35 results on '"Raghu R. Chivukula"'
Search Results
2. Rethinking the Physician–Scientist Pathway
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Neir Eshel and Raghu R. Chivukula
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Biomedical Research ,Career Choice ,National Institutes of Health (U.S.) ,Physicians ,Humans ,Internship and Residency ,General Medicine ,Schools, Medical ,United States ,Education - Abstract
Physician-scientists have the potential to generate fundamental as well as translational breakthroughs. But many trainees who intend to pursue a hybrid career in research and patient care ultimately leave one or the other behind. In this Invited Commentary, the authors draw from their experience as early-career physician-scientists to frame physician-scientist training as having 2 phases: first, learning to think like a physician-scientist; second, learning to act like a physician-scientist. These phases roughly correspond to (1) clinical training (from medical school through residency or fellowship) that incorporates research exposure, and (2) a structured period of graduated research independence once the physician-scientist has become clinically autonomous. There are many effective ways to pursue each phase; what matters most is flexibility in the first phase and sustained support in the second. Accordingly, the authors suggest many potential reforms, including at the levels of the National Institutes of Health, private funders, as well as universities and research hospitals. The authors argue that rethinking physician-scientist training to support individualized paths to an independent hybrid career can help recruit and retain physician-scientists for years to come.
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- 2022
3. Cystic Fibrosis and the Cells of the Airway Epithelium: What Are Ionocytes and What Do They Do?
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Brian M. Lin, Raghu R. Chivukula, Jayaraj Rajagopal, Avinash Waghray, and Viral Shah
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Cystic Fibrosis ,Cell ,Cystic Fibrosis Transmembrane Conductance Regulator ,Epithelial Cells ,respiratory system ,Biology ,medicine.disease ,Cystic fibrosis ,Epithelium ,Cystic fibrosis transmembrane conductance regulator ,Pathology and Forensic Medicine ,Cell biology ,Pathogenesis ,Mice ,medicine.anatomical_structure ,medicine ,biology.protein ,Animals ,Humans ,Epithelial Physiology ,Respiratory epithelium ,Inner ear - Abstract
Cystic fibrosis (CF) is caused by defects in an anion channel, the cystic fibrosis transmembrane conductance regulator (CFTR). Recently, a new airway epithelial cell type has been discovered and dubbed the pulmonary ionocyte. Unexpectedly, these ionocytes express higher levels of CFTR than any other airway epithelial cell type. However, ionocytes are not the sole CFTR-expressing airway epithelial cells, and CF-associated disease genes are in fact expressed in multiple airway epithelial cell types. The experimental depletion of ionocytes perturbs epithelial physiology in the mouse trachea, but the role of these rare cells in the pathogenesis of human CF remains mysterious. Ionocytes have been described in diverse tissues (kidney and inner ear) and species (frog and fish). We draw on these prior studies to suggest potential roles of airway ionocytes in health and disease. A complete understanding of ionocytes in the mammalian airway will ultimately depend on cell type-specific genetic manipulation Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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- 2022
4. Evidence-Based Management of the Critically Ill Adult With SARS-CoV-2 Infection
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Jason H. Maley, Kathryn A. Hibbert, Raghu R. Chivukula, C. Corey Hardin, and David M. Dudzinski
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Adult ,medicine.medical_specialty ,ARDS ,Critical Care ,Critical Illness ,Disease ,030204 cardiovascular system & hematology ,Critical Care and Intensive Care Medicine ,medicine.disease_cause ,Hypoxemia ,03 medical and health sciences ,0302 clinical medicine ,Intensive care ,medicine ,Humans ,030212 general & internal medicine ,Intensive care medicine ,Coronavirus ,business.industry ,COVID-19 ,Evidence-based management ,medicine.disease ,Triage ,Evidence-Based Practice ,medicine.symptom ,Respiratory Insufficiency ,Multiple organ dysfunction syndrome ,business - Abstract
Human infection by the novel viral pathogen SARS-CoV-2 results in a clinical syndrome termed Coronavirus Disease 2019 (COVID-19). Although the majority of COVID-19 cases are self-limiting, a substantial minority of patients develop disease severe enough to require intensive care. Features of critical illness associated with COVID-19 include hypoxemic respiratory failure, acute respiratory distress syndrome (ARDS), shock, and multiple organ dysfunction syndrome (MODS). In most (but not all) respects critically ill patients with COVID-19 resemble critically ill patients with ARDS due to other causes and are optimally managed with standard, evidence-based critical care protocols. However, there is naturally an intense interest in developing specific therapies for severe COVID-19. Here we synthesize the rapidly expanding literature around the pathophysiology, clinical presentation, and management of COVID-19 with a focus on those points most relevant for intensivists tasked with caring for these patients. We specifically highlight evidence-based approaches that we believe should guide the identification, triage, respiratory support, and general ICU care of critically ill patients infected with SARS-CoV-2. In addition, in light of the pressing need and growing enthusiasm for targeted COVID-19 therapies, we review the biological basis, plausibility, and clinical evidence underlying these novel treatment approaches.
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- 2020
5. The Fast Literature Assessment and Review (FLARE) Initiative. A Collaborative Effort for Timely Literature Appraisal during the Coronavirus Disease Pandemic
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David M. Dudzinski, Raghu R. Chivukula, C. Corey Hardin, Jason H. Maley, Laura N. Brenner, Vladimir Vinarsky, Camille R. Petri, and Tiara F. Calhoun
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2019-20 coronavirus outbreak ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,business.industry ,viruses ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,virus diseases ,Review Literature as Topic ,review literature as topic ,COVID-19 ,General Medicine ,Disease ,medicine.disease_cause ,critical care ,coronavirus disease ,Pandemic ,medicine ,Innovations ,Intensive care medicine ,business ,Coronavirus ,Healthcare system - Abstract
The emergence and worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused major disruptions to the healthcare system and medical education. In response, the scientific community has been acquiring, releasing, and publishing data at a remarkable pace. At the same time, medical practitioners are taxed with greater professional duties than ever before, making it challenging to stay current with the influx of medical literature. To address the above mismatch between data release and provider capacity and to support our colleagues, physicians at the Massachusetts General Hospital have engaged in an electronic collaborative effort focused on rapid literature appraisal and dissemination regarding SARS-CoV-2 with a focus on critical care. Members of the Division of Pulmonary and Critical Care, the Division of Cardiology, and the Department of Medicine at Massachusetts General Hospital established the Fast Literature Assessment and Review (FLARE) team. This group rapidly compiles, appraises, and synthesizes literature regarding SARS-CoV-2 as it pertains to critical care, relevant clinical questions, and anecdotal reports. Daily, FLARE produces and disseminates highly curated scientific reviews and opinion pieces, which are distributed to readers using an online newsletter platform. Interest in our work has escalated rapidly. FLARE was quickly shared with colleagues outside our division, and, in a short time, our audience has grown to include more than 4,000 readers across the globe. Creating a collaborative group with a variety of expertise represents a feasible and acceptable way of rapidly appraising, synthesizing, and communicating scientific evidence directly to frontline clinicians in this time of great need.
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- 2020
6. A human ciliopathy reveals essential functions for NEK10 in airway mucociliary clearance
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Patrick R. Sears, Hanan E. Shamseldin, Heymut Omran, Katharine E. Black, Maimoona A. Zariwala, Vladimir Vinarsky, Evgeni M. Frenkel, David M. Sabatini, Hui Min Leung, Fowzan S. Alkuraya, Michael R. Knowles, Guillermo J. Tearney, Lida P. Hariri, M. Leigh Anne Daniels, Jason H. Yang, Martin S. Taylor, Raghu R. Chivukula, Johnny L. Carson, Ibrahim Almogarri, Daniel T. Montoro, and Gerard W. Dougherty
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0301 basic medicine ,Cell type ,biology ,Mucociliary clearance ,General Medicine ,medicine.disease ,Cystic fibrosis ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cystic fibrosis transmembrane conductance regulator ,Cell biology ,03 medical and health sciences ,Ciliopathy ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,medicine ,biology.protein ,Motile cilium ,Stem cell ,Primary ciliary dyskinesia - Abstract
Mucociliary clearance, the physiological process by which mammalian conducting airways expel pathogens and unwanted surface materials from the respiratory tract, depends on the coordinated function of multiple specialized cell types, including basal stem cells, mucus-secreting goblet cells, motile ciliated cells, cystic fibrosis transmembrane conductance regulator (CFTR)-rich ionocytes, and immune cells1,2. Bronchiectasis, a syndrome of pathological airway dilation associated with impaired mucociliary clearance, may occur sporadically or as a consequence of Mendelian inheritance, for example in cystic fibrosis, primary ciliary dyskinesia (PCD), and select immunodeficiencies3. Previous studies have identified mutations that affect ciliary structure and nucleation in PCD4, but the regulation of mucociliary transport remains incompletely understood, and therapeutic targets for its modulation are lacking. Here we identify a bronchiectasis syndrome caused by mutations that inactivate NIMA-related kinase 10 (NEK10), a protein kinase with previously unknown in vivo functions in mammals. Genetically modified primary human airway cultures establish NEK10 as a ciliated-cell-specific kinase whose activity regulates the motile ciliary proteome to promote ciliary length and mucociliary transport but which is dispensable for normal ciliary number, radial structure, and beat frequency. Together, these data identify a novel and likely targetable signaling axis that controls motile ciliary function in humans and has potential implications for other respiratory disorders that are characterized by impaired mucociliary clearance. Inactivating mutations in a protein kinase, NEK10, cause a genetic bronchiectasis syndrome in humans that is characterized by short motile cilia and impaired mucociliary transport.
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- 2020
7. Systemic Delivery of scAAV8-Encoded MiR-29a Ameliorates Hepatic Fibrosis in Carbon Tetrachloride-Treated Mice.
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Matthew K Knabel, Kalyani Ramachandran, Sunil Karhadkar, Hun-Way Hwang, Tyler J Creamer, Raghu R Chivukula, Farooq Sheikh, K Reed Clark, Michael Torbenson, Robert A Montgomery, Andrew M Cameron, Joshua T Mendell, and Daniel S Warren
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Medicine ,Science - Abstract
Fibrosis refers to the accumulation of excess extracellular matrix (ECM) components and represents a key feature of many chronic inflammatory diseases. Unfortunately, no currently available treatments specifically target this important pathogenic mechanism. MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally repress target gene expression and the development of miRNA-based therapeutics is being actively pursued for a diverse array of diseases. Because a single miRNA can target multiple genes, often within the same pathway, variations in the level of individual miRNAs can potently influence disease phenotypes. Members of the miR-29 family, which include miR-29a, miR-29b and miR-29c, are strong inhibitors of ECM synthesis and fibrosis-associated decreases in miR-29 have been reported in multiple organs. We observed downregulation of miR-29a/b/c in fibrotic livers of carbon tetrachloride (CCl4) treated mice as well as in isolated human hepatocytes exposed to the pro-fibrotic cytokine TGF-β. Importantly, we demonstrate that a single systemic injection of a miR-29a expressing adeno-associated virus (AAV) can prevent and even reverse histologic and biochemical evidence of fibrosis despite continued exposure to CCl4. The observed therapeutic benefits were associated with AAV transduction of hepatocytes but not hepatic stellate cells, which are the main ECM producing cells in fibroproliferative liver diseases. Our data therefore demonstrate that delivery of miR-29 to the hepatic parenchyma using a clinically relevant gene delivery platform protects injured livers against fibrosis and, given the consistent fibrosis-associated downregulation of miR-29, suggests AAV-miR-29 based therapies may be effective in treating a variety of fibroproliferative disorders.
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- 2015
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8. Abstract 293: Identification of a predictive biomarker for liposomal nanoparticle delivery through pan-cancer pooled screening
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Joelle P. Straehla, Natalie Boehnke, Hannah Safford, Mustafa Kocak, Matthew G. Rees, Melissa Ronan, Danny Rosenberg, Charles H. Adelmann, Raghu R. Chivukula, Jaime H. Cheah, Hojun Li, Jennifer A. Roth, Angela N. Koehler, and Paula T. Hammond
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Cancer Research ,Oncology - Abstract
Background: Nanoparticles are a modular technology with great promise for cancer treatment, but one obstacle for clinical implementation is a lack of predictive biomarkers to identify patient groups most likely to benefit from specific nanoformulations. We developed a massively parallel pooled screen to investigate genomic factors underlying NP-cancer cell engagement, and report here the identification of a predictive biomarker that is both formulation-specific and cancer lineage agnostic. Methods: We interrogated the interactions of 35 fluorescent nanoparticle formulations (15 liposomal and 25 polymeric) against 488 pooled, barcoded cancer cell lines using fluorescence-activated cell sorting and binned cells based on strength of association. After sequencing, the relative barcode abundance in each bin was used to generate an association score for each nanoparticle-cell line pair. We identified features predictive of NP-cancer cell association by interfacing this score with multi-omic data from the Cancer Cell Line Encyclopedia. Results: Using machine learning model predictions, we identified thousands of candidate biomarkers both across and within formulations. Expression of the lysosomal transporter SLC46A3 was the top ranked random forest feature for all liposome formulations and was prioritized for further study. Univariate analyses confirmed the significance of this candidate biomarker and indicated a negative relationship, such that low expression of SLC46A3 is highly correlated with high nanoparticle association. This inverse relationship held true across all 22 cancer lineages screened and was recapitulated in a non-pooled screen of 13 cancer cell lines with a range of native SLC46A3 expression. To determine whether modulating SLC46A3 expression is sufficient to negatively regulate uptake of liposomes, we developed a toolkit of engineered cell lines by knocking out SLC46A3 in high-expressing T47D cells and inducing overexpression in low-expressing LOXIMVI cells. Consistent with our hypothesis, we show that SLC46A3 expression is inversely correlated with uptake of liposomal, but not polymeric, nanoparticles. To evaluate the potential clinical utility of SLC46A3 as a biomarker, we tested in vivo delivery of an FDA-approved nanoparticle analog, the drug-free version of liposomal irinotecan, to LOXIMVI flank tumors via intratumoral injection and intravenous administration. For both administration methods, we show that low tumor expression of SLC46A3 correlates with significantly improved delivery of liposomal nanoparticles. Conclusions: We identified SLC46A3 as a negative regulator of liposomal nanoparticle delivery to cancer cells both in vitro and in vivo. Given that liposomal nanoparticles comprise the majority of FDA approvals for cancer indications, we propose SLC46A3 may be a clinically actionable biomarker for patient stratification. Citation Format: Joelle P. Straehla, Natalie Boehnke, Hannah Safford, Mustafa Kocak, Matthew G. Rees, Melissa Ronan, Danny Rosenberg, Charles H. Adelmann, Raghu R. Chivukula, Jaime H. Cheah, Hojun Li, Jennifer A. Roth, Angela N. Koehler, Paula T. Hammond. Identification of a predictive biomarker for liposomal nanoparticle delivery through pan-cancer pooled screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 293.
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- 2022
9. Massively parallel pooled screening reveals genomic determinants of nanoparticle-cell interactions
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Adelmann Ch, Jaime H. Cheah, Angela N. Koehler, Raghu R. Chivukula, Joelle P. Straehla, Matthew G. Rees, Natalie Boehnke, Melissa M. Ronan, Huiyan Li, Jennifer Roth, Hannah Safford, Mustafa Kocak, David M. Sabatini, and Paula T. Hammond
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medicine.anatomical_structure ,Cell ,medicine ,Screening method ,Nanoparticle ,Nanomedicine ,Computational biology ,Cancer cell lines ,Biology ,Massively parallel - Abstract
To accelerate the translation of cancer nanomedicine, we hypothesize that integrated genomic screens will improve understanding of the cellular processes governing nanoparticle trafficking. We developed a massively parallel high-throughput screening method leveraging barcoded, pooled cancer cell lines annotated with multi-omic data to investigate cell association patterns across a nanoparticle library spanning a range of formulations with clinical potential. This approach identified both the materials properties and cell-intrinsic features mediating nanoparticle-cell association. Coupling the data with machine learning algorithms, we constructed genomic nanoparticle trafficking networks and identified nanoparticle-specific biomarkers, including gene expression of SLC46A3. We engineered cell lines to validate SLC46A3 as a biomarker whose expression inversely predicts liposomal nanoparticle uptake both in vitro and in vivo. We further demonstrated the predictive capabilities extend beyond liposomal nanoparticles, regulating both uptake and transfection efficacy of solid lipid nanoparticles. Our work establishes the power of massively parallel pooled cell screens for nanoparticle delivery and enables the identification and utilization of biomarkers to rationally design nanoformulations for specific patient populations.
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- 2021
10. Acid-Base and Hydrogen Ion
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Raghu R. Chivukula and Sheldon Magder
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chemistry.chemical_classification ,Base (chemistry) ,Sodium ,Bicarbonate ,chemistry.chemical_element ,Partial pressure ,Chloride ,Ion ,Solvent ,chemistry.chemical_compound ,chemistry ,Computational chemistry ,Carbon dioxide ,medicine ,medicine.drug - Abstract
All living organisms have tight regulation of the concentration of hydrogen ion ([H+]), or in its more familiar form, pH. This is necessary because of the unique effect of densely charged H+ ion on all structures of water-based solution which is the basic solvent for living organisms. We will mostly use the term [H+] in this chapter because it emphasizes its very low concentration relative to other elements in biological solutions. It also behaves fairly linearly in biological solutions. Assessment of [H+] has traditionally been done by considering [H+] and bicarbonate (HCO3−) as independent variables and their relationship to the partial pressure of carbon dioxide (PCO2). This relationship can be used to describe the changes in [H+] in biological solutions with the help of some empiric equations, and it is part of the approach presented in this chapter. However, it does not explain the physical–chemical processes involved and thus does not give a pathophysiological understanding. A proper physical–chemical analysis requires understanding the role of the true three independent variables. These are the difference in concentrations between strong positive and strong negative ions, which is called the strong ion difference ([SID]), PCO2, and the concentration of weak acids. These three factors determine the [H+] and [HCO3−] which are actually dependent variables. When combined with measurement of base excess, assessment of these three factors can be readily used to determine the mechanisms of altered pH in biological based solutions.
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- 2021
11. Lung Histopathology in Coronavirus Disease 2019 as Compared With Severe Acute Respiratory Sydrome and H1N1 Influenza
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Kathryn A. Hibbert, Jason W. Griffith, Raghu R. Chivukula, Christopher J. Richards, C. Corey Hardin, Yin P Hung, Daniel Okin, Vladimir Vinarsky, Amy Ly, Jason H. Maley, Camille R. Petri, Alyssa Sclafani, Rebecca A. Israel, Yuval Raz, Angela R. Shih, Mari Mino-Kenudson, Laura N. Brenner, Lida P. Hariri, Alexandra K Wong, Jullian A Villalba, Jonah Rubin, Tiara F. Calhoun, Michael A. Gillette, Jehan Alladina, Benjamin D. Medoff, James R. Stone, and Crystal M. North
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,ARDS ,Lung ,medicine.diagnostic_test ,business.industry ,virus diseases ,Autopsy ,medicine.disease ,Critical Care and Intensive Care Medicine ,respiratory tract diseases ,Hypoxemia ,medicine.anatomical_structure ,Respiratory failure ,Internal medicine ,Biopsy ,medicine ,Histopathology ,medicine.symptom ,Diffuse alveolar damage ,business ,Cardiology and Cardiovascular Medicine - Abstract
Background Patients with severe coronavirus disease 2019 (COVID-19) have respiratory failure with hypoxemia and acute bilateral pulmonary infiltrates, consistent with ARDS. Respiratory failure in COVID-19 might represent a novel pathologic entity. Research Question How does the lung histopathology described in COVID-19 compare with the lung histopathology described in SARS and H1N1 influenza? Study Design and Methods We conducted a systematic review to characterize the lung histopathologic features of COVID-19 and compare them against findings of other recent viral pandemics, H1N1 influenza and SARS. We systematically searched MEDLINE and PubMed for studies published up to June 24, 2020, using search terms for COVID-19, H1N1 influenza, and SARS with keywords for pathology, biopsy, and autopsy. Using PRISMA-Individual Participant Data guidelines, our systematic review analysis included 26 articles representing 171 COVID-19 patients; 20 articles representing 287 H1N1 patients; and eight articles representing 64 SARS patients. Results In COVID-19, acute-phase diffuse alveolar damage (DAD) was reported in 88% of patients, which was similar to the proportion of cases with DAD in both H1N1 (90%) and SARS (98%). Pulmonary microthrombi were reported in 57% of COVID-19 and 58% of SARS patients, as compared with 24% of H1N1 influenza patients. Interpretation DAD, the histologic correlate of ARDS, is the predominant histopathologic pattern identified in lung pathology from patients with COVID-19, H1N1 influenza, and SARS. Microthrombi were reported more frequently in both patients with COVID-19 and SARS as compared with H1N1 influenza. Future work is needed to validate this histopathologic finding and, if confirmed, elucidate the mechanistic underpinnings and characterize any associations with clinically important outcomes.
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- 2021
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12. Anticoagulation, immortality, and observations of COVID‐19
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Vladimir Vinarsky, Tiara F. Calhoun, Camille R. Petri, Laura N. Brenner, Raghu R. Chivukula, C. Corey Hardin, and Jason H. Maley
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2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,business.industry ,lcsh:RC633-647.5 ,viruses ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,media_common.quotation_subject ,Hematology ,lcsh:Diseases of the blood and blood-forming organs ,thromboembolism ,Immortality ,Virology ,SARS‐CoV‐2 ,COVID‐19 ,Commentary ,Medicine ,anticoagulation ,business ,thrombosis ,media_common - Abstract
The current coronavirus disease 2019 (COVID‐19) pandemic has produced an understandable sense of urgency among clinicians and researchers to develop, deploy, and report novel treatment strategies. Many centers are therefore using off‐label therapies and reporting early observational results of their experiences.(1‐3) A similar situation arose during the 2014 outbreak of Ebola virus disease (EVD).
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- 2020
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13. An exome-first approach to aid in the diagnosis of primary ciliary dyskinesia
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Raghu R. Chivukula, Waleed Ameen, Talal AlAnzi, Adel S. Alharbi, Khaled Baqais, Afaf Saghier, Mansour Alqwaiee, Hanan E. Shamseldin, Niema Ibrahim, Mais Hashem, Firdous Abdulwahab, Amal Alhashem, Fowzan S. Alkuraya, Ibrahim Al Mogarri, Muslim M. Alsaadi, and Jason H. Yang
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Male ,animal structures ,Ubiquitin-Protein Ligases ,Saudi Arabia ,Gene Expression ,Respiratory Mucosa ,Biology ,Bioinformatics ,Autoantigens ,03 medical and health sciences ,Consanguinity ,Exome Sequencing ,otorhinolaryngologic diseases ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Cilia ,Sinusitis ,Exome ,Genetics (clinical) ,Exome sequencing ,030304 developmental biology ,Primary ciliary dyskinesia ,Phenocopy ,0303 health sciences ,Respiratory Distress Syndrome, Newborn ,Cilium ,030305 genetics & heredity ,Golgi Matrix Proteins ,Nuclear Proteins ,Pneumonia ,medicine.disease ,Phenotype ,Human genetics ,Pedigree ,DNA-Binding Proteins ,Repressor Proteins ,Mutation ,Motile cilium ,Microtubule Proteins ,Female ,Ciliary Motility Disorders ,Transcription Factors - Abstract
Unlike disorders of primary cilium, primary ciliary dyskinesia (PCD) has a much narrower clinical spectrum consistent with the limited tissue distribution of motile cilia. Nonetheless, PCD diagnosis can be challenging due to the overlapping features with other disorders and the requirement for sophisticated tests that are only available in specialized centers. We performed exome sequencing on all patients with a clinical suspicion of PCD but for whom no nasal nitric oxide test or ciliary functional assessment could be ordered. Among 81 patients (56 families), in whom PCD was suspected, 68% had pathogenic or likely pathogenic variants in established PCD-related genes that fully explain the phenotype (20 variants in 11 genes). The major clinical presentations were sinopulmonary infections (SPI) (n = 58), neonatal respiratory distress (NRD) (n = 2), laterality defect (LD) (n = 6), and combined LD/SPI (n = 15). Biallelic likely deleterious variants were also encountered in AKNA and GOLGA3, which we propose as novel candidates in a lung phenotype that overlaps clinically with PCD. We also encountered a PCD phenocopy caused by a pathogenic variant in ITCH, and a pathogenic variant in CEP164 causing Bardet–Biedl syndrome and PCD presentation as a very rare example of the dual presentation of these two disorders of the primary and motile cilia. Exome sequencing is a powerful tool that can help “democratize” the diagnosis of PCD, which is currently limited to highly specialized centers.
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- 2019
14. A Conserved Distal Lung Regenerative Pathway in Acute Lung Injury
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Martin S. Taylor, Walter J. O'Donnell, Richard L. Kradin, Jayaraj Rajagopal, William R. Jeck, B. Taylor Thompson, Martin K. Selig, Laura C. Myers, Avinash Waghray, Carol Farver, Raghu R. Chivukula, and Purushothama Rao Tata
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Adult ,Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Pulmonary Fibrosis ,Fulminant ,medicine.medical_treatment ,Acute Lung Injury ,Lung injury ,Article ,Pathology and Forensic Medicine ,03 medical and health sciences ,Extracorporeal Membrane Oxygenation ,medicine ,Extracorporeal membrane oxygenation ,Humans ,Regeneration ,Lung transplantation ,Diffuse alveolar damage ,Lung ,business.industry ,Regeneration (biology) ,respiratory system ,medicine.disease ,Squamous metaplasia ,respiratory tract diseases ,Treatment Outcome ,030104 developmental biology ,medicine.anatomical_structure ,Female ,business ,Lung Transplantation - Abstract
Improved tools have led to a burgeoning understanding of lung regeneration in mice, but it is not yet known how these insights may be relevant to acute lung injury in humans. We report in detail two cases of fulminant idiopathic acute lung injury requiring extracorporeal membrane oxygenation in previously healthy young adults with acute respiratory distress syndrome, one of whom required lung transplantation. Biopsy specimens showed diffuse alveolar injury with a striking paucity of alveolar epithelial regeneration, rare hyaline membranes, and diffuse contiguous airspace lining by macrophages. This novel constellation was termed diffuse alveolar injury with delayed epithelization. In addition, mirroring data from murine models of lung injury/regeneration, peribronchiolar basaloid pods (previously described as squamous metaplasia) and ciliated bronchiolarization were identified in these patients and in 39% of 57 historical cases with diffuse alveolar damage. These findings demonstrate a common and clinically relevant human disease correlate for murine models of severe acute lung injury. Evidence suggests that peribronchiolar basaloid pods and bronchiolarization are related spatially and temporally and likely represent overlapping sequential stages of the response to severe distal airway injury.
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- 2018
15. Delayed Alveolar Epithelialization: A Distinct Pathology in Diffuse Acute Lung Injury
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Carol Farver, B. Taylor Thompson, Walter J. O'Donnell, Jayaraj Rajagopal, Richard L. Kradin, Laura C. Myers, Martin S. Taylor, William R. Jeck, Purushothama Rao Tata, and Raghu R. Chivukula
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,business.industry ,Lung injury ,Critical Care and Intensive Care Medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030228 respiratory system ,Correspondence ,medicine ,Diffuse alveolar damage ,business - Published
- 2018
16. NEK10 Loss of Function Causes a Novel Human Motile Ciliopathy
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Hui Min Leung, Guillermo J. Tearney, Raghu R. Chivukula, David M. Sabatini, Lida P. Hariri, Avinash Waghray, Katharine E. Black, Daniel T. Montoro, and Jayaraj Rajagopal
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Ciliopathy ,medicine ,Biology ,medicine.disease ,Loss function ,Cell biology - Published
- 2019
17. Author Correction: A human ciliopathy reveals essential functions for NEK10 in airway mucociliary clearance
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Hanan E. Shamseldin, Jason H. Yang, Guillermo J. Tearney, Martin S. Taylor, Gerard W. Dougherty, Raghu R. Chivukula, Daniel T. Montoro, Johnny L. Carson, Heymut Omran, Evgeni M. Frenkel, M. Leigh Anne Daniels, David M. Sabatini, Ibrahim Almogarri, Lida P. Hariri, Michael R. Knowles, Hui Min Leung, Fowzan S. Alkuraya, Katharine E. Black, Maimoona A. Zariwala, Vladimir Vinarsky, and Patrick R. Sears
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Adult ,Adolescent ,Proteome ,Mucociliary clearance ,Respiratory System ,Cystic Fibrosis Transmembrane Conductance Regulator ,Cell Separation ,Article ,General Biochemistry, Genetics and Molecular Biology ,Young Adult ,medicine ,Humans ,NIMA-Related Kinases ,Exome ,Microscopy, Phase-Contrast ,Child ,Microscopy, Video ,business.industry ,Homozygote ,Epithelial Cells ,X-Ray Microtomography ,General Medicine ,Flow Cytometry ,medicine.disease ,Ciliopathies ,Ciliopathy ,HEK293 Cells ,Phenotype ,Mucociliary Clearance ,Mutation ,Immunology ,Female ,Tomography, X-Ray Computed ,Airway ,business - Abstract
Mucociliary clearance, the physiological process by which mammalian conducting airways expel pathogens and unwanted surface materials from the respiratory tract, depends on the coordinated function of multiple specialized cell types, including basal stem cells, mucus-secreting goblet cells, motile ciliated cells, cystic fibrosis transmembrane conductance regulator (CFTR)-rich ionocytes, and immune cells
- Published
- 2020
18. Restitution of Tumor Suppressor MicroRNAs Using a Systemic Nanovector Inhibits Pancreatic Cancer Growth in Mice
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Joshua T. Mendell, Dipankar Pramanik, Raghu R. Chivukula, Nathaniel R. Campbell, Oliver A. Kent, Anirban Maitra, and Collins Karikari
- Subjects
Male ,Cancer Research ,Mice, Nude ,Biology ,Article ,Mice ,Downregulation and upregulation ,Cancer stem cell ,Cell Line, Tumor ,Pancreatic cancer ,microRNA ,medicine ,Animals ,Humans ,Regulation of gene expression ,CD44 ,Gene Transfer Techniques ,medicine.disease ,Xenograft Model Antitumor Assays ,Molecular biology ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,Disease Models, Animal ,MicroRNAs ,Oncology ,Apoptosis ,Cancer cell ,Cancer research ,biology.protein - Abstract
Mis-expression of microRNAs (miRNA) is widespread in human cancers, including in pancreatic cancer. Aberrations of miRNA include overexpression of oncogenic miRs (Onco-miRs) or downregulation of so-called tumor suppressor TSG-miRs. Restitution of TSG-miRs in cancer cells through systemic delivery is a promising avenue for pancreatic cancer therapy. We have synthesized a lipid-based nanoparticle for systemic delivery of miRNA expression vectors to cancer cells (nanovector). The plasmid DNA–complexed nanovector is approximately 100 nm in diameter and shows no apparent histopathologic or biochemical evidence of toxicity upon intravenous injection. Two miRNA candidates known to be downregulated in the majority of pancreatic cancers were selected for nanovector delivery: miR-34a, which is a component of the p53 transcriptional network and regulates cancer stem cell survival, and the miR-143/145 cluster, which together repress the expression of KRAS2 and its downstream effector Ras-responsive element binding protein-1 (RREB1). Systemic intravenous delivery with either miR-34a or miR-143/145 nanovectors inhibited the growth of MiaPaCa-2 subcutaneous xenografts (P < 0.01 for miR-34a; P < 0.05 for miR-143/145); the effects were even more pronounced in the orthotopic (intrapancreatic) setting (P < 0.0005 for either nanovector) when compared with vehicle or mock nanovector delivering an empty plasmid. Tumor growth inhibition was accompanied by increased apoptosis and decreased proliferation. The miRNA restitution was confirmed in treated xenografts by significant upregulation of the corresponding miRNA and significant decreases in specific miRNA targets (SIRT1, CD44 and aldehyde dehydrogenase for miR34a, and KRAS2 and RREB1 for miR-143/145). The nanovector is a platform with potential broad applicability in systemic miRNA delivery to cancer cells. Mol Cancer Ther; 10(8); 1470–80. ©2011 AACR.
- Published
- 2011
19. Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway
- Author
-
Raghu R. Chivukula, Erik A. Wentzel, Steven D. Leach, Shu Liu, Oliver A. Kent, Kwang H. Lee, Michael Mullendore, Joshua T. Mendell, Anirban Maitra, and Georg Feldmann
- Subjects
Down-Regulation ,Biology ,medicine.disease_cause ,Cell Line ,Proto-Oncogene Proteins p21(ras) ,Mice ,Research Communication ,Proto-Oncogene Proteins ,Anti-apoptotic Ras signalling cascade ,microRNA ,Genetics ,medicine ,Animals ,Humans ,Transcription factor ,Psychological repression ,Zebrafish ,Zebrafish Proteins ,biology.organism_classification ,DNA-Binding Proteins ,Pancreatic Neoplasms ,MicroRNAs ,ras Proteins ,Cancer research ,KRAS ,Carcinogenesis ,Transcription Factors ,Developmental Biology - Abstract
Although activating mutations in RAS oncogenes are known to result in aberrant signaling through multiple pathways, the role of microRNAs (miRNAs) in the Ras oncogenic program remains poorly characterized. Here we demonstrate that Ras activation leads to repression of the miR-143/145 cluster in cells of human, murine, and zebrafish origin. Loss of miR-143/145 expression is observed frequently in KRAS mutant pancreatic cancers, and restoration of these miRNAs abrogates tumorigenesis. miR-143/145 down-regulation requires the Ras-responsive element-binding protein (RREB1), which represses the miR-143/145 promoter. Additionally, KRAS and RREB1 are targets of miR-143/miR-145, revealing a feed-forward mechanism that potentiates Ras signaling.
- Published
- 2010
20. Quantification of Global MicroRNA Abundance by Selective Isotachophoresis
- Author
-
Raghu R. Chivukula, Alexandre Persat, Juan G. Santiago, and Joshua T. Mendell
- Subjects
Novel technique ,Chromatography ,Isotachophoresis ,Polymers ,Chemistry ,Total rna ,RNA ,Computational biology ,Microfluidic Analytical Techniques ,Analytical Chemistry ,Electrolytes ,MicroRNAs ,Abundance (ecology) ,microRNA ,Quantitative analysis (chemistry) - Abstract
We here present and demonstrate a novel technique based on isotachophoresis (ITP) for the quantification of global microRNA (miRNA) abundance in total RNA. We leverage the selectivity of ITP to concentrate miRNA and exclude longer RNA molecules from the focused zone. We designed a novel ITP strategy where we initially establish three contiguous zones of sieving polymer, electrolyte, and denaturant concentrations. This allows for successive preconcentration, selection, and detection of miRNA. We optimized chemistry in each zone for high sensitivity and exquisite selectivity for miRNA. This technique allows for the measurement of the total miRNA content in a sample and its comparison between different cell types and tissues. We demonstrated and validated the efficacy of this technique by comparing global miRNA abundance in subconfluent and confluent cell cultures.
- Published
- 2010
21. Prognostic value of left ventricular apical tissue removed for HeartMate II left ventricular assist device placement
- Author
-
Marc K. Halushka, John V. Conte, James O. Mudd, Karl A. Soderlund, Raghu R. Chivukula, and Stuart D. Russell
- Subjects
Adult ,Male ,Cardiac Catheterization ,medicine.medical_specialty ,Time Factors ,Biopsy ,Heart Ventricles ,medicine.medical_treatment ,Population ,Kaplan-Meier Estimate ,Risk Assessment ,Pathology and Forensic Medicine ,Internal medicine ,medicine ,Humans ,Ventricular Assist Device Placement ,Pulmonary wedge pressure ,Ventricular remodeling ,education ,Aged ,Retrospective Studies ,Heart Failure ,Heart transplantation ,education.field_of_study ,Ejection fraction ,Ventricular Remodeling ,business.industry ,Myocardium ,Hemodynamics ,General Medicine ,Middle Aged ,medicine.disease ,Fibrosis ,Treatment Outcome ,Ventricular assist device ,cardiovascular system ,Cardiology ,Heart Transplantation ,Female ,Heart-Assist Devices ,Cardiology and Cardiovascular Medicine ,business ,Destination therapy - Abstract
Background With the increasing use of left ventricular assist devices, the left ventricular apical core has become a more frequently encountered surgical pathology tissue. We investigated the prognostic value of this cardiac tissue in short-term patient mortality. Previous studies have shown that the degree of cardiac fibrosis correlates with improvements in ejection fraction and the likelihood of weaning from an assist device. Methods Left ventricular apical core tissues from 29 sequential subjects who received a HeartMate II continuous axial flow left ventricular assist device were studied retrospectively to determine whether interstitial fibrosis, replacement fibrosis (scar), the presence of mural thrombus, or other histopathologic findings were associated with hemodynamic changes or mortality in this population. Patients received left ventricular assist devices as bridges to transplantation or as destination therapy. Interstitial fibrosis was determined by observer scoring and digital scoring methods. Before and after left ventricular assist device procedure, right heart catheterizations were reviewed for clinical cardiac data. Results The presence of replacement fibrosis in the apical core tissue significantly correlated with decreased improvement in pulmonary capillary wedge pressure after left ventricular assist device placement (P=.02). Ten subjects died over the course of this study. No specimen variables, including scar, interstitial fibrosis, and the presence of mural thrombosis, correlated with patient mortality. Conclusions Pathologic findings in left ventricular apical cores have little prognostic utility in guiding patient management as related to overall 1-year mortality, but may indicate patients who are more likely to positively remodel their hearts.
- Published
- 2009
22. Systemic Delivery of scAAV8-Encoded MiR-29a Ameliorates Hepatic Fibrosis in Carbon Tetrachloride-Treated Mice
- Author
-
Sunil S. Karhadkar, Kalyani Ramachandran, Daniel S. Warren, Matthew K. Knabel, Hun Way Hwang, Robert A. Montgomery, Raghu R. Chivukula, Joshua T. Mendell, Andrew M. Cameron, Farooq H. Sheikh, Tyler J. Creamer, K. Reed Clark, and Michael Torbenson
- Subjects
Liver Cirrhosis ,medicine.medical_treatment ,Genetic Vectors ,lcsh:Medicine ,Gene delivery ,Cell Line ,Mice ,Downregulation and upregulation ,Fibrosis ,Transforming Growth Factor beta ,medicine ,Hepatic Stellate Cells ,Animals ,Humans ,lcsh:Science ,Carbon Tetrachloride ,Regulation of gene expression ,Multidisciplinary ,biology ,lcsh:R ,Transforming growth factor beta ,Dependovirus ,medicine.disease ,3. Good health ,Extracellular Matrix ,MicroRNAs ,Cytokine ,Gene Expression Regulation ,Immunology ,Hepatic stellate cell ,Cancer research ,biology.protein ,Hepatocytes ,lcsh:Q ,Chemical and Drug Induced Liver Injury ,Hepatic fibrosis ,Research Article - Abstract
Fibrosis refers to the accumulation of excess extracellular matrix (ECM) components and represents a key feature of many chronic inflammatory diseases. Unfortunately, no currently available treatments specifically target this important pathogenic mechanism. MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally repress target gene expression and the development of miRNA-based therapeutics is being actively pursued for a diverse array of diseases. Because a single miRNA can target multiple genes, often within the same pathway, variations in the level of individual miRNAs can potently influence disease phenotypes. Members of the miR-29 family, which include miR-29a, miR-29b and miR-29c, are strong inhibitors of ECM synthesis and fibrosis-associated decreases in miR-29 have been reported in multiple organs. We observed downregulation of miR-29a/b/c in fibrotic livers of carbon tetrachloride (CCl4) treated mice as well as in isolated human hepatocytes exposed to the pro-fibrotic cytokine TGF-β. Importantly, we demonstrate that a single systemic injection of a miR-29a expressing adeno-associated virus (AAV) can prevent and even reverse histologic and biochemical evidence of fibrosis despite continued exposure to CCl4. The observed therapeutic benefits were associated with AAV transduction of hepatocytes but not hepatic stellate cells, which are the main ECM producing cells in fibroproliferative liver diseases. Our data therefore demonstrate that delivery of miR-29 to the hepatic parenchyma using a clinically relevant gene delivery platform protects injured livers against fibrosis and, given the consistent fibrosis-associated downregulation of miR-29, suggests AAV-miR-29 based therapies may be effective in treating a variety of fibroproliferative disorders.
- Published
- 2014
23. Tumor suppression by miR-26 overrides potential oncogenic activity in intestinal tumorigenesis
- Author
-
Abier Abdelnaby, Joselin L. Anandam, Guanglu Shi, John C. Mansour, James A. Richardson, Lauren R Zeitels, Adam C. Yopp, Raghu R. Chivukula, Asha Acharya, Divya Chivukula, Joshua T. Mendell, and Glen C. Balch
- Subjects
Adenoma ,Colorectal cancer ,Carcinogenesis ,Transgene ,Mice, Transgenic ,medicine.disease_cause ,Mice ,Research Communication ,Intestinal mucosa ,Cell Movement ,Glioma ,microRNA ,Intestinal Neoplasms ,Genetics ,medicine ,Tumor Cells, Cultured ,PTEN ,Animals ,Humans ,Intestinal Mucosa ,Psychological repression ,Cell Proliferation ,biology ,medicine.disease ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Immunology ,Cancer research ,biology.protein ,Developmental Biology - Abstract
Down-regulation of miR-26 family members has been implicated in the pathogenesis of multiple malignancies. In some settings, including glioma, however, miR-26-mediated repression of PTEN promotes tumorigenesis. To investigate the contexts in which the tumor suppressor versus oncogenic activity of miR-26 predominates in vivo, we generated miR-26a transgenic mice. Despite measureable repression of Pten, elevated miR-26a levels were not associated with malignancy in transgenic animals. We documented reduced miR-26 expression in human colorectal cancer and, accordingly, showed that miR-26a expression potently suppressed intestinal adenoma formation in Apcmin/+ mice, a model known to be sensitive to Pten dosage. These studies reveal a tumor suppressor role for miR-26 in intestinal cancer that overrides putative oncogenic activity, highlighting the therapeutic potential of miR-26 delivery to this tumor type.
- Published
- 2014
24. Visual illusion in virtual world alters women?s target-directed walking
- Author
-
Lei Hao, Kathleen A. Turano, Jane M. Eisinger, John C. Hicks, Raghu R. Chivukula, and Sidhartha Chaudhury
- Subjects
Adult ,Male ,Adolescent ,genetic structures ,media_common.quotation_subject ,Illusion ,Walking ,Space (commercial competition) ,behavioral disciplines and activities ,Task (project management) ,Sex Factors ,Perception ,Humans ,Induced movement ,media_common ,Optical illusion ,Distance Perception ,General Neuroscience ,Motor control ,Illusions ,Action (philosophy) ,Head Movements ,Space Perception ,Linear Models ,Female ,Psychology ,Social psychology ,Photic Stimulation ,Psychomotor Performance ,psychological phenomena and processes ,Cognitive psychology - Abstract
In this study we investigated whether a visual illusion located in far space alters a person's open-loop, target-directed walking path in the same manner as it alters the perception of the target's position. Through the use of immersive VR the subject was able to walk physically to the location of a target embedded in a scene that was manipulated to create a visual illusion, known as the induced Roelofs effect. This illusion has been shown to alter the perception of a target's position. The experiment consisted of two tasks: a perception task and an action task. In the perception task, subjects viewed the scene for 1 s, it disappeared, and they were to report the target's location verbally. The results showed that the visual illusion altered the reported positions in all but one subject. In the action task, subjects viewed the scene for 1 s, it disappeared, and the subjects were asked to walk to the target's location. The results showed that the illusion significantly altered the walking paths of most of the women and less than half of the men. A significant gender effect was observed; women's walking paths deviated, on average, by 7.1 degrees and men's, by only 2.0 degrees . These results indicate that action tasks in far space are susceptible to the effects of visual illusions, unlike the action tasks in near space that reportedly have been resistant to them. Furthermore, the significant gender effect suggests that men and women either have different strategies and/or employ different mechanisms when executing a visually guided task in far space.
- Published
- 2004
25. Abate and Switch: miR-145 in Stem Cell Differentiation
- Author
-
Joshua T. Mendell and Raghu R. Chivukula
- Subjects
Biochemistry, Genetics and Molecular Biology(all) ,Cellular differentiation ,Rex1 ,fungi ,Cell Differentiation ,Biology ,Embryonic stem cell ,General Biochemistry, Genetics and Molecular Biology ,Cell biology ,Kruppel-Like Factor 4 ,MicroRNAs ,SOX2 ,stomatognathic system ,KLF4 ,microRNA ,embryonic structures ,Gene silencing ,Animals ,Humans ,Gene Silencing ,biological phenomena, cell phenomena, and immunity ,Cell potency ,Embryonic Stem Cells - Abstract
MicroRNAs have been implicated as regulators of embryonic stem (ES) cell self-renewal and pluripotency. In this issue, Xu et al. (2009) demonstrate that miR-145 facilitates ES cell differentiation by repressing the core pluripotency factors OCT4, SOX2, and KLF4, thereby silencing the self-renewal program.
- Published
- 2009
- Full Text
- View/download PDF
26. An essential mesenchymal function for miR-143/145 in intestinal epithelial regeneration
- Author
-
Asha Acharya, Eric W. Mills, Guanglu Shi, Joshua T. Mendell, Glen C. Balch, Joselin L. Anandam, Raghu R. Chivukula, Lauren R Zeitels, John C. Mansour, Anirban Maitra, Adam C. Yopp, and Abier Abdelnaby
- Subjects
Colorectal cancer ,Biology ,Editorials: Cell Cycle Features ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Mesoderm ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Intestinal mucosa ,Downregulation and upregulation ,Somatomedins ,microRNA ,Paracrine Communication ,medicine ,Animals ,Humans ,Regeneration ,Intestinal Mucosa ,Myofibroblasts ,030304 developmental biology ,0303 health sciences ,Biochemistry, Genetics and Molecular Biology(all) ,Regeneration (biology) ,Mesenchymal stem cell ,Dextran Sulfate ,medicine.disease ,MicroRNAs ,030220 oncology & carcinogenesis ,Immunology ,Colonic Neoplasms ,Cancer research ,Wound healing ,Carcinogenesis ,Insulin-Like Growth Factor Binding Protein 5 - Abstract
SummaryDownregulation of the miR-143/145 microRNA (miRNA) cluster has been repeatedly reported in colon cancer and other epithelial tumors. In addition, overexpression of these miRNAs inhibits tumorigenesis, leading to broad consensus that they function as cell-autonomous epithelial tumor suppressors. We generated mice with deletion of miR-143/145 to investigate the functions of these miRNAs in intestinal physiology and disease in vivo. Although intestinal development proceeded normally in the absence of these miRNAs, epithelial regeneration after injury was dramatically impaired. Surprisingly, we found that miR-143/145 are expressed and function exclusively within the mesenchymal compartment of intestine. Defective epithelial regeneration in miR-143/145-deficient mice resulted from the dysfunction of smooth muscle and myofibroblasts and was associated with derepression of the miR-143 target Igfbp5, which impaired IGF signaling after epithelial injury. These results provide important insights into the regulation of epithelial wound healing and argue against a cell-autonomous tumor suppressor role for miR-143/145 in colon cancer.
- Published
- 2013
27. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver
- Author
-
Bo Wang, Huban Kutay, Janaiah Kota, Shu-Hao Hsu, Kalpana Ghoshal, K. Reed Clark, Jianhua Yu, Krista M. D. La Perle, Samson T. Jacob, Jerry R. Mendell, Michael A. Caligiuri, Min Wei, Lianbo Yu, Joshua T. Mendell, Stefan Costinean, Raghu R. Chivukula, Shoumei Bai, and Hsiaoyin Mao
- Subjects
Carcinoma, Hepatocellular ,Mice, 129 Strain ,Cell Survival ,Neutrophils ,Hepatitis C virus ,Genes, myc ,Gene Expression ,Biology ,medicine.disease_cause ,Monocytes ,Mice ,Liver Neoplasms, Experimental ,microRNA ,MiR-122 ,medicine ,Animals ,Humans ,Genes, Tumor Suppressor ,RNA, Neoplasm ,3' Untranslated Regions ,Cell Proliferation ,Hepatitis ,Mice, Knockout ,Base Sequence ,Fatty liver ,Liver Neoplasms ,General Medicine ,medicine.disease ,Lipid Metabolism ,Lipids ,digestive system diseases ,Fatty Liver ,MicroRNAs ,Liver ,Hepatocellular carcinoma ,Immunology ,Cancer research ,Cytokines ,Tumor necrosis factor alpha ,Carcinogenesis ,Research Article - Abstract
miR-122, an abundant liver-specific microRNA (miRNA), regulates cholesterol metabolism and promotes hepatitis C virus (HCV) replication. Reduced miR-122 expression in hepatocellular carcinoma (HCC) correlates with metastasis and poor prognosis. Nevertheless, the consequences of sustained loss of function of miR-122 in vivo have not been determined. Here, we demonstrate that deletion of mouse Mir122 resulted in hepatosteatosis, hepatitis, and the development of tumors resembling HCC. These pathologic manifestations were associated with hyperactivity of oncogenic pathways and hepatic infiltration of inflammatory cells that produce pro-tumorigenic cytokines, including IL-6 and TNF. Moreover, delivery of miR-122 to a MYC-driven mouse model of HCC strongly inhibited tumorigenesis, further supporting the tumor suppressor activity of this miRNA. These findings reveal critical functions for miR-122 in the maintenance of liver homeostasis and have important therapeutic implications, including the potential utility of miR-122 delivery for selected patients with HCC and the need for careful monitoring of patients receiving miR-122 inhibition therapy for HCV.
- Published
- 2012
28. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model
- Author
-
Chrystal L. Montgomery, Janaiah Kota, K. Reed Clark, Michael Torbenson, Kathryn A. O'Donnell, Tsung Cheng Chang, Jerry R. Mendell, Joshua T. Mendell, Erik A. Wentzel, Perumal Vivekanandan, Hun-Way Hwang, and Raghu R. Chivukula
- Subjects
Carcinoma, Hepatocellular ,Genetic Vectors ,HUMDISEASE ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Article ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cyclins ,microRNA ,medicine ,Gene silencing ,Animals ,Cyclin D2 ,030304 developmental biology ,Cyclin ,0303 health sciences ,Biochemistry, Genetics and Molecular Biology(all) ,Liver Neoplasms ,Dependovirus ,medicine.disease ,3. Good health ,Disease Models, Animal ,MicroRNAs ,Apoptosis ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Systemic administration ,Cancer research ,RNA ,Carcinogenesis ,Liver cancer - Abstract
SUMMARY Therapeutic strategies based on modulation of microRNA (miRNA) activity hold great promise due to the ability of these small RNAs to potently influence cellular behavior. In this study, we investigated the efficacy of a miRNA replacement therapy for liver cancer. We demonstrate that hepatocellular carcinoma (HCC) cells exhibit reduced expression of miR-26a, a miRNA that is normally expressed at high levels in diverse tissues. Expression of this miRNA in liver cancer cells in vitro induces cell-cycle arrest associated with direct targeting of cyclins D2 and E2. Systemic administration of this miRNA in a mouse model of HCC using adeno-associated virus (AAV) results in inhibition of cancer cell proliferation, induction of tumor-specific apoptosis, and dramatic protection from disease progression without toxicity. These findings suggest that delivery of miRNAs that are highly expressed and therefore tolerated in normal tissues but lost in disease cells may provide a general strategy for miRNA replacement therapies.
- Published
- 2008
29. Circular reasoning: microRNAs and cell-cycle control
- Author
-
Joshua T. Mendell and Raghu R. Chivukula
- Subjects
biology ,Kinase ,Cell Cycle ,Apoptosis ,Cell cycle ,Biochemistry ,Article ,Cell biology ,RNA silencing ,MicroRNAs ,Cyclin-dependent kinase ,Cyclins ,Neoplasms ,microRNA ,biology.protein ,Animals ,Humans ,Molecular Biology ,Transcription factor ,E2F Transcription Factors ,Cell Division ,Cyclin ,Transcription Factors - Abstract
MicroRNAs (miRNAs) have attracted considerable attention because of their important roles in development, normal physiology, and disease states including cancer. Recent studies have identified specific miRNAs that regulate the cell cycle and have documented that the loss or gain of miRNA-mediated cell-cycle control contributes to malignancy. miRNAs regulate classic cell-cycle control pathways by directly targeting proteins such as E2F transcription factors, cyclin-dependent kinases (Cdks), cyclins and Cdk inhibitors. Moreover, from recent findings, it has been suggested that miRNAs themselves might be subject to cell-cycle dependent regulation. Together, these observations indicate that the reciprocal control of RNA silencing and the metazoan cell cycle impacts cellular behavior and disease.
- Published
- 2008
30. Rapid Accomodation of an A1 Renal Allograft after Preconditioning for ABO-Incompatible Transplantation
- Author
-
Daniel S. Warren, William M. Baldwin, Christopher E. Simpkins, Geoff Allen, Raghu R. Chivukula, Jayme E. Locke, Mark Haas, Dorry L. Segev, Robert A. Montgomery, Karen King, and Janis M. Taube
- Subjects
medicine.medical_specialty ,surgical procedures, operative ,business.industry ,Immunology ,medicine ,Renal allograft ,ABO-incompatible transplantation ,business ,medicine.disease ,Kidney transplantation ,Surgery - Abstract
Background: Successful ABO-incompatible (ABOi) kidney transplantation of non-A2 renal allografts requires preconditioning to reduce anti-blood group antibody to safe lev-els in order to avoid hyperacu
- Published
- 2008
31. Characterization of two small animal models for the evaluation of antibody-mediated rejection therapies in transplantation
- Author
-
Barbara A. Wasowska, Robert A. Montgomery, William M. Baldwin, Zhaoli Sun, Geoff Allen, Christopher E. Simpkins, Raghu R. Chivukula, Daniel E. Warren, Sara K. Cooke, and Christopher J. Sonnenday
- Subjects
Transplantation ,business.industry ,Small animal ,Immunology ,Antibody mediated rejection ,Medicine ,Surgery ,business - Published
- 2006
32. Sex differences in the influence of context on spatial localization revealed in open-loop walking
- Author
-
Jane M. Eisinger, John C. Hicks, Raghu R. Chivukula, Kathleen A. Turano, and Sidhartha Chaudhury
- Subjects
Ophthalmology ,Computer science ,Open-loop controller ,Context (language use) ,Spatial localization ,Sensory Systems ,Cognitive psychology - Published
- 2002
33. Restitution of tumor suppressor microRNAs using a systemic nanovector inhibits pancreatic cancer growth in mice.
- Author
-
Pramanik D, Campbell NR, Karikari C, Chivukula R, Kent OA, Mendell JT, and Maitra A
- Subjects
- Animals, Cell Line, Tumor, Disease Models, Animal, Gene Expression Regulation, Neoplastic, Gene Transfer Techniques, Humans, Male, Mice, Mice, Nude, MicroRNAs genetics, MicroRNAs metabolism, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Xenograft Model Antitumor Assays, MicroRNAs administration & dosage, Pancreatic Neoplasms therapy
- Abstract
Mis-expression of microRNAs (miRNA) is widespread in human cancers, including in pancreatic cancer. Aberrations of miRNA include overexpression of oncogenic miRs (Onco-miRs) or downregulation of so-called tumor suppressor TSG-miRs. Restitution of TSG-miRs in cancer cells through systemic delivery is a promising avenue for pancreatic cancer therapy. We have synthesized a lipid-based nanoparticle for systemic delivery of miRNA expression vectors to cancer cells (nanovector). The plasmid DNA-complexed nanovector is approximately 100 nm in diameter and shows no apparent histopathologic or biochemical evidence of toxicity upon intravenous injection. Two miRNA candidates known to be downregulated in the majority of pancreatic cancers were selected for nanovector delivery: miR-34a, which is a component of the p53 transcriptional network and regulates cancer stem cell survival, and the miR-143/145 cluster, which together repress the expression of KRAS2 and its downstream effector Ras-responsive element binding protein-1 (RREB1). Systemic intravenous delivery with either miR-34a or miR-143/145 nanovectors inhibited the growth of MiaPaCa-2 subcutaneous xenografts (P < 0.01 for miR-34a; P < 0.05 for miR-143/145); the effects were even more pronounced in the orthotopic (intrapancreatic) setting (P < 0.0005 for either nanovector) when compared with vehicle or mock nanovector delivering an empty plasmid. Tumor growth inhibition was accompanied by increased apoptosis and decreased proliferation. The miRNA restitution was confirmed in treated xenografts by significant upregulation of the corresponding miRNA and significant decreases in specific miRNA targets (SIRT1, CD44 and aldehyde dehydrogenase for miR34a, and KRAS2 and RREB1 for miR-143/145). The nanovector is a platform with potential broad applicability in systemic miRNA delivery to cancer cells., (©2011 AACR)
- Published
- 2011
- Full Text
- View/download PDF
34. Rapid accomodation of an A1 renal allograft after preconditioning for ABO-incompatible transplantation.
- Author
-
Allen G, Simpkins CE, Segev D, Warren D, King K, Taube J, Locke J, Baldwin W, Haas M, Chivukula R, and Montgomery RA
- Subjects
- Adult, Antigens, CD20 analysis, Antigens, CD20 immunology, Female, Graft Rejection, Humans, Immunoglobulins, Intravenous therapeutic use, Plasmapheresis, Transplantation, Homologous, ABO Blood-Group System immunology, Blood Group Incompatibility prevention & control, Kidney Transplantation immunology, Transplantation Conditioning
- Abstract
Background: Successful ABO-incompatible (ABOi) kidney transplantation of non-A2 renal allografts requires preconditioning to reduce anti-blood group antibody to safe lev-els in order to avoid hyperacute rejection. Unfortunately, early post-transplant acute antibody-mediated rejection remains a problem in these patients and can result in rapid graft loss. A number of investigators have encountered ABOi recipients who have had no evidence of allograft injury in the setting of elevated titers of anti-ABO antibody, a protective phenomenon that has been termed 'accommodation'. Little is known about the time course of accommodation. We report a case of a successful ABOi renal transplant recipient who had evidence of accommodation within the first week following transplantation., Case Report: The patient is a 36-year-old, highly sensitized blood group.woman who underwent live donor transplantation from her human leukocyte antigen-identical blood group A1 brother following therapy with plasmapheresis and low-dose intravenous immunoglobulin for an initial anti-A anti-human globulin antibody titer of 512. Within the first week following transplantation, her anti-A titer rose to 128 without change in her renal function. At 1 month following transplantation, her anti-A titer had risen to 256 at which time a biopsy was per-formed that demonstrated no evidence of antibody-mediated rejection., Conclusion: This patient demonstrates that accommodation of the renal allograft following ABOi transplantation may take place in the early postoperative period in the setting of high titer antibody. The implications for postoperative management of the ABOi patient and the need for future investigation in this area are discussed., (Copyright (c) 2009 S. Karger AG, Basel.)
- Published
- 2009
- Full Text
- View/download PDF
35. Visual illusion in virtual world alters women's target-directed walking.
- Author
-
Chaudhury S, Eisinger JM, Hao L, Hicks J, Chivukula R, and Turano KA
- Subjects
- Adolescent, Adult, Female, Head Movements physiology, Humans, Linear Models, Male, Photic Stimulation, Sex Factors, Distance Perception physiology, Illusions physiology, Psychomotor Performance physiology, Space Perception physiology, Walking physiology
- Abstract
In this study we investigated whether a visual illusion located in far space alters a person's open-loop, target-directed walking path in the same manner as it alters the perception of the target's position. Through the use of immersive VR the subject was able to walk physically to the location of a target embedded in a scene that was manipulated to create a visual illusion, known as the induced Roelofs effect. This illusion has been shown to alter the perception of a target's position. The experiment consisted of two tasks: a perception task and an action task. In the perception task, subjects viewed the scene for 1 s, it disappeared, and they were to report the target's location verbally. The results showed that the visual illusion altered the reported positions in all but one subject. In the action task, subjects viewed the scene for 1 s, it disappeared, and the subjects were asked to walk to the target's location. The results showed that the illusion significantly altered the walking paths of most of the women and less than half of the men. A significant gender effect was observed; women's walking paths deviated, on average, by 7.1 degrees and men's, by only 2.0 degrees . These results indicate that action tasks in far space are susceptible to the effects of visual illusions, unlike the action tasks in near space that reportedly have been resistant to them. Furthermore, the significant gender effect suggests that men and women either have different strategies and/or employ different mechanisms when executing a visually guided task in far space.
- Published
- 2004
- Full Text
- View/download PDF
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