Research Milestones

2016

• Doug Johnson, Justin Balko, Melissa Hicks, Jason Becker, David Slosky, Elizabeth Phillips, Mark Pilkinton, Dan Roden and Javid Moslehi described the first cases of fatal myocarditis, characterized by T-cell and macrophage infiltrates, in patients with melanoma after treatment with immune checkpoint inhibitors and identified this side effect in 0.27% of patients treated with ipilimumab and nivolumab based on pharmacovigilience.
• Nancy Cox Eric Gamazon of the Vanderbilt Genetics Institute and a team of others developed a robust methodology for imputing tissue-specific gene expression based on Genotype-Tissue Expression (GTEx) data.
• Sara Van Driest, Quinn Wells, Sarah Stallings, William Bush, Ben Shoemake, Josh Denny and Dan Roden demonstrated that the identification of rare functional variants in SCN5A and KCNH2 are not robustly associated with either arrhythmia or QT prolongation, suggesting notifying patients of incidental genetic findings may not always be appropriate.

2015

• Tim Blackwell, Joy Cogan, Jonathan Kropski, William Lawson, Mark Steele, Lisa Lancaster, Lisa Young, James Loyd and team identified a rare variant in the gene encoding for telomere elongation helicase 1 (RTEL1) that is associated with familial interstitial pneumonia and short telomere length.
• Leora Horn,co-authored a pivotal trial demonstrating that nivolumab was superior to docetaxel in patients with advanced nonsquamous non-small cell lung cancer that have progressed during or after platinum-based chemotherapy.
• Eric Gamazon of the Vanderbilt Genetics Institute, Nancy Cox and collaborators developed a gene-based association method for mapping traits using reference transcriptome data, known as PrediXcan.

2014

• Wei Zheng , Ben Zhang and colleagues carried out a large scale study of East Asians which identified six new loci associated with colorectal cancer risk.
• Ning Wei, Rupesh Chaturvedi, Keith T. Wilson, and collaborators found that peroxisome proliferator-activated receptor δ promoted colonic inflammation and tumor growth.
• Jin Chen, Shan Wang , Dana M. Brantley-Sieders and colleagues revealed that genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC.
• Robert J. Coffey, Cunxi Li, Yang Wang, Zheng Cao, Ramona Graves-Deal, Anne Powell and collaborators uncovered how excess PLAC8 promotes an unconventional ERK2-dependent EMT in colon cancer.
• David M. Aronoff and colleagues discovered that Prostaglandin E₂ suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cells.
• Billy Hudson, Julie Hudson, Aaron Fidler, Roberto Vanacore, Sergei Chetyrkin, Vadim Pedchenko, Gautam Bhave, Dorin-Bogdan Borza and other researchers in the Aspirnauts Inititiative discovered that a unique covalent bond in basement membrane is a primordial innovation for tissue evolution.

2013

• Dorin-Bogdan Borza’s research group uncovered how the neonatal Fc Receptor Promotes Immune Complex-Mediated Glomerular Disease.
• Wes Ely, Pratik P. Pandharipande, Robert S. Dittus. Gordon R. Bernard, Eduard E. Vasilevskis, Nathan E. Brummel, James C. Jackson, Timothy D. Girard other other BRAIN ICU investigators revealed how survivors of long-term illness often suffer from a disabling prolonged form of cognitive impairment.
• William Pao, Monica Red Brewer, Lai Darson and collaborators reported the mechanism for activation of mutated epidermal growth factor receptors in lung cancer.
• Mark Boothby , James W. Thomas and colleagues defined the requirement for Rictor in homeostasis and function of mature B lymphoid cells.
• Carlos Arteaga , Ariella Hanker, Justin M. Balko, Christian D. Young, Violetta Sanchez, Cammie R. Sutton, and collaborators discovered how mutations in PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies.
• Robert J. Coffey’s group elucidated the transformation of polarized epithelial cells by apical mistrafficking of epiregulin.
• Richard M. Peek Jr., Jennifer M. Noto, Jennifer Gaddy, Blanca Piazuelo, Judith Romero-Gallo, Giovanni Suarez, John Loh, Douglas Morgan, Keith Wilson, Pelayo Correa, Timothy Cover, and colleagues illuminated how iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans.

2012

• April Pettit and colleagues described the index case of fungal meningitis related to injection with contaminated steroids and triggered a public health response to prevent additional cases and deaths.
• Rick Peek and colleagues demonstrate that iron deficiency accelerates H. pylori-induced carcinogenesis.
• Ray Harris’s group identifies a critical role for CSF-1 signaling in recovery from acute kidney injury.
• Volker Haase shows that hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis.
• William Pao, and others identify BRAF gene mutations in some lung cancers with acquired resistance to EFR inhibitors.
• Sunil Kripalani and the Pharmacist Intervention for Low Literacy in Cardiovascular Disease Study Group find no beneficial effect of a pharmacist intervention on clinically important medication errors.
• Justin Balko , Carlos Arteaga, and others identify deficiency of dual specificity protein phosphatase 4 (DUSP4), an ERK phosphatase, as a mechanism of drug resistance in breast cancer.
• Takamune Takahashi’s group finds that thrombospondin-1 acts as a ligand for CD148 tyrosine phosphatase.
• Jeff Sosman, with Igor Puzanov, leads landmark trial studying the effect of vemurafenib on survival in BRAF V600-mutant advanced melanoma.

2011

• Chris Williams reports that blood vessel epicardial substance prevents epithelial-mesenchymal transition, a critical step in the progression of epithelial colorectal carcinomas.
• William Pao and Mia Levy launch MyCancerGenome, the first internet-based decision support tool to help physicians and researchers track the latest developments in personalized cancer medicine and connect with clinical research trials for their patients.
• Harvey J. Murff, Theodore Speroff, and colleagues develop new methods using natural language processing to detect adverse events after surgery using an electronic medical record.
• Robert Miller, John Newman, and James Sheller identify bronchiolitis obliterans in men during military service in Iraq and Afghanistan.

2010

• Josh Denney, Dan Roden and others demonstrate the feasibility of using a phenome-wide scan to discover gene-disease associations.
• Billy Hudson, Vadim Pedchenko, and others describe the molecular mechanism of Goodpasture's disease, in which conformational change in the alpha3NC1 and alpha5NC1 domain subunits of type IV collagen in the glomerular basement membrane elicits an autoimmune response.
• Tim Sterling and colleagues report results of an international clinical trial that supports a new, shorter, and more effective chemotherapeutic regimen for treatment of latent tuberculosis.
• Olivier Boutaud, John Oates, Jack Roberts and others report that Acetaminophen inhibits hemoprotein-catalyzed lipid peroxidation and attenuates rhabdomyolysis-induced renal failure.
• Dan Roden, Dawood Darbar and others identify genetic variants contributing to cardiac arrhythmias.

2009

• Kathy Murray and Mike Stein, together with Wayne Ray, report the effect of antipsychotic medications on the risk of sudden death.
• Richard D'Aquila and colleagues indicate that the APOBEC3 defense system in lymphocytes can partially defend against HIV-1 at physiological levels of expression, even if HIV-1 expresses a countermeasure, highlighting the potential of attempting to increase expression of these defensive proteins.
• Keipp Talbot and colleagues report how immunization of school age children against influenza impacts older adults.
• Alfred George identified a genetic modifier of congenital long-QT syndrome.

2008

• John Oates and Clinical Pharmacology fellow David Adler describe a patient with inherited phospholipase C2 deficiency characterized by impaired eicosanoid biosynthesis, small intestinal ulceration and platelet dysfunction.
• Mike Stein, Dan Roden and Ute Schwartz identify genetic determinants of the initial response to warfarin.
• Spryos Kalams, David Haas, and colleagues identify HIV-specific CD8+ T cells in CSF of HIV-infected subjects.
• Tom Talbot plays a prominent national leadership role to increase immunization of health care workers against influenza.
• Pingsheng Wu, Tina Hartert and colleagues demonstrate winter virus seasonality as a causal factor in asthma development.
• Alfred George discovered the functional basis for familial migraine associated with brain sodium channel mutations.

2007

• Tim Sterling, ChristinaFiske and colleagues identify risk factors and immunogenetic predictors of extrapulmonary tuberculosis.
• Tim Sterling, Vlada Melekhin, and colleagues find that pregnancy slows HIV-1 immunodeficiency progression during antiretroviral therapy.
• Wonder Drake and colleagues demonstrate immune responses to specific mycobacterial antigens in sarcoidosis, strengthening support for a pathogenetic role identified by their earlier findings of an association of mycobacterial nucleic acids with sarcoidosis.
• Jeffrey Smith defined single nucleotide polymorphisms spanning the entire zebrafish genome.
• Alfred George elucidated functional consequences of heart sodium channel mutations that predispose to sudden infant death syndrome
• Tim Blackwell and colleagues report that NF-κB pathway signaling is important for lung cancer development
• James Loyd and colleagues discovered that telomerase mutations cause disease in some families with idiopathic pulmonary fibrosis

2006

• Bjorn Knollmann and others in the division identify a role for Casq2 deficiency in catecholamine-induced polymorphic ventricular tachycardia.
• David Haas and colleagues identify genomic predictors of response to, and toxicity of, antiretroviral drugs.
• Ela Knapik identified the gene encoding a secretory vesicle coat protein as essential for craniofacial development.
• Gordon Bernard, Art Wheeler and the ARDS network investigators report that a conservative strategy of fluid management reduces the duration of mechanical ventilation and intensive care without increasing nonpulmonary-organ failures in patients with Acute Lung Injury.

2005

• Dan Roden and colleagues identify genetic factors that predispose to drug-induced cardiac arrhythmia.
• Todd Hulgan, Tim Sterling, Bryan Shepherd and colleagues are the first to identify that the percentage of CD4+ T lymphocytes independently adds to the absolute count for clinical prediction HIV disease progression during antiretroviral therapy.
• Tim Cover and colleagues define multi-functional effects of a Helicobacter pylori toxin, VacA.
• Guanqing Wu discovered the functional importance of the recessive polycystic kidney disease gene in morphogenesis of renal tubular. cells
• Michelle Southard-Smith discovered genetic modifiers of murine Hirschsprung disease using genome-wide linkage analysis
• Matt Breyer and colleagues demonstrate that thiazolidinediones expand body fluid volume through PPAR stimulation of ENaC-mediated renal salt absorption.
• Tom Talbot, Tina Hartert, William Schaffner, and Marie Griffin report that asthma is an independent risk factor for invasive pneumococcal disease.
• Wes Ely, Gordon Bernard, Robert Dittus and colleagues demonstrate that delirium in a critical determinant of ICU mortality.

2004

• Spyros Kalams and colleagues determine that a limited T-cell receptor repertoire on virus-specific cytotoxic T cells is associated with escape from antiviral cytotoxic T lymphocyte responses.
• Neil Bhowmick, Eric Neilson, and Hal Moses demonstrate that stromal fibroblasts in interstitial tissues can regulate the oncogenicity of adjacent epithelium.

2003

• David Carbone, Piere Maisson, Yu Shyr, Richard Caprioli, and colleagues identify the subset changes in the proteome in small cell lung cancer
• William Schaffner and colleagues investigate an outbreak of pseudomonas infections caused by defective bronchoscopes. This results in a global recall of these bronchoscopes.

2002

• Dan Roden and colleagues identify genetic factors that predispose to drug-induced cardiac arrhythmia.
• Doug Vaughan and colleagues engineer the first transgenic animal model to develop spontaneous coronary arterial thrombosis and myocardial infarction.
• Munirathinam Sundaramoorthy and Billy Hudson describe the structure of the NC1 domain from type IV collagen and identify the putative quaternary structures of the Goodpasture antibody binding sites in the NC1 domain of alpha-3 (IV) collagen.
• Peggy Kendall and Tom Thomas demonstrate that the natural autoantibody repertoire of nonobese diabetic mice is highly active.
• Matt Breyer identifies mechanism of COX-2 selective inhibitors in development or exacerbation of hypertension.
• Wonder Drake and colleagues report that a novel mycobacterium is a possible etiologic agent of sarcoidosis based on molecular genetic evidence.
• David Johnson and colleagues demonstrate in a randomized study no current regimen was superior to cisplatin and paclitaxel in patients with advanced non-small-cell lung cancer.
• Eric Neilson and colleagues demonstrate that tissue fibroblasts derive locally from epithelium through epithelial-mesenchymal transition.
• Alfred George repairs a mutant chloride channel using a trans-splicing ribozyme.

2001

• Wes Ely, Gordon Bernard, and Robert Dittus develop and validate first method of monitoring delirium in ICU patients, eventually translated into over 8 languages and now implemented by ICUs all over the world as routine ICU management.
• Jorge Capdevila reports novel P450 arachidonic acid metabolites are important regulators of blood pressure.
• Gordon Bernard, Wes Ely, and colleagues report on the efficacy and safety of recombinant human activated protein C for treatment of patients with severe sepsis for the Prowess Sepsis Study Group.
• Doug Kernodle and colleagues demonstrate that the secreted iron-cofactored superoxide dismutase of Mycobacterium tuberculosis inhibits host immune responses and apoptosis, and describe the prototype of a highly effective live-attenuated tuberculosis vaccine based on diminishing microbial immune-inhibitory capacity.

2000

• Ray Harris describes the mechanism by which COX-2-derived prostaglandins regulate renal renin expression and secretion.
• Robert Coffey and colleagues report on the successful treatment of Menetrier's disease with a monoclonal antibody against the epidermal growth factor receptor.
• Mark Anderson and colleagues establish second messenger activation of calcium entry into heart cells by calmodulin kinase II.
• Gordon Bernard reports for the ARDS network that a lower tidal volume than used traditionally results in decreased mortality and increases the number of days without ventilator use.
• David Robertson, Italo Biaggioni, and colleagues demonstrate that orthostatic intolerance and orthostatic tachycardia in some patients is associated with a norepinephrine-transporter deficiency.
• Walter Smalley, Marie Griffin, and Wayne Ray report that FDA-mandated black box warnings on Cisapride do not significantly alter physician prescribing behavior, ultimately eventuating in Cisapride being withdrawn from the market.
• Richard D'Aquila and colleagues demonstrate that drug resistant HIV variants remain archived in CD4+ T lymphocytes for years after emergence, even when not detectable in actively replicating virus.
• John Newman, John Phillips, Jim Loyd, and colleagues discover the mutation in the bone morphogenic protein type II receptor underlying primary pulmonary hypertension.
• Richard Peek and colleagues report that activation of b-catenin in gastric epithelium by carcinogenic Helicobacter pylori contribute to the formation of gastric cancers.