Digital Commons Network^™

Animal Models In Systemic Sclerosis: An Update, Xiongjie Bi, Tingting Mills, Minghua Wu

Faculty, Staff and Student Publications

Purpose of review: Systemic sclerosis (SSc) is a multisystem autoimmune connective tissue disease characterized by early inflammation followed by excessive fibrosis in the skin and internal organs. Enhancing our comprehension of SSc pathogenesis is essential to develop effective therapeutic strategies. Animal models that mimic one or more aspects of SSc have been proven to be a valuable resource for investigating disease mechanisms. This review aims to provide an updated overview of the existing SSc animal models and the potentially relevant pathways to SSc pathogenesis.

Recent findings: This review focuses on the most recently generated and investigated animal models, which delve …

Post-Zygotic Rescue Of Meiotic Errors Causes Brain Mosaicism And Focal Epilepsy, Katherine E Miller, Adithe C Rivaldi, Noriyuki Shinagawa, Sahib Sran, Jason B Navarro, Jesse J Westfall, Anthony R Miller, Ryan D Roberts, Yassmine Akkari, Rachel Supinger, Mark E Hester, Mohammad Marhabaie, Meethila Gade, Jinfeng Lu, Olga Rodziyevska, Meenakshi B Bhattacharjee, Gretchen K Von Allmen, Edward Yang, Hart G W Lidov, Chellamani Harini, Manish N Shah, Jeffrey Leonard, Jonathan Pindrik, Ammar Shaikhouni, James E Goldman, Christopher R Pierson, Diana L Thomas, Daniel R Boué, Adam P Ostendorf, Elaine R Mardis, Annapurna Poduri, Daniel C Koboldt, Erin L Heinzen, Tracy A Bedrosian

Faculty, Staff and Student Publications

Somatic mosaicism is a known cause of neurological disorders, including developmental brain malformations and epilepsy. Brain mosaicism is traditionally attributed to post-zygotic genetic alterations arising in fetal development. Here we describe post-zygotic rescue of meiotic errors as an alternate origin of brain mosaicism in patients with focal epilepsy who have mosaic chromosome 1q copy number gains. Genomic analysis showed evidence of an extra parentally derived chromosome 1q allele in the resected brain tissue from five of six patients. This copy number gain is observed only in patient brain tissue, but not in blood or buccal cells, and is strongly enriched …

Interplay Of Hypoxia-Inducible Factors And Oxygen Therapy In Cardiovascular Medicine, Yafen Liang, Wei Ruan, Yandong Jiang, Richard Smalling, Xiaoyi Yuan, Holger K Eltzschig

Faculty, Staff and Student Publications

Mammals have evolved to adapt to differences in oxygen availability. Although systemic oxygen homeostasis relies on respiratory and circulatory responses, cellular adaptation to hypoxia involves the transcription factor hypoxia-inducible factor (HIF). Given that many cardiovascular diseases involve some degree of systemic or local tissue hypoxia, oxygen therapy has been used liberally over many decades for the treatment of cardiovascular disorders. However, preclinical research has revealed the detrimental effects of excessive use of oxygen therapy, including the generation of toxic oxygen radicals or attenuation of endogenous protection by HIFs. In addition, investigators in clinical trials conducted in the past decade have …

Interplay Between Epigenetic And Genetic Alterations In Inborn Errors Of Immunity, Javier Rodríguez-Ubreva, Celia L Calvillo, Lisa R Forbes Satter, Esteban Ballestar

Faculty, Staff and Students Publications

Inborn errors of immunity (IEIs) comprise a variety of immune conditions leading to infections, autoimmunity, allergy, and cancer. Some IEIs have no identified mutation(s), while others with identical mutations can display heterogeneous presentations. These observations suggest the involvement of epigenetic mechanisms. Epigenetic alterations can arise from downstream activation of cellular pathways through both extracellular stimulation and genetic-associated changes, impacting epigenetic enzymes or their interactors. Therefore, we posit that epigenetic alterations and genetic defects do not exclude each other as a disease-causing etiology. In this opinion, encompassing both basic and clinical viewpoints, we focus on selected IEIs with mutations in transcription …

Effectiveness Of Icosapent Ethyl On First And Total Cardiovascular Events In Patients With Metabolic Syndrome, But Without Diabetes: Reduce-It Metsyn, Michael Miller, Deepak L Bhatt, Eliot A Brinton, Terry A Jacobson, Philippe Gabriel Steg, Armando Lira Pineda, Steven B Ketchum, Ralph T Doyle, Jean-Claude Tardif, Christie M Ballantyne

Faculty, Staff and Students Publications

Aims: Metabolic syndrome (MetSyn) is associated with high risk of cardiovascular (CV) events, irrespective of statin therapy. In the overall REDUCE-IT study of statin-treated patients, icosapent ethyl (IPE) reduced the risk of the primary composite endpoint (CV death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or unstable angina requiring hospitalization) and the key secondary composite endpoint (CV death, non-fatal myocardial infarction, or non-fatal stroke).

Methods and results: REDUCE-IT was an international, double-blind trial that randomized 8179 high CV risk statin-treated patients with controlled LDL cholesterol and elevated triglycerides, to IPE 4 g/day or placebo. The current study evaluated the pre-specified …

The Development, Content And Response Process Validation Of A Caregiver-Reported Severity Measure For Cdkl5 Deficiency Disorder, Sonja I Ziniel, Alexandra Mackie, Jacinta Saldaris, Helen Leonard, Peter Jacoby, Eric D Marsh, Bernhard Suter, Elia Pestana-Knight, Heather E Olson, Dana Price, Judith Weisenberg, Rajsekar Rajaraman, Gina Vanderveen, Tim A Benke, Jenny Downs, Scott Demarest

Faculty, Staff and Students Publications

BACKGROUND: CDKL5 Deficiency Disorder (CDD) is a severe X-linked developmental and epileptic encephalopathy. Existing developmental outcome measures have floor effects and cannot capture incremental changes in symptoms. We modified the caregiver portion of a CDD clinical severity assessment (CCSA) and assessed content and response-process validity.

METHODS: We conducted cognitive interviews with 15 parent caregivers of 1-39-year-old children with CDD. Caregivers discussed their understanding and concerns regarding appropriateness of both questions and answer options. Item wording and questionnaire structure were adjusted iteratively to ensure questions were understood as intended.

RESULTS: The CCSA was refined during three rounds of cognitive interviews into …

Understanding And Managing Anxiety Sensitivity During Critical Illness And Long-Term Recovery, Leanne M Boehm, Claire M Bird, Ann Marie Warren, Valerie Danesh, Megan M Hosey, Joanne Mcpeake, Kelly M Potter, Han Su, Tammy L Eaton, Mark B Powers

Faculty, Staff and Students Publications

Anxiety sensitivity is a fear of symptoms associated with anxiety (eg, rapid respiration and heart rate, perspiration), also known as "fear of fear." This fear is a misinterpretation of nonthreatening symptoms as threatening across 3 domains: physical ("When my heart rate increases, I'm afraid I may have a heart attack"), social ("If people see me perspire, I fear they will negatively evaluate me"), and cognitive ("When I feel these symptoms, I fear it means I'm going crazy or will lose control and do something dangerous like disconnect my IV"). These thoughts stimulate the sympathetic nervous system, resulting in stronger sensations …

Feasibility Of A Dietary Intervention To Modify Gut Microbial Metabolism In Patients With Hematopoietic Stem Cell Transplantation, Mary M Riwes, Jonathan L Golob, John Magenau, Mengrou Shan, Gregory Dick, Thomas Braun, Thomas M Schmidt, Attaphol Pawarode, Sarah Anand, Monalisa Ghosh, John Maciejewski, Darren King, Sung Choi, Gregory Yanik, Marcus Geer, Ethan Hillman, Costas A Lyssiotis, Muneesh Tewari, Pavan Reddy

Faculty, Staff and Students Publications

Evaluation of the impact of dietary intervention on gastrointestinal microbiota and metabolites after allogeneic hematopoietic stem cell transplantation (HCT) is lacking. We conducted a feasibility study as the first of a two-phase trial. Ten adults received resistant potato starch (RPS) daily from day −7 to day 100. The primary objective was to test the feasibility of RPS and its effect on intestinal microbiome and metabolites, including the short-chain fatty acid butyrate. Feasibility met the preset goal of 60% or more, adhering to 70% or more doses; fecal butyrate levels were significantly higher when participants were on RPS than when they …

Research Priorities For Pediatric Emergency Care To Address Disparities By Race, Ethnicity, And Language, Elyse N Portillo, Chris A Rees, Emily A Hartford, Zachary C Foughty, Michelle L Pickett, Colleen K Gutman, Bashar S Shihabuddin, Eric W Fleegler, Corrie E Chumpitazi, Tiffani J Johnson, David Schnadower, Kathy N Shaw

Faculty, Staff and Students Publications

IMPORTANCE: Health care disparities are well-documented among children based on race, ethnicity, and language for care. An agenda that outlines research priorities for disparities in pediatric emergency care (PEC) is lacking.

OBJECTIVE: To investigate research priorities for disparities in PEC among medical personnel, researchers, and health care-affiliated community organizations.

DESIGN, SETTING, AND PARTICIPANTS: In this survey study, a modified Delphi approach was used to investigate research priorities for disparities in PEC. An initial list of research priorities was developed by a group of experienced PEC investigators in 2021. Partners iteratively assessed the list through 2 rounds of electronic surveys using …

P2y2 Purinergic Receptor Gene Deletion Protects Mice From Bacterial Endotoxin And Sepsis-Associated Liver Injury And Mortality, Athis R Arunachalam, Sanju S Samuel, Arunmani Mani, Janielle P Maynard, Kelsey M Stayer, Eric Dybbro, Subapradha Narayanan, Aalekhya Biswas, Saliha Pathan, Krishnakant Soni, Abu Hena Mostafa Kamal, Chandra Shekar R Ambati, Nagireddy Putluri, Moreshwar S Desai, Sundararajah Thevananther

Faculty, Staff and Students Publications

The liver plays a significant role in regulating a wide range of metabolic, homeostatic, and host-defense functions. However, the impact of liver injury on the host's ability to control bacteremia and morbidity in sepsis is not well understood. Leukocyte recruitment and activation lead to cytokine and chemokine release, which, in turn, trigger hepatocellular injury and elevate nucleotide levels in the extracellular milieu. P2Y2 purinergic receptors, G protein-coupled and activated by extracellular ATP/UTP, are expressed at the cell surface of hepatocytes and nonparenchymal cells. We sought to determine whether P2Y2 purinergic receptor function is necessary for the maladaptive host response to …

Pediatric Microsurgery And Free-Tissue Transfer, Heather R Burns, Anna J Skochdopole, Richardo Alfaro Zeledon, William C Pederson

Faculty, Staff and Students Publications

Advancements in microsurgery, along with increased microsurgical experience in pediatric patients, have made free-tissue transfer a reliable modality for pediatric bone and soft tissue reconstruction today. Free-tissue transfer is most commonly used in children for the coverage of large or complex defects resulting from traumatic, oncologic, or congenital etiologies. While flap success and complication rates between pediatric and adult populations are similar, special considerations must be taken into account within the pediatric population. In this article, we will describe common indications, technical nuances, and clinical considerations for the management of the pediatric free-tissue transfer patient.

Anthocyanins: Molecular Aspects On Their Neuroprotective Activity, César A Zaa, Álvaro J Marcelo, Zhiqiang An, José L Medina-Franco, Marco A Velasco-Velázquez

Faculty, Staff and Student Publications

Anthocyanins are a type of flavonoids that give plants and fruits their vibrant colors. They are known for their potent antioxidant properties and have been linked to various health benefits. Upon consumption, anthocyanins are quickly absorbed and can penetrate the blood-brain barrier (BBB). Research based on population studies suggests that including anthocyanin-rich sources in the diet lower the risk of neurodegenerative diseases. Anthocyanins exhibit neuroprotective effects that could potentially alleviate symptoms associated with such diseases. In this review, we compiled and discussed a large body of evidence supporting the neuroprotective role of anthocyanins. Our examination encompasses human studies, animal models, …

The Influence Of Obesity On Outcomes With Immune Checkpoint Blockade: Clinical Evidence And Potential Biological Mechanisms, Andrew W Hahn, Neha Venkatesh, Pavlos Msaouel, Jennifer L Mcquade

Faculty, Staff and Student Publications

Immune checkpoint blockade (ICB) is a mainstay of treatment for advanced cancer, yet tumor response and host toxicity are heterogenous in those patients who receive ICB. There is growing interest in understanding how host factors interact with tumor intrinsic properties and the tumor microenvironment to influence the therapeutic index with ICB. Obesity, defined by body mass index, is a host factor associated with improved outcomes in select cancers when treated with ICB. While the biological mechanism for this obesity paradox is not fully understood, pre-clinical and translational studies suggest obesity may potentially impact tumor metabolism, inflammation, and angiogenesis. Herein, we …

Correction: Microrna 603 Acts As A Tumor Suppressor And Inhibits Triple-Negative Breast Cancer Tumorigenesis By Targeting Elongation Factor 2 Kinase, Recep Bayraktar, Martin Pichler, Pinar Kanlikilicer, Cristina Ivan, Emine Bayraktar, Nermin Kahraman, Burcu Aslan, Serpil Oguztuzun, Mustafa Ulasli, Ahmet Arslan, George Calin, Gabriel Lopez-Berestein, Bulent Ozpolat

Faculty, Staff and Student Publications

No abstract provided.

Sdc1 And Itga2 As Novel Prognostic Biomarkers For Pdac Related To Ipmn, Chuan-Long Zhang, Qian Shen, Fu-Dong Liu, Fan Yang, Meng-Qi Gao, Xiao-Chen Jiang, Yi Li, Xi-Yuan Zhang, Ge-Er En, Xue Pan, Bo Pang

Faculty, Staff and Student Publications

The existing biomarkers are insufficient for predicting the prognosis of pancreatic ductal adenocarcinoma (PDAC). Intraductal papillary mucinous neoplasm (IPMN) is a precursor to PDAC; therefore, identifying biomarkers from differentially expressed genes (DEGs) of PDAC and IPMN is a new and reliable strategy for predicting the prognosis of PDAC. In this study, four datasets were downloaded from the Gene Expression Omnibus database and standardized using the R package 'limma.' A total of 51 IPMN and 81 PDAC samples were analyzed, and 341 DEGs in PDAC and IPMN were identified; DEGs were involved in the extracellular matrix and tumor microenvironment. An acceptable …

Toll-Like Receptor 4 And Cd11b Expressed On Microglia Coordinate Eradication Of Candida Albicans Cerebral Mycosis, Yifan Wu, Shuqi Du, Lynn H Bimler, Kelsey E Mauk, Léa Lortal, Nessim Kichik, James S Griffiths, Radim Osicka, Lizhen Song, Katherine Polsky, Lydia Kasper, Peter Sebo, Jill Weatherhead, J Morgan Knight, Farrah Kheradmand, Hui Zheng, Jonathan P Richardson, Bernhard Hube, Julian R Naglik, David B Corry

Faculty, Staff and Students Publications

The fungal pathogen Candida albicans is linked to chronic brain diseases such as Alzheimer's disease (AD), but the molecular basis of brain anti-Candida immunity remains unknown. We show that C. albicans enters the mouse brain from the blood and induces two neuroimmune sensing mechanisms involving secreted aspartic proteinases (Saps) and candidalysin. Saps disrupt tight junction proteins of the blood-brain barrier (BBB) to permit fungal brain invasion. Saps also hydrolyze amyloid precursor protein (APP) into amyloid β (Aβ)-like peptides that bind to Toll-like receptor 4 (TLR4) and promote fungal killing in vitro while candidalysin engages the integrin CD11b (Mac-1) on microglia. …

Braf Inhibitors In Metastatic Colorectal Cancer And Mechanisms Of Resistance: A Review Of The Literature, Patricia Guerrero, Víctor Albarrán, María San Román, Carlos González-Merino, Coral García De Quevedo, Jaime Moreno, Juan Carlos Calvo, Guillermo González, Inmaculada Orejana, Jesús Chamorro, Íñigo Martínez-Delfrade, Blanca Morón, Belén De Frutos, María Reyes Ferreiro

Faculty, Staff and Students Publications

Metastatic colorectal cancer (mCRC) with mutated BRAF exhibits distinct biological and molecular features that set it apart from other subtypes of CRC. Current standard treatment for these tumors involves a combination of chemotherapy (CT) and VEGF inhibitors. Recently, targeted therapy against BRAF and immunotherapy (IT) for cases with microsatellite instability (MSI) have been integrated into clinical practice. While targeted therapy has shown promising results, resistance to treatment eventually develops in a significant portion of responsive patients. This article aims to review the available literature on mechanisms of resistance to BRAF inhibitors (BRAFis) and potential therapeutic strategies to overcome them.

A Small-Molecule Inhibitor Of Topbp1 Exerts Anti-Myc Activity And Synergy With Parp Inhibitors, Fang-Tsyr Lin, Kang Liu, Lidija A Wilhelms Garan, Helena Folly-Kossi, Yongcheng Song, Shwu-Jiuan Lin, Weei-Chin Lin

Faculty, Staff and Students Publications

We have previously identified TopBP1 (topoisomerase IIβ-binding protein 1) as a promising target for cancer therapy, given its role in the convergence of Rb, PI(3)K/Akt, and p53 pathways. Based on this, we conducted a large-scale molecular docking screening to identify a small-molecule inhibitor that specifically targets the BRCT7/8 domains of TopBP1, which we have named 5D4. Our studies show that 5D4 inhibits TopBP1 interactions with E2F1, mutant p53, and Cancerous Inhibitor of Protein Phosphatase 2A. This leads to the activation of E2F1-mediated apoptosis and the inhibition of mutant p53 gain of function. In addition, 5D4 disrupts the interaction of TopBP1 …

Ligand-Displaying Escherichia Coli Cells And Minicells For Programmable Delivery Of Toxic Payloads Via Type Iv Secretion Systems, Yang Grace Li, Kouhei Kishida, Natsumi Ogawa-Kishida, Peter J Christie

Faculty, Staff and Student Publications

Bacterial type IV secretion systems (T4SSs) are highly versatile macromolecular translocators and offer great potential for deployment as delivery systems for therapeutic intervention. One major T4SS subfamily, the conjugation machines, are well-adapted for delivery of DNA cargoes of interest to other bacteria or eukaryotic cells but generally exhibit modest transfer frequencies and lack specificity for target cells. Here, we tested the efficacy of a surface-displayed nanobody/antigen (Nb/Ag) pairing system to enhance the conjugative transfer of IncN (pKM101), IncF (F/pOX38), or IncP (RP4) plasmids, or of mobilizable plasmids including those encoding CRISPR/Cas9 systems (pCrispr), to targeted recipient cells. Escherichia coli donors …

Early Antibody Treatment, Inflammation, And Risk Of Post-Covid Conditions, Kelly A Gebo, Sonya L Heath, Yuriko Fukuta, Xianming Zhu, Sheriza Baksh, Allison G Abraham, Feben Habtehyimer, David Shade, Jessica Ruff, Malathi Ram, Oliver Laeyendecker, Reinaldo E Fernandez, Eshan U Patel, Owen R Baker, Shmuel Shoham, Edward R Cachay, Judith S Currier, Jonathan M Gerber, Barry Meisenberg, Donald N Forthal, Laura L Hammitt, Moises A Huaman, Adam Levine, Giselle S Mosnaim, Bela Patel, James H Paxton, Jay S Raval, Catherine G Sutcliffe, Shweta Anjan, Thomas Gniadek, Seble Kassaye, Janis E Blair, Karen Lane, Nichol A Mcbee, Amy L Gawad, Piyali Das, Sabra L Klein, Andrew Pekosz, Evan M Bloch, Daniel Hanley, Arturo Casadevall, Aaron A R Tobian, David J Sullivan, Cssc-004 Consortium

Faculty, Staff and Students Publications

Post-COVID conditions (PCCs) are common and have significant morbidity. Risk factors for PCC include advancing age, female sex, obesity, and diabetes mellitus. Little is known about treatment, inflammation, and PCC. Among 882 individuals with confirmed SARS-CoV-2 infection participating in a randomized trial of COVID-19 convalescent plasma (CCP) vs control plasma with available biospecimens and symptom data, the association between early CCP treatment, cytokine levels, and PCC was evaluated. Cytokine and chemokine levels were assessed at baseline, day 14, and day 90 using a multiplexed sandwich immunoassay (Meso Scale Discovery). Presence of any self-reported PCC symptoms was assessed at day 90. …

Tgf-Β1 In Aplysia: Role In Long-Term Changes In The Excitability Of Sensory Neurons And Distribution Of Tβr-Ii-Like Immunoreactivity, Muhammad S Khan, Eun Kim, Quentin Le Hingrat, Adam Kleinman, Alessandro Ferrari, Jose C Sammartino, Elena Percivalle, Cuiling Xu, Shaohua Huang, Thomas W Kenniston, Irene Cassaniti, Fausto Baldanti, Ivona Pandrea, Andrea Gambotto, Cristian Apetrei

Faculty, Staff and Student Publications

The study provides important insights into the immunogenicity and efficacy of a tetravalent protein subunit vaccine candidate against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The vaccine induced both humoral and cellular immune responses in nonhuman primates with controlled SIVagm infection and was able to generate Omicron variant-specific antibodies without specifically vaccinating with Omicron. These findings suggest that the tetravalent composition of the vaccine candidate could provide broad protection against multiple SARS-CoV-2 variants while minimizing the risk of immune escape and the emergence of new variants. Additionally, the use of rhesus macaques with controlled SIVsab infection may better represent vaccine …

Constitutive Interleukin-7 Cytokine Signaling Enhances The Persistence Of Epstein-Barr Virus-Specific T-Cells, Sandhya Sharma, Tim Sauer, Bilal A Omer, Thomas Shum, Lisa A Rollins, Cliona M Rooney

Faculty, Staff and Students Publications

The efficacy of therapeutic T-cells is limited by a lack of positive signals and excess inhibitory signaling in tumor microenvironments. We previously showed that a constitutively active IL7 receptor (C7R) enhanced the persistence, expansion, and anti-tumor activity of T-cells expressing chimeric antigen receptors (CARs), and C7R-modified GD2.CAR T-cells are currently undergoing clinical trials. To determine if the C7R could also enhance the activity of T-cells recognizing tumors via their native T-cell receptors (TCRs), we evaluated its effects in Epstein–Barr virus (EBV)-specific T-cells (EBVSTs) that have produced clinical benefits in patients with EBV-associated malignancies. EBVSTs were generated by stimulation of peripheral …

Returning Incidentally Discovered Hepatitis C Rna-Seq Results To Copdgene Study Participants, Edwin K Silverman, Arthur Y Kim, Barry J Make, Elizabeth A Regan, Jarrett D Morrow, Craig P Hersh, James O'Brien, James D Crapo, Nadia N Hansel, Gerard Criner, Eric L Flenaugh, Douglas Conrad, Richard Casaburi, Russell P Bowler, Nicola A Hanania, R Graham Barr, Surya P Bhatt, Frank C Sciurba, Antonio Anzueto, Meilan K Han, Charlene E Mcevoy, Alejandro P Comellas, Dawn L Demeo, Richard Rosiello, Jeffrey L Curtis, Tricia Uchida, Carla Wilson, P Pearl O'Rourke

Faculty, Staff and Students Publications

The consequences of returning infectious pathogen test results identified incidentally in research studies have not been well-studied. Concerns include identification of an important health issue for individuals, accuracy of research test results, public health impact, potential emotional distress for participants, and need for IRB permissions. Blood RNA-sequencing analysis for non-human RNA in 3984 participants from the COPDGene study identified 228 participants with evidence suggestive for hepatitis C virus (HCV) infection. We hypothesized that incidentally discovered HCV results could be effectively returned to COPDGene participants with attention to the identified concerns. In conjunction with a COPDGene Participant Advisory Panel, we developed …

Mga-Seq: Robust Identification Of Extrachromosomal Dna And Genetic Variants Using Multiple Genetic Abnormality Sequencing, Da Lin, Yanyan Zou, Xinyu Li, Jinyue Wang, Qin Xiao, Xiaochen Gao, Fei Lin, Ningyuan Zhang, Ming Jiao, Yu Guo, Zhaowei Teng, Shiyi Li, Yongchang Wei, Fuling Zhou, Rong Yin, Siheng Zhang, Lingyu Xing, Weize Xu, Xiaofeng Wu, Bing Yang, Ke Xiao, Chengchao Wu, Yingfeng Tao, Xiaoqing Yang, Jing Zhang, Sheng Hu, Shuang Dong, Xiaoyu Li, Shengwei Ye, Zhidan Hong, Yihang Pan, Yuqin Yang, Haixiang Sun, Gang Cao

Children’s Nutrition Research Center Staff Publications

Genomic abnormalities are strongly associated with cancer and infertility. In this study, we develop a simple and efficient method - multiple genetic abnormality sequencing (MGA-Seq) - to simultaneously detect structural variation, copy number variation, single-nucleotide polymorphism, homogeneously staining regions, and extrachromosomal DNA (ecDNA) from a single tube. MGA-Seq directly sequences proximity-ligated genomic fragments, yielding a dataset with concurrent genome three-dimensional and whole-genome sequencing information, enabling approximate localization of genomic structural variations and facilitating breakpoint identification. Additionally, by utilizing MGA-Seq, we map focal amplification and oncogene coamplification, thus facilitating the exploration of ecDNA's transcriptional regulatory function.

Recent Advances In The Synthesis And Antioxidant Activity Of Low Molecular Mass Organoselenium Molecules, João M Anghinoni, Paloma T Birmann, Marcia J Da Rocha, Caroline S Gomes, Michael J Davies, César A Brüning, Lucielli Savegnago, Eder J Lenardão

Faculty, Staff and Student Publications

Selenium is an essential trace element in living organisms, and is present in selenoenzymes with antioxidant activity, like glutathione peroxidase (GPx) and thioredoxin reductase (TrxR). The search for small selenium-containing molecules that mimic selenoenzymes is a strong field of research in organic and medicinal chemistry. In this review, we review the synthesis and bioassays of new and known organoselenium compounds with antioxidant activity, covering the last five years. A detailed description of the synthetic procedures and the performed in vitro and in vivo bioassays is presented, highlighting the most active compounds in each series.

Association Of Dcis Size And Margin Status With Risk Of Developing Breast Cancer Post-Treatment: Multinational, Pooled Cohort Study, Renée S J M Schmitz, Alexandra W Van Den Belt-Dusebout, Karen Clements, Yi Ren, Chiara Cresta, Jasmine Timbres, Yat-Hee Liu, Danalyn Byng, Thomas Lynch, Brian A Menegaz, Deborah Collyar, Terry Hyslop, Samantha Thomas, Jason K Love, Michael Schaapveld, Proteeti Bhattacharjee, Marc D Ryser, Elinor Sawyer, E Shelley Hwang, Alastair Thompson, Jelle Wesseling, Esther H Lips, Marjanka K Schmidt

Faculty, Staff and Student Publications

OBJECTIVE: To examine the association between size and margin status of ductal carcinoma in situ (DCIS) and risk of developing ipsilateral invasive breast cancer and ipsilateral DCIS after treatment, and stage and subtype of ipsilateral invasive breast cancer.

DESIGN: Multinational, pooled cohort study.

SETTING: Four large international cohorts.

PARTICIPANTS: Patient level data on 47 695 women with a diagnosis of pure, primary DCIS between 1999 and 2017 in the Netherlands, UK, and US who underwent surgery, either breast conserving or mastectomy, often followed by radiotherapy or endocrine treatment, or both.

MAIN OUTCOME MEASURES: The main outcomes were 10 year cumulative …

Diaph1-Mfn2 Interaction Regulates Mitochondria-Sr/Er Contact And Modulates Ischemic/Hypoxic Stress, Gautham Yepuri, Lisa M Ramirez, Gregory G Theophall, Sergei V Reverdatto, Nosirudeen Quadri, Syed Nurul Hasan, Lei Bu, Devi Thiagarajan, Robin Wilson, Raquel López Díez, Paul F Gugger, Kaamashri Mangar, Navneet Narula, Stuart D Katz, Boyan Zhou, Huilin Li, Aleksandr B Stotland, Roberta A Gottlieb, Ann Marie Schmidt, Alexander Shekhtman, Ravichandran Ramasamy

Faculty, Staff and Student Publications

Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. …

Enolase Inhibitors As Early Lead Therapeutics Against Trypanosoma Brucei, Colm P Roster, Danielle Lavigne, Jillian E Milanes, Emily Knight, Heidi D Anderson, Sabrina Pizarro, Elijah M Harding, Meredith T Morris, Victoria C Yan, Cong-Dat Pham, Florian Muller, Samuel Kwain, Kerrick C Rees, Brian Dominy, Daniel C Whitehead, Md Nasir Uddin, Steven W Millward, James C Morris

Faculty, Staff and Student Publications

Glucose metabolism is critical for the African trypanosome, Trypanosoma brucei, serving as the lone source of ATP production for the bloodstream form (BSF) parasite in the glucose-rich environment of the host blood. Recently, phosphonate inhibitors of human enolase (ENO), the enzyme responsible for the interconversion of 2-phosphoglycerate (2-PG) to phosphoenolpyruvate (PEP) in glycolysis or PEP to 2-PG in gluconeogenesis, have been developed for the treatment of glioblastoma multiforme (GBM). Here, we have tested these agents against T. brucei ENO (TbENO) and found the compounds to be potent enzyme inhibitors and trypanocides. For example, (1-hydroxy-2-oxopyrrolidin-3-yl) phosphonic acid (deoxy-SF2312) …

The Lin28b/Wnt5a Axis Drives Pancreas Cancer Through Crosstalk Between Cancer Associated Fibroblasts And Tumor Epithelium, Zhaoqi Shu, Minghe Fan, Bo Tu, Zhiheng Tang, Haojie Wang, Haimeng Li, Hengchao Li, Meng Yuan, Jingru Bai, Sihan Huo, Lina Wang, Wei-Guo Zhu, Wei Wang, Xiaoyun Liu, Shaokun Shu, Ying Zhao

Faculty, Staff and Student Publications

Bidirectional signal transduction between tumor epithelial cells and tumor microenvironment (TME) is important for tumor development. Here we show that Lin28b/let-7 pathway is indispensable for modulating the expression of Wnt5a in tumor epithelium, which could be secreted and then up-regulates Lin28b in cancer-associated fibroblasts (CAFs). Moreover, we demonstrate that Lin28b in CAFs promoted growth of PDAC by inducing cytokine PCSK9's production. Using an orthotopic mouse model of PDAC, we find that depletion of Lin28b in CAFs reduced tumor weight, highlighting the importance of Lin28b in PDAC stroma. Thus, our study shows that the Lin28b-Wnt5a axis plays a critical role in …

Wastewater Sequencing Reveals Community And Variant Dynamics Of The Collective Human Virome, Michael Tisza, Sara Javornik Cregeen, Vasanthi Avadhanula, Ping Zhang, Tulin Ayvaz, Karen Feliz, Kristi L Hoffman, Justin R Clark, Austen Terwilliger, Matthew C Ross, Juwan Cormier, Hannah Moreno, Li Wang, Katelyn Payne, David Henke, Catherine Troisi, Fuqing Wu, Janelle Rios, Jennifer Deegan, Blake Hansen, John Balliew, Anna Gitter, Kehe Zhang, Runze Li, Cici X Bauer, Kristina D Mena, Pedro A Piedra, Joseph F Petrosino, Eric Boerwinkle, Anthony W Maresso

Faculty, Staff and Student Publications

Wastewater is a discarded human by-product, but its analysis may help us understand the health of populations. Epidemiologists first analyzed wastewater to track outbreaks of poliovirus decades ago, but so-called wastewater-based epidemiology was reinvigorated to monitor SARS-CoV-2 levels while bypassing the difficulties and pit falls of individual testing. Current approaches overlook the activity of most human viruses and preclude a deeper understanding of human virome community dynamics. Here, we conduct a comprehensive sequencing-based analysis of 363 longitudinal wastewater samples from ten distinct sites in two major cities. Critical to detection is the use of a viral probe capture set targeting …