies have investigated the use of targeted therapy as a first-line treatment for pLGG. Here, the authors reviewed their institutional experience with using a personalized medicine approach to patients with newly diagnosed pLGGs.

METHODS: All pediatric patients at the authors' institution who had been treated with dabrafenib or trametinib for pLGG without first receiving conventional chemotherapy or radiation were retrospectively reviewed. …

Metformin Is Associated With Reduced Covid-19 Severity In Patients With Prediabetes., Lauren E Chan, Elena Casiraghi, Bryan Laraway, Ben D Coleman, Hannah Blau, Adnin Zaman, Nomi L Harris, Kenneth Wilkins, Blessy Antony, Michael Gargano, Giorgio Valentini, David Sahner, Melissa Haendel, Peter N Robinson, Carolyn Bramante, Justin Reese

Faculty Research 2022

AIMS: Studies suggest that metformin is associated with reduced COVID-19 severity in individuals with diabetes compared to other antihyperglycemics. We assessed if metformin is associated with reduced incidence of severe COVID-19 for patients with prediabetes or polycystic ovary syndrome (PCOS), common diseases that increase the risk of severe COVID-19.

METHODS: This observational, retrospective study utilized EHR data from 52 hospitals for COVID-19 patients with PCOS or prediabetes treated with metformin or levothyroxine/ondansetron (controls). After balancing via inverse probability score weighting, associations with COVID-19 severity were assessed by logistic regression.

RESULTS: In the prediabetes cohort, when compared to levothyroxine, metformin was …

Dpc29 Promotes Mitochondrial Translation Post-Initation In Saccharomyces Cerevisiae, Kyle Andrew Hubble

Graduate School of Biomedical Sciences Theses and Dissertations

Although the cytosolic and bacterial translation systems are well studied, much less is known about translation in mitochondria. In the yeast Saccharomyces cerevisiae, mitochondrial gene expression is predominately regulated by translational activators. These regulators are thought to promote translation by binding the elongated 5’-UTRs on their target mRNAs. Since mammalian mitochondrial mRNAs generally lack 5’-UTRs, they must regulate translation by other mechanisms. As expected, most yeast translational activators lack orthologues in mammals. Recently, a mitochondrial gene-specific translational activator, TACO1, was reported in mice and humans. To better define its role in mitochondrial translation I examined the yeast TACO1 orthologue, DPC29. …

Blackcurrants Reduce The Risk Of Postmenopausal Osteoporosis: A Pilot Double-Blind, Randomized, Placebo-Controlled Clinical Trial., Briana M Nosal, Junichi R Sakaki, Zachary Macdonald, Kyle Mahoney, Kijoon Kim, Matthew Madore, Staci Thornton, Thi Dong Binh Tran, George M. Weinstock, Elaine Choung-Hee Lee, Ock K Chun

Faculty Research 2022

Beneficial effects of blackcurrant supplementation on bone metabolism in mice has recently been demonstrated, but no studies are available in humans. The current study aimed to examine the dose-dependent effects of blackcurrant in preventing bone loss and the underlying mechanisms of action in adult women. Forty peri- and early postmenopausal women were randomly assigned into one of three treatment groups for 6 months: (1) a placebo (control group, n = 13); (2) 392 mg/day of blackcurrant powder (low blackcurrant, BC, group, n = 16); and (3) 784 mg/day of blackcurrant powder (high BC group, n = 11). The significance of …

Myc Regulates A Pan-Cancer Network Of Co-Expressed Oncogenic Splicing Factors., Laura M Urbanski, Mattia Brugiolo, Sunghee Park, Brittany Lynn Angarola, Nathan Leclair, Marina Yurieva, Phil Palmer, Sangram Keshari Sahu, Olga Anczuków

Faculty Research 2022

MYC is dysregulated in >50% of cancers, but direct targeting of MYC has been clinically unsuccessful. Targeting downstream MYC effector pathways represents an attractive alternative. MYC regulates alternative mRNA splicing, but the mechanistic links between MYC and the splicing machinery in cancer remain underexplored. Here, we identify a network of co-expressed splicing factors (SF-modules) in MYC-active breast tumors. Of these, one is a pan-cancer SF-module correlating with MYC activity across 33 tumor types. In mammary cell models, MYC activation leads to co-upregulation of pan-cancer module SFs and to changes in >4,000 splicing events. In breast cancer organoids, co-overexpression of the …

Transposable Element-Mediated Rearrangements Are Prevalent In Human Genomes., Parithi Balachandran, Isha A Walawalkar, Jacob I Flores, Jacob N Dayton, Peter A Audano, Christine R Beck

Faculty Research 2022

Transposable elements constitute about half of human genomes, and their role in generating human variation through retrotransposition is broadly studied and appreciated. Structural variants mediated by transposons, which we call transposable element-mediated rearrangements (TEMRs), are less well studied, and the mechanisms leading to their formation as well as their broader impact on human diversity are poorly understood. Here, we identify 493 unique TEMRs across the genomes of three individuals. While homology directed repair is the dominant driver of TEMRs, our sequence-resolved TEMR resource allows us to identify complex inversion breakpoints, triplications or other high copy number polymorphisms, and additional complexities. …

A Genomically And Clinically Annotated Patient-Derived Xenograft Resource For Preclinical Research In Non-Small Cell Lung Cancer., Xing Yi Woo, Anuj Srivastava, Philip C Mack, Joel H. Graber, Brian J Sanderson, Michael W Lloyd, Mandy Chen, Sergii Domanskyi, Regina Gandour-Edwards, Rebekah A Tsai, James G. Keck, Mingshan Cheng, Margaret Bundy, Emily L Jocoy, Jonathan W Riess, William Holland, Stephen C. Grubb, James G Peterson, Grace Stafford, Carolyn Paisie, Steven Neuhauser, Radha Krishna Murthy Karuturi, Joshy George, Allen K. Simons, Margaret Chavaree, Clifford G Tepper, Neal Goodwin, Susan Airhart, Primo N Lara, Thomas H Openshaw, Edison Liu, David R Gandara, Carol J Bult

Faculty Research 2022

UNLABELLED: Patient-derived xenograft (PDX) models are an effective preclinical in vivo platform for testing the efficacy of novel drugs and drug combinations for cancer therapeutics. Here we describe a repository of 79 genomically and clinically annotated lung cancer PDXs available from The Jackson Laboratory that have been extensively characterized for histopathologic features, mutational profiles, gene expression, and copy-number aberrations. Most of the PDXs are models of non-small cell lung cancer (NSCLC), including 37 lung adenocarcinoma (LUAD) and 33 lung squamous cell carcinoma (LUSC) models. Other lung cancer models in the repository include four small cell carcinomas, two large cell neuroendocrine …

High-Temporal Resolution Profiling Reveals Distinct Immune Trajectories Following The First And Second Doses Of Covid-19 Mrna Vaccines., Darawan Rinchai, Sara Deola, Gabriele Zoppoli, Basirudeen Syed Ahamed Kabeer, Sara Taleb, Igor Pavlovski, Selma Maacha, Giusy Gentilcore, Mohammed Toufiq, Lisa Mathew, Li Liu, Fazulur Rehaman Vempalli, Ghada Mubarak, Stephan Lorenz, Irene Sivieri, Gabriella Cirmena, Chiara Dentone, Paola Cuccarolo, Daniele Roberto Giacobbe, Federico Baldi, Alberto Garbarino, Benedetta Cigolini, Paolo Cremonesi, Michele Bedognetti, Alberto Ballestrero, Matteo Bassetti, Boris P Hejblum, Tracy Augustine, Nicholas Van Panhuys, Rodolphe Thiebaut, Ricardo Branco, Tracey Chew, Maryam Shojaei, Kirsty Short, Carl G Feng, Predict-19 Consortium, Susu M Zughaier, Andrea De Maria, Benjamin Tang, Ali Ait Hssain, Davide Bedognetti, Jean-Charles Grivel, Damien Chaussabel

Faculty Research 2022

Knowledge of the mechanisms underpinning the development of protective immunity conferred by mRNA vaccines is fragmentary. Here, we investigated responses to coronavirus disease 2019 (COVID-19) mRNA vaccination via high-temporal resolution blood transcriptome profiling. The first vaccine dose elicited modest interferon and adaptive immune responses, which peaked on days 2 and 5, respectively. The second vaccine dose, in contrast, elicited sharp day 1 interferon, inflammation, and erythroid cell responses, followed by a day 5 plasmablast response. Both post-first and post-second dose interferon signatures were associated with the subsequent development of antibody responses. Yet, we observed distinct interferon response patterns after each …

Gzmk(High) Cd8(+) T Effector Memory Cells Are Associated With Cd15(High) Neutrophil Abundance In Non-Metastatic Colorectal Tumors And Predict Poor Clinical Outcome, Silvia Tiberti, Carlotta Catozzi, Ottavio Croci, Mattia Ballerini, Danilo Cagnina, Chiara Soriani, Caterina Scirgolea, Zheng Gong, Jiatai He, Angeli D Macandog, Amir Nabinejad, Carina B Nava Lauson, Arianna Quinte', Giovanni Bertalot, Wanda L Petz, Simona P Ravenda, Valerio Licursi, Paola Paci, Marco Rasponi, Luca Rotta, Nicola Fazio, Guangwen Ren, Uberto Fumagalli-Romario, Martin H Schaefer, Stefano Campaner, Enrico Lugli, Luigi Nezi, Teresa Manzo

Faculty Research 2022

CD8+ T cells are a major prognostic determinant in solid tumors, including colorectal cancer (CRC). However, understanding how the interplay between different immune cells impacts on clinical outcome is still in its infancy. Here, we describe that the interaction of tumor infiltrating neutrophils expressing high levels of CD15 with CD8+ T effector memory cells (TEM) correlates with tumor progression. Mechanistically, stromal cell-derived factor-1 (CXCL12/ SDF-1) promotes the retention of neutrophils within tumors, increasing the crosstalk with CD8+ T cells. As a consequence of the contact-mediated inter- action with neutrophils, CD8+ T cells are skewed to produce high levels of GZMK, …

Bifidobacterial Carbohydrate/Nucleoside Metabolism Enhances Oxidative Phosphorylation In White Adipose Tissue To Protect Against Diet-Induced Obesity., Gihyeon Kim, Youngmin Yoon, Jin Ho Park, Jae Won Park, Myung-Guin Noh, Hyun Kim, Changho Park, Hyuktae Kwon, Jeong-Hyeon Park, Yena Kim, Jinyoung Sohn, Shinyoung Park, Hyeonhui Kim, Sun-Kyoung Im, Yeongmin Kim, Ha Yung Chung, Myung Hee Nam, Jee Young Kwon, Il Yong Kim, Yong Jae Kim, Ji Hyeon Baek, Hak Su Kim, George M Weinstock, Belong Cho, Charles Lee, Sungsoon Fang, Hansoo Park, Je Kyung Seong

Faculty Research 2022

BACKGROUND: Comparisons of the gut microbiome of lean and obese humans have revealed that obesity is associated with the gut microbiome plus changes in numerous environmental factors, including high-fat diet (HFD). Here, we report that two species of Bifidobacterium are crucial to controlling metabolic parameters in the Korean population.

RESULTS: Based on gut microbial analysis from 99 Korean individuals, we observed the abundance of Bifidobacterium longum and Bifidobacterium bifidum was markedly reduced in individuals with increased visceral adipose tissue (VAT), body mass index (BMI), blood triglyceride (TG), and fatty liver. Bacterial transcriptomic analysis revealed that carbohydrate/nucleoside metabolic processes of Bifidobacterium …