Annual Review
SELECTED NIH INTRAMURAL RESEARCH ACCOMPLISHMENTS 2007

Discoveries that add to the body of knowledge about normal and abnormal biological functions and behavior

Identification of disease genes

Detection in a genome-wide association study of new genetic variants in a previously unsuspected region on chromosome 8q24 associated with increased risk of prostate cancer in men of European ancestry (NCI-DCEG, NCI-CCR)

Identification in a genome-wide association study of breast cancer of four single-nucleotide polymorphisms in the FGFR2 gene that are highly associated with sporadic postmenopausal breast cancer in women of European ancestry (NCI-DCEG, NCI-CCR, NCI-DCP)

Discovery of HAX1 mutations in some cases of autosomal recessive severe congenital neutropenia (NCBI/NLM)

Identification of a homozygous point mutation in the 31 untranslated region of the p14 gene (also known as the MAPBPIP gene) as the cause of a newly characterized syndrome combining severe congenital neutropenia, hypopig mentation, B-cell defects, and short stature (NCBI/NLM)

Identification of mutations in the STAT3 (signal transducer and activator of transcription 3) gene as the cause of hyper-IgE syndrome, also known as Job’s syndrome (NIAID, NHGRI, NCI, NCBI, CDER)

Discovery using retrovirus-mediated RNA interference of several unexpected roles of the DISC1 (disrupted-in-schizophrenia–1) gene in the development of new neurons in the adult hippocampus (NICHD)

Identification of the genes that cause—and elucidation of the pathways leading to—recessive osteogenesis imperfecta (OI), a relatively rare form of OI at the most severe end of the clinical spectrum (NICHD)

Identification in a genome-wide association scan of genetic variants in the FTO gene associated with obesity-related traits in BMI, hip circumference, and body weight, providing a novel entrée to corresponding pathways and a target for possible therapeutic approaches (NIA)

Identification of a deletion mutation of ITPR1 as the cause of spinocerebral ataxia 15, an inherited adult-onset neurological disease, further implicating calcium regulation in the pathobiology of this disorder and enabling an accurate molecular diagnosis that can be applied presymptomatically (NIA, NINDS, NICHD)

Identification of a new gene, FANCN, that is defective in Fanconia anemia patients of complementation group N and also resembles PALB2, suggesting it is also a breast cancer susceptibility gene (NIA)

Identification of a single ancient allele of the insulin-like growth factor gene as the major contributor to small size across dog breeds, shedding light on the evolution of complex traits (NHGRI)

Identification of at least four new genetic variants associated with increased risk of diabetes (IGF2BP2, CDKAL1, CDKN2A, and CDKN2B), bringing to at least 10 the number of genetic variants confidently associated with increased susceptibility to type 2 diabetes (NHGRI)

Identification of a common variant of the STAT4 gene, which encodes a protein involved in immune cell activation and differentiation, as a contributor to susceptibility to two autoimmune diseases, rheumatoid arthritis and systemic lupus erythematosus (NIAMS)

Identification in a genome-wide association study of a locus on chromosome 9 that includes two rheumatoid arthritis susceptibility genes, TRAF1 (TNF receptor–associated factor 1) and C5 (complement component 5) (NIAMS)

The finding on FMRI scans that two gene variants implicated in schizophrenia interact to degrade the brain's ability to process information and consequently impair working memory in otherwise normal adults (NIMH)

Important new animal models

Demonstration in a mouse model that anthrax lethal toxin produces shock that is insensitive to fluid administration and that the anthrax edema toxin produces much greater decreases in blood pressure than lethal toxin, suggesting that both the pathogenesis and the response to conventional therapy for anthrax-induced shock differ substantially from conventional septic shock and require new management approaches (CC, NIAID)

Development of an experimental uveitis model by exposing mice to the same retinal antigen but under different inductive conditions, eliciting a disease that differs from the currently used model clinically, histologically, and immunologically and shedding light on the heterogeneous nature of uveitis in humans (NEI)

Demonstration in mice of a potential new route to prevention of salivary gland damage—by protecting the microvascular endothelial cells in the gland—in patients undergoing irradiation for head and neck cancer (NIDCR, NCI)

Demonstration for the first time that siRNA as expressed by a lentiviral vector is both safe and efficacious in a large- animal model in a study that achieved downregulation of CCR5 expression in nonhuman primates, with evidence of continuing SIV resistance to simian immunodeficiency virus in transduced cells for at least two years (NHLBI)

Identification in animal models of infection that the production of high concentrations of the novel phenol-soluble modulins is key to the severity of community-associated methicillin-resistant staph infections (NIAID)

Study in mouse models of neurodegeneration of the newly identified protective pathway—called preemptive quality control—that attenuates the adverse consequences of protein misfolding in the endoplasmic reticulum (NICHD)

Demonstration of a potential role of glutamate-dopamine interactions in a mouse model of schizophrenia lacking functional GluR1 (AMPA) glutamate receptors (NIAAA)

Description of a novel, brain-penetrant, orally active corticotropin-releasing factor receptor antagonist with efficacy in animal models of alcoholism (NIAAA)

Demonstration in a rat model of human metabolic syndrome that the green tea polyphenol epigallocatechin gallate lowers blood pressure, improves endo-thelial dysfunction, increases insulin sensitivity, and protects against myocardial ischemia and reperfusion injury as well as conventional therapy with the ACE inhibitor enalapril (NCCAM)

Findings in mouse studies that neurons express several Toll-like receptors (TLRs), whose levels increase and promote cell death in response to stroke-induced energy, establishing an adverse effect of TLR activation in neurons and inflammatory immune cells that may worsen the outcome of a stroke and providing a rationale for therapeutic stroke interventions that target TLR-signaling pathways (NIA)

The finding that resveratrol, a polyphenolic compound found in red grapes, improves health and survival in middle-aged overweight male mice on a high-calorie diet, the first demonstration of health and survival effects of resveratrol in mammals (NIA)

The finding in a rat-reinstatement model that injections of peptide YY3-36, a gastrointestinal-derived hormone, decreased typical cue-induced high-fat food seeking behavior, suggesting a role for this peptide in preventing relapse of poor eating habits among people on a diet (NIDA)

Basic discoveries in cell, molecular, and structural biology with implications for the treatment of human disease

Determination of the molecular composition of tip links, which connect the tops of stereocilia found on sensory cells in the inner ear and are thought to convey the force to gates in mechanoelectrical transduction channels (NIDCD)

Twin study evidence that dichotic listening—the ability to identify and distinguish different stimuli presented simultaneously to each ear, which is related to normal interhemisperic information processing—is a highly heritable trait (NIDCD)

Enhanced understanding of ABC transporters with the finding that "silent" mutations in a multidrug-resistance gene affect cancer diagnosis and treatment (NCI-CCR)

Keener insight into DNA damage with the visualization of DNA breaks in living cells and the finding that ATM (ataxia-telangiectasia mutated kinase) prevents the persistence and propagation of DNA breaks (NCI-CCR)

Elucidation of the role of chaperones in the identification of an acetylation site in the middle domain of Hsp90 that regulates its function, coupled with the finding that asymmetric deceleration of ClpB or Hsp104 ATPase activity unleashes protein-remodeling activity (NCI-CCR)

Finding that junctional adhesion molecule–C regulates the vascular endothelial barrier, advancing the understanding of angiogenesis (NCI-CCR)

Discovery of nonhistone Scm3 as a crucial component of the core of yeast centromere, advancing knowledge of chromosome biology (NCI-CCR)

Finding that frequent engagement of the classical and alternative NF-kB pathways by diverse genetic abnormalities promotes cell survival in multiple myeloma (NCI-CCR)

Discovery in a well-characterized clinical model of acute inflammation that inhibition of cyclooxygenase-2 (COX-2) by drugs such as ibuprofen modulates gene expression besides the COX-2 cascade; these changes in gene expression may be associated with both the analgesic and the toxic effects of these widely used drugs (NINR, NIDCR)

Finding that acetaminophen, widely used for pain management as an alternative to drugs like ibuprofen and COX-2 inhibitors, alters the release of inflammatory mediators and expression patterns of genes related to COX-2 much as drugs like ibuprofen and COX-2 inhibitors do, raising the possibility of similar adverse effects as well (NIDCR, NINR)

Elucidation of novel mechanisms by which omega-3 long-chain polyunsaturated fatty acids and macular xanthophylls influence angiogenic, inflammatory, and cell-survival pathways implicated in the pathogenesis of age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity (NEI, NIAAA, ODS)

Discovery that expansion of Th17 cells in normal human blood by IL-2 is a cause of human inflammatory and autoimmune diseases and that antagonism of Th17 by IFN-g and IL-27 could be used for treatment of two human chronic ocular inflammatory diseases, uveitis or scleritis (NEI)

Identification of progenitor cells residing in a unique extracellular niche in human and mouse tendon that have universal stem-cell characteristics, including clonogenicity, multipotency, and self-renewal capacity, thereby opening up new approaches to help mend torn or degenerating tendons (NIDCR)

Establishment of the existence of a dysregulated signaling network in head and neck cancer, thereby identifying novel molecular targets for the prevention and treatment of these malignancies (NIDCR, NCI)

Discovery of random cell migration and self-organization during gland development that lead to tissue engineering of three-dimensional salivary gland precursors by self-assembly of dissociated cells (NIDCR)

Identification of a much more extensive mitochondrial phosphoproteome signaling pathway than previously recognized, including the identification of specific phosphorylation sites within the entire oxidative phosphorylation processes and the demonstration that phosphorylation is a regulatory mechanism of MnSOD activity (NHLBI)

Elucidation of the catalytic process by which hemoglobin converts nitrite to nitric oxide, with implications for the understanding of normal physiology and the therapeutic application of this "new chemistry" (NHLBI)

Discovery of a novel immunogenic antigen encoded by human endogenous retrovirus type E that is selectively expressed in the majority of clear-cell kidney cancers but not in normal tissues and elicits immune responses resulting in regression of metastatic kidney cancer after allogeneic hematopoietic cell transplantation (NHLBI)

Discovery of a regulatory role for CD40 ligand in loss of bone mass, revealed in a study involving patients with X-linked hyper-IgM syndrome (NIAID, CC, NCI)

New insight into potential cellular and molecular mechanisms underlying the genetic link between CX3CL1 and CX3CR1 and atherosclerosis, suggesting that this chemokine—chemokine receptor pair may be considered a pro-inflammatory target in the prevention and treatment of atherosclerosis (NIAID)

Discovery of the first component, called TRC40, of a novel membrane protein insertion pathway for tail-anchored proteins, adding to the knowledge of normal cellular function (NICHD)

Findings related to the role of brain-derived neurotrophic factor in depression and anxiety that suggest that BDNF is a target of antidepressants (NICHD, NIMH)

Findings that several amino acid derivatives of b-cyclodextrin block ion conductance through pores formed by both anthrax lethal toxin and Staphylococcus aureus a-hemolysin, raising the prospect of new effective therapies against various pathogens that use pore-forming proteins (NICHD)

Characterization of mammalian genes involved in iron-cluster synthesis and development of methods to assess cluster biogenesis, with implications for treatment of neurodegenerative and hematologic conditions such as Parkinson’s disease and refractory anemias (NICHD)

Discovery that cannabinoids mediate analgesia largely via peripheral CB1 receptors, which may help guide the development of peripherally restricted CB1 agonists as analgesics without any central side effects (NIAAA)

Finding of excessive telomere loss and reduced T-cell immune function among caregivers of Alzheimer’s patients, establishing a link between chronic stress, lymphocyte lifespan, and aging (NIA)

Further elucidation of the DNA repair functions of FANCJ, the Fanconi anemia protein associated with FA complementation group J, based on studies demonstrating its interactions with proteins associated with breast and colon cancer; and the identification of replication protein A as the first regulatory partner of FANCJ in DNA repair and the maintenance of genomic stability (NIA)

Finding, in a genome-wide search for genes with RNA polymerase II stalled within the promoter-proximal region, that regulated stalling of polymerase elongation occurs at hundreds of genes that respond to stimuli and developmental signals, establishing that polymerase stalling is an important mechanism in the regulation of gene transcriptional responses to dynamic environmental and developmental cues (NIEHS)

Solving the crystal structure of DNA polymerase m, providing new insights into the repair of potentially cytotoxic double-strand DNA breaks that can be induced by chemotherapeutic agents and by physical and chemical agents in the environment (NIEHS)

Derivation of a detailed molecular model of the retromer cargo-recognition subcomplex by combining X-ray crystallography, computer-enhanced electron microscopy, and bioinformatic analysis, elucidating many of the cellular functions performed by the retromer complex, such as iron-transporter recycling and processing of the amyloid precursor protein (NIDDK, NIAMS, NICHD)

Demonstration of a new function for RNA: playing a direct role in the repair of double-strand breaks in chromosomal DNA by serving as a template at the break site, potentially leading to new directions in gene targeting given that RNA can be amplified at will within cells (NIEHS)

Discovery that the high-mobility group box 1 protein specifically interacts with the base excision–repair intermediate and accumulates at sites of oxidative DNA damage in living cells, suggesting that it serves as a novel base excision–repair cofactor (NIEHS)

Identification of an enzymatic pathway that freezes the chromatin environment to ensure that DNA lesions are properly repaired (NIAMS, NCI)

Demonstration that interleukin-2, acting via the transcription factor Stat5, promotes the differentiation of immunosuppressive regulatory T cells but inhibits the generation of proinflammatory T cells that produce IL-17 (NIAMS, NIAID, NIDDK)

First demonstration that the "master" regulator MyoD requires an RNA helicase and a noncoding RNA to promote muscle gene expression and differentiation of skeletal muscle cells (NIAMS)

Identification of the sphingolipid sphingosine-1-phosphate as an important regulator of allergic responses and the discovery of its possible role as a determinant of anaphylaxis (NIAMS, NIDDK)

The finding of reduced occurrence of post-traumatic stress disorder among combat veterans who sustain damage to either of two brain areas–the ventromedial prefrontal cortex or an anterior temporal area that includes the amygdala–suggesting that these two areas are critically involved in PTSD (NINDS)

The finding that GABAergic circuits are not engaged by thalamocortical input in the neonate, but are poised for a remarkably coordinated development of feedforward inhibition at the end of the first postnatal week, a critical event in the development of a functional circuit in the mammalian brain (NINDS)

Demonstration that voltage-sensor paddle motifs are modular structural motifs in ion channels and in other voltage-sensitive membrane proteins and that they are important pharmacological targets (NINDS)

Finding that new cell lines from mouse epiblast share defining features with human embryonic stem cells and can enhance understanding of how pluripotent cells generate distinct fates during early development (NINDS, NCI)

Elucidation of biochemical mechanisms underlying the ability of the green tea polyphenol epigallocatechin gallate to stimulate production of nitric oxide from vascular endothelial cells and to inhibit hepatic gluconeogenesis, findings relevant to potential cardiovascular and metabolic health benefits of drinking green tea (NCCAM)

Identification of a new endoplasmic reticulum chaperone protein, called the sigma-1 receptor, which under normal physiological conditions, senses and transmits the ER calcium level to mitochondria to increase bioenergetics and in deteriorating conditions translocates to the whole ER to promote cell survival by preventing protein aggregations—with implications for diseases in which sigma-1 receptors have a role, such as addiction, depression, amnesia, stroke, and cancer (NIDA)

Finding that blockade of brain endocannabinoid CB1 receptors by AM251, a novel CB1 receptor antagonist, alters the breakpoint for intravenous cocaine self-administration and attenuates cocaine-enhanced electrical brain-stimulation reward, suggesting that AM251 or other more selective and potent CB1 receptor antagonists deserve further study as potentially effective anti-cocaine medications (NIDA)

Demonstration by pharmacologic MRI that a novel dopamine D3 receptor antagonist blocks the targeted receptors in the nucleus accumbens, the likely mechanism by which it produces anti-cocaine-like effects in vivo, suggesting that such compounds may be used to further elucidate the role of dopamine D3 receptors in drug abuse and may serve as leads for therapeutic agents to treat addiction (NIDA)

Demonstration on MRI that in youth with attention deficit hyperactivity disorder, the brain matures in a normal pattern but is delayed three years in some regions, on average, compared with that of youth without the disorder, suggesting that ADHD may be a disorder of brain-maturational delay (NIMH)

Completion of the first prospective study of cortical brain development before and after the onset of pediatric bipolar disorder, revealing a distinct pattern of developmental change—asymmetric gains and losses of gray matter—compared with that of healthy youth and of those with childhood-onset schizophrenia (NIMH)

The finding that a variation in a gene called GRIK4, which codes for a kainic acid–type glutamate receptor, appears to make people with depression more likely to respond to the medication citalopram than are people without the variation, suggesting that the glutamate system plays a role in modulating response to selective serotonin reuptake inhibitors (NIMH, NHGRI, NIAAA)

Identification of a key step in the silencing of the FMR1 gene that causes fragile-X mental retardation syndrome–SIRT1 deacetylation, a late event in gene silencing—suggesting that SIRT1 inhibition and reactivation of FMR1 in neurons may be possible (NIDDK)

Development of new or improved instruments and technologies for use in research and medicine

Development of novel techniques to map human histone methylations that showed correlations between chromosome banding patterns and unique histone modifications, as well as associations with chromosome breakpoints detected in TY cell cancers, providing new insights into the function of histone methylation and chromatin organization in genome function (NHLBI)

Development of an ultrasensitive, faster method for detecting infectious prions using seeded conversion of recombinant prion protein, which should facilitate improvements in the practicality of diagnostic prion assays as well as in fundamental studies of structure and formation of the scrapie prion protein isoform (NIAID)

Development of an automated lab-on-a-chip immunoassay for inflammatory biomarkers in newborns (NIBIB)

Development of a microcalorimetric method to determine the thermodynamics of multiprotein complex assembly, with applications to signaling complexes important in T-cell activation (NIBIB, NCI)

Use of a combination of solid-state nuclear magnetic resonance data and electron microscopy data to develop a full model of the molecular structure of amylin fibrils, a pancreatic peptide that may contribute to the destruction of insulin-producing cells in patients with type 2 diabetes, elucidating the generic propensity of peptides and proteins to form amyloid fibrils and potentially facilitating the development of therapeutic agents (NIDDK, NIBIB)

Development of a novel procedure that allows rapid and accurate determination of a protein's three-dimensional structure using only chemical shifts as input data, applicable to proteins of up to 130 residues, but can be extended to larger sizes when supplemented with a small fraction of the commonly used regular NOE restraints (NIDDK)

Development of a new equation to determine the cumulative energy deficit required to lose a pound of body weight that includes initial body fat in the calculation and accounts for why individuals with lower initial body fat require less than the 3,500-kcal deficit per pound of weight loss (NIDDK)

Development of a third-generation human mitochondria-focused cDNA microarray (hMitChip3) and its bioinfor-matics tools: the chip consists of the 37 mitochondrial DNA-encoded genes, 1,098 nuclear DNA-encoded and mitochondria-related genes, and 225 controls, each in triplicate; the bioinformatic software includes data-analysis procedures and a customized database for interpretation of results (NCCAM)

Advances in imaging

Development of a real-time system for intraoperative visualization of fluores-cently labeled tissue, demonstrated on surgical resection in metastatic murine ovarian cancer (NIBIB, NCI, CIT)

Demonstration that MRI can be used to guide X-ray procedures using conventional equipment to test cell therapies for heart disease (NHLBI) Development of an easily implemented imaging technique in the spatial frequency domain capable of acquiring both the scattering and the absorption distributions in a single exposure, which should help broaden the imaging applications of X-ray scattering (NHLBI)

Development of a new fluorescence collection device—total emission detection—that greatly increases fluorescence light collection in a two-photon microscope, with the potential for decreasing photodamage and allowing for deeper imaging in thick tissue and faster imaging for dynamic studies (NHLBI)

n Development and demonstration of scanning transmission electron tomography for imaging cellular proteins labeled with heavy-atom cluster nanoparticles (NIBIB, NIDDK)

The use of novel fluorescence imaging approaches combined with quantitative analysis and mathematical modeling to further elucidate cellular processes, such as membrane partitioning and its role in protein sorting and transport in the Golgi apparatus, biogenesis and turnover of peroxisomes, mitochondrial morphology and its regulation of cell-cycle progression, control of primary cilia dynamics, intercellular transfer between stem and niche cells, origin of autophagosomes, and PALM (live-cell photoactivation localization microscopy) for single-particle tracking (NICHD)

Further elucidation of blood and lymphatic vessel formation during vertebrate embryogenesis through the development of confocal microangiography and high-resolution in vivo imaging of zebrafish blood vessels, elucidating a pathway of artery specification, establishing a role for neuronal guidance factors in vascular patternings, illuminating vascular tube formation in vivo, and identifying a lymphatic vascular system in zebrafish (NICHD)

Improved MRI contrast and resolution that allows visualization of laminar cortical architecture of human brain based on magnetic properties of tissue (NINDS)

Development of a method to combine measurements of intensities and photon trajectories with theory and simulations to rigorously determine distances in single-molecule FRET (fluorescence resonance energy transfer) experiments (NIDDK)

Improvement on matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) with MALDI-ion mobility orthogonal time-of-flight MS (MALDI-IM-TOFMS) as a means to directly probe tissue to map and image distribution of analytes and elucidate molecular structure with minimal preparation (NIDA)

Advances in bioinformatics

Introduction of dbGaP (database of genotypes and phenotypes) to archive and distribute genome-wide association studies and other data that explore the connection between phenotype and genotype, with the aim of facilitating research into the genetic causes of disease and accelerating the advance of personalized medicine (NCBI/NLM)

Publication by the ENCODE Consortium of landmark papers that advance the collective knowledge of human genome organization, function, and evolution, including elaboration of transcriptional regulation and chromatin structure (NHGRI, NCI)

Development of new or improved approaches for preventing or delaying the onset or progression of disease and disability

Identification of rapamycin as an effective agent for the prevention of tobacco carcinogen–induced lung tumors (NCI-CCR)

Demonstration that complications of sickle cell disease, such as pulmonary hypertension, priapism, leg ulceration, and stroke, are directly linked to the intensity of hemolysis, providing new insights into treatments (CC, NHLBI)

Development of a risk-assessment tool, called the CARE model, that provides a more accurate assessment of invasive breast cancer risk in African American women than the currently available NCI Breast Cancer Risk Assessment Tool (NCI-DCEG, NICHD)

Identification of two new components of the Fanconi anemia (FA) core complex: FAAP 24 and FAAP 100, with implications for further understanding of the FA–breast cancer–associated DNA damage repair pathway and for screening potential anticancer drugs that facilitate or block interactions between the FA core complex and DNA (NIA)

The finding that gynecomastia in three otherwise healthy prepubertal boys with normal serum concentrations of endogenous steroids was associated with the topical application of products that contained lavender and tea tree oils, both of which were found to have estrogenic and antiandrogenic activities in human cell-line studies (NIEHS)

The finding that patients with rheumatoid arthritis who were treated with hydroxychloroquine were much less likely to develop diabetes mellitus than those not treated with hydroxychloroquine, suggesting this medication may be useful to prevent development of diabetes in those at risk (NIAMS)Completion of recruitment for the first phase I study of a whole-plant mistletoe extract given together with chemotherapy in patients with advanced solid tumors (NCCAM)

Launch of an exploratory study to evaluate the ability of the green tea polyphenol epigallocatechin gallate to simultaneously improve metabolic and cardiovascular actions of insulin in healthy, obese, hypertensive, or diabetic subjects (NCCAM)

Conduct of a clinical study of the role of endocrine-immune dysfunction in patients with active rheumatoid arthritis, aimed at gathering data that may provide further support for investigating selected CAM interventions, such as DHEA and stress-reduction techniques in similar populations of RA patients (NCCAM, NIAMS, NCI, CC)

Vaccine development

Identification and structural definition of a site of vulnerability on the HIV-1 Env gp120 glycoprotein that is recognized by the broadly neutralizing antibody b12 and is involved in the attachment of gp120 to CD4 (VRC/NIAID, NCI)

Identification of mutations in influenza A subtype H5N1 (avian) hemagglutinin (HA) that alter its specificity for sialic acid (SA) either by decreasing a-2,3-SA or increasing a-2,6-SA recognition, a finding that can guide the development of preemptive vaccines and therapeutic monoclonal antibodies that can be evaluated before the emergence of human-adapted H5N1 strains (VRC/NIAID)

Identification in patient sera of a potent and broad HIV-1 neutralization capacity mapped to the primary receptor CD4 binding region of HIV-1 Env gp120 glycoprotein, a finding that could lead to improved vaccine immunogens (VRC/NIAID)

Finding that preserved central memory CD4+ T lymphocytes are associated with prolonged survival in pathogenic SIV-challenged monkeys immunized with plasmid DNA and replication-defective adenoviral vectors encoding SIV proteins, with implications for immune correlates of vaccine efficacy in humans (VRC/NIAID)

Finding in a mouse model that the highly lethal 1918 pandemic influenza virus is susceptible to immune protection by a preventive hemagglutinin DNA vaccine (VRC/NIAID)

Identification of new antigens that may be potential targets for new therapeutics or vaccines to help control malaria (NIAID)

Development of a vectored vaccine delivered nasally that protected rhesus monkeys against Ebola virus challenge, in the first study in which topical immunization through the respiratory tract achieved prevention of a viral hemorrhagic fever infection in a primate model (NIAID)

Demonstration of the immunogenicity and induction of protective immunity by recombinant hepatitis C virus—like particles (HCV-LP) in chimpanzees; immunized animals developed HCV-specific cellular immune responses (NIDDK)

Development of new or improved ways to diagnose disease and disability

Gene expression patterns

Expression profiling to develop new biomarkers for liver cancer and to reveal a signature of high cancer risk in benign tumor (NCI-CCR)

Characterization of the clinical manifestations of children with Hutchinson-Gilford progeria syndrome, including sclerotic skin changes, joint contractures, bone abnormalities, alopecia, growth impairment, elevated blood pressure, reduced vascular compliance, low-frequency conductive hearing loss, functional oral deficits, abnormal prothrombin times, and elevated platelet counts, setting the stage for the evaluation of interventional therapies (NHGRI, CC, NHLBI, NIDCD, NIDCR, NICHD, NEI, NCI, OD)

The finding that gene-expression patterns derived from blood cells are a near-match to liver gene-expression patterns and predict acute acetaminophen exposure in rats more reliably than traditional clinical parameters, suggesting a means to ascertain exposure levels well before liver damage is detected by classical parameters and supporting the potential use of genomic markers in the blood as surrogates for clinical markers of potential acute liver damage (NIEHS)

Development of new or improved ways to treat disease and disability

Blood levels of NF-kB–related serum factors found to be biomarkers of therapeutic response and survival in patients treated for advanced oropharyngeal cancer (NIDCD, NCI)

Development of darunavir (approved by the FDA) and other protease inhibitors that block the dimerization process of HIV-1 protease (NCI-CCR)

New data from adult nephropathic cystinosis patients seen at the NIH Clinical Center from 1986 to 2006 showing that chronic oral cysteamine therapy results in taller and heavier individuals with lower cholesterol levels and lower frequencies of myopathy, diabetes, pulmonary dysfunction, hypothyroidism, and death, pointing to cysteamine as the treatment of choice for cystinosis patients of all ages (NHGRI)

Improvement in the rate of gene transfer in patients with adenosine deaminase deficiency by using chemotherapy to reduce the number of patient marrow cells to make room for the corrected ones, with subsequent marked improvement in T-cell numbers and immune function (NHGRI, NCI, NHLBI, NIDDK)

High-dose idebenone shown to improve neurological outcome in patients with Friedreich’s ataxia in a randomized controlled trial (NINDS)