Digital Commons Network^™

Combining The Tyrosine Kinase Inhibitor Cabozantinib And The Mtorc1/2 Inhibitor Sapanisertib Blocks Erk Pathway Activity And Suppresses Tumor Growth In Renal Cell Carcinoma, Yige Wu, Siqi Chen, Xiaolu Yang, Kazuhito Sato, Preet Lal, Yuefan Wang, Andrew T Shinkle, Michael C Wendl, Tina M Primeau, Yanyan Zhao, Alanna Gould, Hua Sun, Jacqueline L Mudd, Jeremy Hoog, R Jay Mashl, Matthew A Wyczalkowski, Chia-Kuei Mo, Ruiyang Liu, John M Herndon, Sherri R Davies, Di Liu, Xi Ding, Yvonne A Evrard, Bryan E Welm, David Lum, Mei Yee Koh, Alana L Welm, Jeffrey H Chuang, Jeffrey A Moscow, Funda Meric-Bernstam, Ramaswamy Govindan, Shunqiang Li, James Hsieh, Ryan C Fields, Kian-Huat Lim, Cynthia X Ma, Hui Zhang, Li Ding, Feng Chen

Faculty, Staff and Student Publications

Current treatment approaches for renal cell carcinoma (RCC) face challenges in achieving durable tumor responses due to tumor heterogeneity and drug resistance. Combination therapies that leverage tumor molecular profiles could offer an avenue for enhancing treatment efficacy and addressing the limitations of current therapies. To identify effective strategies for treating RCC, we selected ten drugs guided by tumor biology to test in six RCC patient-derived xenograft (PDX) models. The multitargeted tyrosine kinase inhibitor (TKI) cabozantinib and mTORC1/2 inhibitor sapanisertib emerged as the most effective drugs, particularly when combined. The combination demonstrated favorable tolerability and inhibited tumor growth or induced tumor …

Plants As Vectors For Environmental Prion Transmission, Christina M Carlson, Samuel Thomas, Matthew W Keating, Paulina Soto, Nicole M Gibbs, Haeyoon Chang, Jamie K Wiepz, Annabel G Austin, Jay R Schneider, Rodrigo Morales, Christopher J Johnson, Joel A Pedersen

Faculty, Staff and Student Publications

Prions cause fatal neurodegenerative diseases and exhibit remarkable durability, which engenders a wide array of potential exposure scenarios. In chronic wasting disease of deer, elk, moose, and reindeer and in scrapie of sheep and goats, prions are transmitted via environmental routes and the ability of plants to accumulate and subsequently transmit prions has been hypothesized, but not previously demonstrated. Here, we establish the ability of several crop and other plant species to take up prions via their roots and translocate them to above-ground tissues from various growth media including soils. We demonstrate that plants can accumulate prions in above-ground tissues …

Targeting Eif4a Triggers An Interferon Response To Synergize With Chemotherapy And Suppress Triple-Negative Breast Cancer, Na Zhao, Elena B Kabotyanski, Alexander B Saltzman, Anna Malovannaya, Xueying Yuan, Lucas C Reineke, Nadia Lieu, Yang Gao, Diego A Pedroza, Sebastian J Calderon, Alex J Smith, Clark Hamor, Kazem Safari, Sara Savage, Bing Zhang, Jianling Zhou, Luisa M Solis, Susan G Hilsenbeck, Cheng Fan, Charles M Perou, Jeffrey M Rosen

Faculty, Staff and Students Publications

Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A with zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages toward an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade. Mechanistic studies revealed that zotatifin reprograms the tumor translational landscape, inhibits the translation of Sox4 …

Gap Junctions Or Hemichannel-Dependent And Independent Roles Of Connexins In Fibrosis, Epithelial-Mesenchymal Transitions, And Wound Healing, Yuting Li, Francisca M Acosta, Jean X Jiang

Faculty, Staff and Student Publications

Fibrosis initially appears as a normal response to damage, where activated fibroblasts produce large amounts of the extracellular matrix (ECM) during the wound healing process to assist in the repair of injured tissue. However, the excessive accumulation of the ECM, unresolved by remodeling mechanisms, leads to organ dysfunction. Connexins, a family of transmembrane channel proteins, are widely recognized for their major roles in fibrosis, the epithelial-mesenchymal transition (EMT), and wound healing. Efforts have been made in recent years to identify novel mediators and targets for this regulation. Connexins form gap junctions and hemichannels, mediating communications between neighboring cells and inside …

Recombination-Mediated Dissemination Of Methicillin-Resistant S Aureus Clonal Complex 1 In The Egyptian Health Care Settings, Salma W Elsayed, Reem A Elghaish, Eman Badr, Shaimaa F Mouftah, Nehal A Saif, Iman S Naga, Ahmed H Shata, Ben Pascoe, Samuel K Sheppard, Mohamed Elhadidy

Faculty, Staff and Student Publications

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a rapidly evolving pathogen that is frequently associated with outbreaks and sustained epidemics. This study investigated the population structure, resistome, virulome, and the correlation between antimicrobial resistance determinants with phenotypic resistance profiles of 36 representative hospital-acquired MRSA isolates recovered from hospital settings in Egypt.

Results: The community-acquired MRSA lineage, clonal complex 1 (CC1) was the most frequently detected clone, followed by three other globally disseminated clones, CC121, CC8, and CC22. Most isolates carried SCCmec type V and more than half of isolates demonstrated multi-drug resistant phenotypes. Resistance to linezolid, a last resort antibiotic for …

Identification Of Candidate Dna Methylation Biomarkers Related To Alzheimer’S Disease Risk By Integrating Genome And Blood Methylome Data, Yanfa Sun, Jingjing Zhu, Yaohua Yang, Zichen Zhang, Hua Zhong, Guanghua Zeng, Dan Zhou, Richard S Nowakowski, Jirong Long, Chong Wu, Lang Wu

Faculty, Staff and Student Publications

Alzheimer disease (AD) is a common neurodegenerative disease with a late onset. It is critical to identify novel blood-based DNA methylation biomarkers to better understand the extent of the molecular pathways affected in AD. Two sets of blood DNA methylation genetic prediction models developed using different reference panels and modelling strategies were leveraged to evaluate associations of genetically predicted DNA methylation levels with AD risk in 111,326 (46,828 proxy) cases and 677,663 controls. A total of 1,168 cytosine-phosphate-guanine (CpG) sites showed a significant association with AD risk at a false discovery rate (FDR) < 0.05. Methylation levels of 196 CpG sites were correlated with expression levels of 130 adjacent genes in blood. Overall, 52 CpG sites of 32 genes showed consistent association directions for the methylation-gene expression-AD risk, including nine genes (CNIH4, THUMPD3, SERPINB9, MTUS1, CISD1, FRAT2, CCDC88B, FES, and SSH2) firstly reported as AD risk genes. Nine of 32 genes were enriched in dementia and AD disease categories (P values ranged from 1.85 × 10-4 to 7.46 × 10-6), and 19 genes in a neurological disease network (score = 54) were also observed. Our findings improve the understanding of genetics and etiology for AD.

Monitoring Glucocorticoid Receptor In Plasma-Derived Extracellular Vesicles As A Marker Of Resistance To Androgen Receptor Signaling Inhibition In Prostate Cancer, Emanuela Gentile, Andrew W Hahn, Jian H Song, Anh Hoang, Peter D A Shepherd, Sumankalai Ramachandran, Nora M Navone, Eleni Efstathiou, Mark Titus, Paul G Corn, Sue-Hwa Lin, Christopher J Logothetis, Theocharis Panaretakis

Faculty, Staff and Student Publications

Disease progression following androgen ablation was shown to be associated with upregulation of the glucocorticoid receptor (GR). Longitudinal monitoring of GR expression in circulating extracellular vesicles (EV) may reflect changes in the tumor cell and facilitates detection of acquired resistance. We utilized LNCaP, LREX cells and a patient-derived xenograft, MDA PDX 322-2-6a, for in vitro and in vivo experiments. Plasma-derived EVs were isolated from patients with localized high-risk prostate cancer undergoing androgen ablation. The mRNA levels of GR in EVs and their responsive genes were detected by transcriptome analysis, qRT-PCR and the protein levels by Western blot analysis. We detected …

Decreased Fxr Agonism In The Bile Acid Pool Is Associated With Impaired Fxr Signaling In A Pig Model Of Pediatric Nafld, Magdalena A Maj, Douglas G Burrin, Rodrigo Manjarín

Faculty, Staff and Students Publications

The objective of this study was to investigate whether the impairment of farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling in juvenile pigs with non-alcoholic fatty liver disease (NAFLD) is associated with changes in the composition of the enterohepatic bile acid pool. Eighteen 15-day-old Iberian pigs, pair-housed in pens, were allocated to receive either a control (CON) or high-fructose, high-fat (HFF) diet. Animals were euthanized in week 10, and liver, blood, and distal ileum (DI) samples were collected. HFF-fed pigs developed NAFLD and had decreased FGF19 expression in the DI and lower FGF19 levels in the blood. Compared with …

Oncogenic Kras Drives Lipofibrogenesis To Promote Angiogenesis And Colon Cancer Progression, Wen-Hao Hsu, Kyle A Labella, Yiyun Lin, Ping Xu, Rumi Lee, Cheng-En Hsieh, Lei Yang, Ashley Zhou, Jonathan M Blecher, Chang-Jiun Wu, Kangyu Lin, Xiaoying Shang, Shan Jiang, Denise J Spring, Yan Xia, Peiwen Chen, John Paul Shen, Scott Kopetz, Ronald A Depinho

Faculty, Staff and Student Publications

Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer, KRAS* suppresses antitumor immunity to promote tumor invasion and metastasis. Here, we uncovered that KRAS* transforms the phenotype of carcinoma-associated fibroblasts (CAF) into lipid-laden CAFs, promoting angiogenesis and tumor progression. Mechanistically, KRAS* activates the transcription factor CP2 (TFCP2) that upregulates the expression of the proadipogenic factors BMP4 and WNT5B, triggering the transformation of CAFs into lipid-rich CAFs. These lipid-rich CAFs, in turn, produce VEGFA to spur angiogenesis. In KRAS*-driven colorectal cancer mouse models, genetic or pharmacologic neutralization of TFCP2 reduced lipid-rich CAFs, lessened tumor angiogenesis, and improved overall survival. …

Formate Supplementation Enhances Antitumor Cd8+ T-Cell Fitness And Efficacy Of Pd-1 Blockade, Jared H Rowe, Ilaria Elia, Osmaan Shahid, Emily F Gaudiano, Natalia E Sifnugel, Sheila Johnson, Amy G Reynolds, Megan E Fung, Shakchhi Joshi, Martin W Lafleur, Joon Seok Park, Kristen E Pauken, Joshua D Rabinowitz, Gordon J Freeman, Marcia C Haigis, Arlene H Sharpe

Faculty, Staff and Student Publications

UNLABELLED: The tumor microenvironment (TME) restricts antitumor CD8+ T-cell function and immunotherapy responses. Cancer cells compromise the metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate that one-carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T-cell fitness and antitumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T-cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti-PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for …

Inclisiran: Where Are We On Safety, Efficacy, And Clinical Effectiveness Of Sirna Therapies For Prevention?, Christie M Ballantyne, Abdul Mannan Khan Minhas, Carl E Orringer

Faculty, Staff and Students Publications

No abstract provided.

Circulating Senescent Myeloid Cells Infiltrate The Brain And Cause Neurodegeneration In Histiocytic Disorders, C Matthias Wilk, Flurin Cathomas, Orsolya Török, Jessica Le Berichel, Matthew D Park, Camille Bigenwald, George R Heaton, Pauline Hamon, Leanna Troncoso, Brooks P Scull, Diana Dangoor, Aymeric Silvin, Ryan Fleischmann, Meriem Belabed, Howard Lin, Elias Merad Taouli, Steffen Boettcher, Long Li, Antonio Aubry, Markus G Manz, Julia K Kofler, Zhenyu Yue, Sergio A Lira, Florent Ginhoux, John F Crary, Kenneth L Mcclain, Jennifer L Picarsic, Scott J Russo, Carl E Allen, Miriam Merad

Faculty, Staff and Students Publications

Neurodegenerative diseases (ND) are characterized by progressive loss of neuronal function. Mechanisms of ND pathogenesis are incompletely understood, hampering the development of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatory neoplastic disorder caused by hematopoietic progenitors expressing mitogen-activated protein kinase (MAPK)-activating mutations that differentiate into senescent myeloid cells that drive lesion formation. Some individuals with LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we showed that LCH-ND was caused by myeloid cells that were clonal with peripheral LCH cells. Circulating BRAFV600E

Nitric Oxide Is Required For Lung Alveolarization Revealed By Deficiency Of Argininosuccinate Lyase, Zixue Jin, Ming-Ming Jiang, Brendan Lee

Faculty, Staff and Students Publications

Inhaled nitric oxide (NO) therapy has been reported to improve lung growth in premature newborns. However, the underlying mechanisms by which NO regulates lung development remain largely unclear. NO is enzymatically produced by three isoforms of nitric oxide synthase (NOS) enzymes. NOS knockout mice are useful tools to investigate NO function in the lung. Each single NOS knockout mouse does not show obvious lung alveolar phenotype, likely due to compensatory mechanisms. While mice lacking all three NOS isoforms display impaired lung alveolarization, implicating NO plays a pivotal role in lung alveolarization. Argininosuccinate lyase (ASL) is the only mammalian enzyme capable …

Allelic Strengths Of Encephalopathy-Associated Uba5 Variants Correlate Between In Vivo And In Vitro Assays, Xueyang Pan, Albert N Alvarez, Mengqi Ma, Shenzhao Lu, Michael W Crawford, Lauren C Briere, Oguz Kanca, Shinya Yamamoto, David A Sweetser, Jenny L Wilson, Ruth J Napier, Jonathan N Pruneda, Hugo J Bellen

Faculty, Staff and Students Publications

Protein UFMylation downstream of the E1 enzyme UBA5 plays essential roles in development and endoplasmic reticulum stress. Variants in the UBA5 gene are associated with developmental and epileptic encephalopathy 44 (DEE44), an autosomal recessive disorder characterized by early-onset encephalopathy, movement abnormalities, global developmental delay, intellectual disability, and seizures. DEE44 is caused by at least 12 different missense variants described as loss of function (LoF), but the relationships between genotypes and molecular or clinical phenotypes remain to be established. We developed a humanized UBA5 fly model and biochemical activity assays in order to describe in vivo and in vitro genotype–phenotype relationships …

Metformin: A Potential Treatment For Acne, Hidradenitis Suppurativa And Rosacea, Minah Cho, Yu Ri Woo, Sang Hyun Cho, Jeong Deuk Lee, Hei Sung Kim

Faculty, Staff and Student Publications

Metformin is a widely used drug for treatment of diabetes mellitus, due to its safety and efficacy. In addition to its role as an antidiabetic drug, numerous beneficial effects of metformin have enabled its use in various diseases. Considering the anti-androgenic, anti-angiogenic, anti-fibrotic and antioxidant properties of metformin, it may have the potential to improve chronic inflammatory skin diseases. However, further evidence is needed to confirm the efficacy of metformin in dermatological conditions, This review focuses on exploring the therapeutic targets of metformin in acne vulgaris, hidradenitis suppurativa and rosacea, by studying their pathogeneses.

High-Fidelity Large-Diversity Monoclonal Mammalian Cell Libraries By Cell Cycle Arrested Recombinase-Mediated Cassette Exchange, Chuan Chen, Zening Wang, Minhyo Kang, Ki Baek Lee, Xin Ge

Faculty, Staff and Student Publications

Mammalian cells carrying defined genetic variations have shown great potentials in both fundamental research and therapeutic development. However, their full use was limited by lack of a robust method to construct large monoclonal high-quality combinatorial libraries. This study developed cell cycle arrested recombinase-mediated cassette exchange (aRMCE), able to provide monoclonality, precise genomic integration and uniform transgene expression. Via optimized nocodazole-mediated mitotic arrest, 20% target gene replacement efficiency was achieved without antibiotic selection, and the improved aRMCE efficiency was applicable to a variety of tested cell clones, transgene targets and transfection methods. As a demonstration of this versatile method, we performed …

Immunoproximity Biotinylation Reveals The Axon Initial Segment Proteome, Wei Zhang, Yu Fu, Luxin Peng, Yuki Ogawa, Xiaoyun Ding, Anne Rasband, Xinyue Zhou, Maya Shelly, Matthew N Rasband, Peng Zou

Faculty, Staff and Students Publications

The axon initial segment (AIS) is a specialized neuronal compartment required for action potential generation and neuronal polarity. However, understanding the mechanisms regulating AIS structure and function has been hindered by an incomplete knowledge of its molecular composition. Here, using immuno-proximity biotinylation we further define the AIS proteome and its dynamic changes during neuronal maturation. Among the many AIS proteins identified, we show that SCRIB is highly enriched in the AIS both in vitro and in vivo, and exhibits a periodic architecture like the axonal spectrin-based cytoskeleton. We find that ankyrinG interacts with and recruits SCRIB to the AIS. However, …

Detection Of Prions In The Urine Of Patients Affected By Sporadic Creutzfeldt-Jakob Disease, M Talke

Faculty, Staff and Student Publications

Objective

Currently, it is unknown whether infectious prions are present in peripheral tissues and biological fluids of patients affected by sporadic Creutzfeldt–Jakob disease (sCJD), the most common prion disorder in humans. This represents a potential risk for inter‐individual prion infection. The main goal of this study was to evaluate the presence of prions in urine of patients suffering from the major subtypes of sCJD.

Methods

Urine samples from sCJD patients spanning the six major subtypes were tested. As controls, we used urine samples from people affected by other neurological or neurodegenerative diseases as well as healthy controls. These samples were …

The Dna Glycosylase Neil2 Is Protective During Sars-Cov-2 Infection, Nisha Tapryal, Anirban Chakraborty, Kaushik Saha, Azharul Islam, Lang Pan, Koa Hosoki, Ibrahim M Sayed, Jason M Duran, Joshua Alcantara, Vanessa Castillo, Courtney Tindle, Altaf H Sarker, Maki Wakamiya, Victor J Cardenas, Gulshan Sharma, Laura E Crotty Alexander, Sanjiv Sur, Debashis Sahoo, Gourisankar Ghosh, Soumita Das, Pradipta Ghosh, Istvan Boldogh, Tapas K Hazra

Faculty, Staff and Students Publications

SARS-CoV-2 infection-induced aggravation of host innate immune response not only causes tissue damage and multiorgan failure in COVID-19 patients but also induces host genome damage and activates DNA damage response pathways. To test whether the compromised DNA repair capacity of individuals modulates the severity of COVID-19 infection, we analyze DNA repair gene expression in publicly available patient datasets and observe a lower level of the DNA glycosylase NEIL2 in the lungs of severely infected COVID-19 patients. This observation of lower NEIL2 levels is further validated in infected patients, hamsters and ACE2 receptor-expressing human A549 (A549-ACE2) cells. Furthermore, delivery of recombinant …

The Defined Tlr3 Agonist, Nexavant, Exhibits Anti-Cancer Efficacy And Potentiates Anti-Pd-1 Antibody Therapy By Enhancing Immune Cell Infiltration, Seung-Hwan Lee, Young-Ho Choi, Soon Myung Kang, Min-Gyu Lee, Arnaud Debin, Eric Perouzel, Seung-Beom Hong, Dong-Ho Kim

Faculty, Staff and Student Publications

Nexavant was reported as an alternative to the TLR3 agonist of Poly(I:C) and its derivatives. The physicochemical properties, signaling pathways, anti-cancer effects, and mechanisms of Nexavant were investigated. The distinctive characteristics of Nexavant compared to that of Poly(I:C) were demonstrated by precise quantification, enhanced thermostability, and increased resistance to RNase A. Unlike Poly(I:C), which activates TLR3, RIG-I, and MDA5, Nexavant stimulates signaling through TLR3 and RIG-I but not through MDA5. Compared to Poly(I:C), an intratumoral Nexavant treatment led to a unique immune response, immune cell infiltration, and suppression of tumor growth in various animal cancer models. Nexavant therapy outperformed anti-PD-1 …

Ewsr1::Atf1 Orchestrates The Clear Cell Sarcoma Transcriptome In Human Tumors And A Mouse Genetic Model, Benjamin B Ozenberger, Li Li, Emily R Wilson, Alexander J Lazar, Jared J Barrott, Kevin B Jones

Faculty, Staff and Student Publications

Clear cell sarcoma (CCS) is a rare, aggressive malignancy that most frequently arises in the soft tissues of the extremities. It is defined and driven by expression of one member of a family of related translocation-generated fusion oncogenes, the most common of which is EWSR1::ATF1. The EWSR1::ATF1 fusion oncoprotein reprograms transcription. However, the binding distribution of EWSR1::ATF1 across the genome and its target genes remain unclear. Here, we interrogated the genomic distribution of V5-tagged EWSR1::ATF1 in tumors it had induced upon expression in mice that also recapitulated the transcriptome of human CCS. ChIP-sequencing of V5-EWSR1::ATF1 identified previously unreported motifs …

Therapeutic Effect Of Echinococcus Granulosus Cyst Fluid On Bacterial Sepsis In Mice, Shuying Wang, Donghui Jiang, Feifei Huang, Yayun Qian, Meitao Qi, Huihui Li, Xiaoli Wang, Zhi Wang, Kaigui Wang, Yin Wang, Pengfei Du, Bin Zhan, Rui Zhou, Liang Chu, Xiaodi Yang

Faculty, Staff and Students Publications

BACKGROUND: The primary pathophysiological process of sepsis is to stimulate a massive release of inflammatory mediators to trigger systemic inflammatory response syndrome (SIRS), the major cause of multi-organ dysfunction and death. Like other helminths, Echinococcus granulosus induces host immunomodulation. We sought to determine whether E. granulosus cyst fluid (EgCF) displays a therapeutic effect on sepsis-induced inflammation and tissue damage in a mouse model.

METHODS: The anti-inflammatory effects of EgCF were determined by in vitro culture with bone marrow-derived macrophages (BMDMs) and in vivo treatment of BALB/C mice with cecal ligation and puncture (CLP)-induced sepsis. The macrophage phenotypes were determined by …

Nicotinic Acetylcholine Receptor Signaling Maintains Epithelial Barrier Integrity, Nadja S Katheder, Kristen C Browder, Diana Chang, Ann De Maziere, Pekka Kujala, Suzanne Van Dijk, Judith Klumperman, Tzu-Chiao Lu, Hongjie Li, Zijuan Lai, Dewakar Sangaraju, Heinrich Jasper

Faculty, Staff and Students Publications

Disruption of epithelial barriers is a common disease manifestation in chronic degenerative diseases of the airways, lung, and intestine. Extensive human genetic studies have identified risk loci in such diseases, including in chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases. The genes associated with these loci have not fully been determined, and functional characterization of such genes requires extensive studies in model organisms. Here, we report the results of a screen in

Novel Insights Into The Pathogenesis Of Human Post-Primary Tuberculosis From Archival Material Of The Pre-Antibiotic Era, 1931-1947, Syeda Mariam Riaz, Kurt Hanevik, Lars Helgeland, Lisbet Sviland, Robert L Hunter, Tehmina Mustafa

Faculty, Staff and Student Publications

OBJECTIVES: Primary and post-primary tuberculosis (TB) are distinct entities. The aim of this study was to study the histopathology of primary and post-primary TB by using the unique human autopsy material from the pre-antibiotic era, 1931-1947.

MATERIAL AND METHODS: Autopsy data were collected from the autopsy journals, and the human tissue was collected from the pathology archives at the Department of Pathology, the Gades Institute.

RESULTS: Histological presentations of TB lesions showed great diversity within a single lung. Post-primary TB starts as a pneumonia forming early lesions, characterized by the infiltration of foamy macrophages containing mycobacterial antigens within alveoli, and …

Zuccagnia Punctata Cav, A Potential Environmentally Friendly And Sustainable Bionematicide For The Control Of Argentinean Horticultural Crops, Sofía Manrique, Jessica Gómez, Mauricio Piñeiro, Belén Ariza Sampietro, Maria L Peschiutta, Alejandro Tapia, Mario J Simirgiotis, Beatriz Lima

Faculty, Staff and Student Publications

This research was designed to investigate the metabolite profiling, phenolics, and flavonoids content as well as the potential nematicidal properties of decoction (ZpDe), orange-yellow resin (ZpRe) and essential oil (ZpEO) from Argentinean medicinal plant Zuccagnia punctata Cav. Additionally, the antioxidant and antibacterial properties of ZpDe and ZpEO were determined. Metabolite profiling was obtained by an ultrahigh-resolution liquid chromatography MS analysis (UHPLC-ESI-QTOF/OT-MS-MS) and GCMS. The nematicidal activity was assayed by a standardized method against Meloidogyne incognita. The antioxidant properties were screened by four methods: (2,2-diphenyl-1-picrylhydrazyl assay (DPPH), Trolox equivalent antioxidant activity assay (TEAC), ferric-reducing antioxidant power assay (FRAP), and lipid …

Whole Genome Analysis Of Snv And Indel Polymorphism In Common Marmosets (Callithrix Jacchus), R Alan Harris, Muthuswamy Raveendran, Wes Warren, Hillier W Ladeana, Chad Tomlinson, Tina Graves-Lindsay, Richard E Green, Jenna K Schmidt, Julia C Colwell, Allison T Makulec, Shelley A Cole, Ian H Cheeseman, Corinna N Ross, Saverio Capuano, Evan E Eichler, Jon E Levine, Jeffrey Rogers

Faculty, Staff and Students Publications

The common marmoset (Callithrix jacchus) is one of the most widely used nonhuman primate models of human disease. Owing to limitations in sequencing technology, early genome assemblies of this species using short-read sequencing suffered from gaps. In addition, the genetic diversity of the species has not yet been adequately explored. Using long-read genome sequencing and expert annotation, we generated a high-quality genome resource creating a 2.898 Gb marmoset genome in which most of the euchromatin portion is assembled contiguously (contig N50 = 25.23 Mbp, scaffold N50 = 98.2 Mbp). We then performed whole genome sequencing on 84 marmosets …

Benefits Of Sharing Neurophysiology Data From The Brain Initiative Research Opportunities In Humans Consortium, Vasiliki Rahimzadeh, Kathryn Maxson Jones, Mary A Majumder, Michael J Kahana, Ueli Rutishauser, Ziv M Williams, Sydney S Cash, Angelique C Paulk, Jie Zheng, Michael S Beauchamp, Jennifer L Collinger, Nader Pouratian, Amy L Mcguire, Sameer A Sheth

Center for Medical Ethics and Health Policy Staff Publications

Sharing human brain data can yield scientific benefits, but because of various disincentives, only a fraction of these data is currently shared. We profile three successful data-sharing experiences from the NIH BRAIN Initiative Research Opportunities in Humans (ROH) Consortium and demonstrate benefits to data producers and to users.

Do We Still Need Aspirin In Coronary Artery Disease?, Muhammad Haisum Maqsood, Glenn N Levine, Neal D Kleiman, David Hasdai, Barry F Uretsky, Yochai Birnbaum

Faculty, Staff and Students Publications

Aspirin has for some time been used as a first-line treatment for acute coronary syndromes, including ST-elevation myocardial infarction, for secondary prevention of established coronary disease, and for primary prevention in patients at risk of coronary artery disease. Although aspirin has been in use for decades, the available evidence for its efficacy largely predates the introduction of other drugs, such as statins and P2Y12 inhibitors. Based on recent trials, the recommendation for aspirin use as primary prevention has been downgraded. In addition, P2Y12 inhibitors given as a single antiplatelet therapy have been associated with a lower incidence of bleeding than …

Association Between Viral Infections And Glioma Risk: A Two-Sample Bidirectional Mendelian Randomization Analysis, Sheng Zhong, Wenzhuo Yang, Zhiyun Zhang, Yangyiran Xie, Lin Pan, Jiaxin Ren, Fei Ren, Yifan Li, Haoqun Xie, Hongyu Chen, Davy Deng, Jie Lu, Hui Li, Bo Wu, Youqi Chen, Fei Peng, Vinay K Puduvalli, Ke Sai, Yunqian Li, Ye Cheng, Yonggao Mou

Faculty, Staff and Student Publications

Background: Glioma is one of the leading types of brain tumor, but few etiologic factors of primary glioma have been identified. Previous observational research has shown an association between viral infection and glioma risk. In this study, we used Mendelian randomization (MR) analysis to explore the direction and magnitude of the causal relationship between viral infection and glioma.

Methods: We conducted a two-sample bidirectional MR analysis using genome-wide association study (GWAS) data. Summary statistics data of glioma were collected from the largest meta-analysis GWAS, involving 12,488 cases and 18,169 controls. Single-nucleotide polymorphisms (SNPs) associated with exposures were used as instrumental …

Chromosome 10q2432 Variants Associate With Brain Arterial Diameters In Diverse Populations: A Genome-Wide Association Study, Minghua Liu, Farid Khasiyev, Sanjeev Sariya, Antonio Spagnolo-Allende, Danurys L Sanchez, Howard Andrews, Qiong Yang, Alexa Beiser, Ye Qiao, Emy A Thomas, Jose Rafael Romero, Tatjana Rundek, Adam M Brickman, Jennifer J Manly, Mitchell Sv Elkind, Sudha Seshadri, Christopher Chen, Saima Hilal, Bruce A Wasserman, Giuseppe Tosto, Myriam Fornage, Jose Gutierrez

Faculty, Staff and Student Publications

Background: Brain arterial diameters (BADs) are novel imaging biomarkers of cerebrovascular disease, cognitive decline, and dementia. Traditional vascular risk factors have been associated with BADs, but whether there may be genetic determinants of BADs is unknown.

Methods and results: The authors studied 4150 participants from 6 geographically diverse population-based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). Brain arterial diameters for 13 segments were measured and averaged to obtain a global measure of BADs as well as the posterior and anterior circulations. A genome-wide association study revealed 14 variants at one locus associated with global BAD at genome-wide …