T H E   N I H    C A T A L Y S T      M A R C H  – A P R I L   2007

Annual Review


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

Identification of disease genes

Finding that autoreactive B-cell responses to RNA-related antigens in mice are due to TLR7 gene duplication, reflecting the importance of minor genetic mutations in autoimmunity and suggesting TLR7 as another potential target for lupus therapies (NIAID, NCI)

Identification of the K55R polymorphism variant allele in association with increased risk of coronary heart disease in Caucasians in a community-based study of atherosclerosis risk, implicating EPHX2 as a potential cardiovascular disease-susceptibility gene (NIEHS)

Variants in MC1R, the gene encoding the melanocortin-1 receptor, found to confer a higher risk of mutations in the BRAF oncogene and in melanoma not associated with chronic sun-induced damage (NCI)

Mutations in the gene coding for glucocerebrosidase found on autopsy in 23 percent of patients with dementia with Lewy bodies, a neurodegenerative disease with some symptoms of both Alzheimer’s and Parkinson’s diseases; mutations may interfere with the clearance of a-synuclein or promote its aggregation (NHGRI)

Single mutations in the human master regulator p53 found to dramatically alter cellular response to environmental stress, potentially exerting an effect on tumor development and therapeutic efficacy (NIEHS)

Important new animal models

n Scrapie-infected transgenic mice expressing prion protein lacking the GPI membrane anchor: a model to study heart amyloidosis, develop a blood-based diagnostic test to identify brain-wasting diseases, and explore ways to rid blood of infectious prion disease agents (NIAID)

n Development of a transgenic mouse model of glaucoma, with mouse lines containing bacterial artificial chromosome with a point mutation in the human or mouse myocilin gene, with the demonstration of pathological changes in the eye similar to those seen in human glaucoma patients (NEI, NCI)

n Development of a mouse model for primary intraocular lymphoma and the demonstration that direct injection into the eye of a B-cell–specific immunotoxin (CD22-Pseudomonas exotoxin construct) can clear the tumor, suggesting a therapeutic strategy in the human disease (NEI, NCI)

n Development of a mouse-activity monitoring system that quantifies the activity of caged mice, enabling the analysis of the behavioral effects of experimental cancer treatments or genetic manipulations (NCI, CIT)

n Mast cell findings in a mouse model of Smith-Lemli-Opitz syndrome (SLOS) present the first evidence of lipid raft dysfunction in SLOS and help explain the observed association of allergy with the syndrome (NIAMS, NICHD)

n Finding in a mouse model that natural killer cells ameliorate liver fibrosis through killing activated stellate cells, elucidating the role of innate immunity in this condition (NIAAA)

n Demonstration that mutant mice lacking the M3 muscarinic acetylcholine receptor subtype in pancreatic b-cells display impaired glucose tolerance and greatly reduced insulin release; conversely, overexpression confers resistance to diet-induced hyperglycemia, suggesting that enhanced signaling through b-cell muscarinic receptors may represent a new avenue of type 2 diabetes treatment (NIDDK)

n Demonstration in a mouse model of mitochondrial dysfunction that disruption of the gene for mitochondrial transcription factor A in dopamine (DA) neurons creates respiratory chain deficiency in midbrain DA neurons and a parkinsonism phenotype (NIDA)

n Finding that a corticotropin-releasing factor 1 receptor antagonist—antalarmin—can block stress-induced reinstatement of food-seeking behavior in a rat relapse model, suggesting that CRF1 receptor antagonists be considered in the treatment of maladaptive eating habits (NIDA, NIDDK)

n Finding that drugs that inhibit g-secretase, the enzyme that activates Notch protein, reduce brain cell damage and improve functional outcome in a focal ischemic stroke mouse model, suggesting that Notch signaling is a novel therapeutic target for the treatment of stroke (NIA)

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

n Discovery of a novel bacterium associated with necrotizing lymphadenitis in a patient with chronic granulomatous disease, with additional cases subsequently identified, demonstrating the application of Koch's postulates to a modern infectious disease (NIAID, CC, NCI)

n Finding of an adaptive response by Yersinia pestis to extracellular effectors of innate immunity—antimicrobial reactive nitrogen molecules induced by plague infection—during bubonic plague (NIAID)

n First evidence, via expression profiling of human mast cells during ingestion of Escherichia coli, that mast cells encountering bacteria reprogram their responses to improve their innate immune function (NIAID)

n Discovery of Kaposi’s sarcoma–associated herpesvirus fusion-entry receptor—cystine transporter xCT—with implications for the study of genetic and environmental factors in xCT expression among different groups of people and the development of new treatment strategies (NIAID)

n Identification of a cellular receptor for the varicella-zoster virus and for cell-to-cell spread of virus, with evidence that molecules that block the interaction of the receptor with the virus glycoprotein might be used to inhibit varicella-zoster infection in people (NIAID)

n Demonstration of immune correlates of vaccine efficacy in monkeys immunized with plasmid DNA and replication-defective adenoviral vectors encoding SIV proteins and then challenged with pathogenic SIV (VRC)

n Finding that T-cell–based vaccines can protect against the destruction of the CD4 memory compartment following acute SIV infection, and that this protection correlates directly with longer lifespan of infected animals (VRC, NIAID)

n Finding that preferential infection reduces the lifespan of HIV-specific CD4+ T cells in vivo and thereby compromises the generation of effective immune responses to the virus itself–and that this central feature in the pathophysiology of HIV infection can be influenced by the cross-reactivity of responding CD4+ T cells (VRC)

n Finding that Toll-like receptor agonists influence the magnitude and quality of memory T-cell responses after prime-boost immunization in nonhuman primates, thus providing significant insights for designing prime-boost immunization regimens that optimize Th1 and CD8+ T cell responses (VRC)

n Discovery of a novel mechanism by which cytokines and inflammatory mediators can promote vascular permeability, with implications for the treatment of acute and chronic inflammation, tissue damage following stroke and myocardial infarction, diabetic retinopathy, macular degeneration, and tumor-induced angiogenesis (NIDCR)

n Discovery of an essential role for the Akt-mTOR pathway in the action of an oncogenic Kaposi’s sarcoma virus gene to induce sarcomagenesis, providing a rationale for the clinical evaluation of mTOR inhibitors in the treatment of Kaposi’s sarcoma (NIDCR)

n Discovery that IFN-a mediates CD4+ T cell anti-HIV activity by increasing expression of the cellular APOBEC cytidine deaminase and that bolstering APOBEC can inhibit HIV infection, which may lead to new therapeutic strategies targeting host molecules rather than viral molecules (NIDCR)

n Discovery that enzyme Cdk5 regulates pain sensation through direct phosphorylation of a pain receptor (TRPV1), identifying it as a potential drug target for developing analgesics to treat pain (NIDCR, NINDS)

n Analysis of the role of members of the PBC family of homeodomain proteins—extrodenticle and homothorax—in Drosophila muscle development, with implications for the current models of how translocational activity of extrodenticle causes cancer (NICHD, NCI, CBER-FDA)

n Analysis of acoustic wave propagation showing that the graded spiral curvature of the cochlea enhances its sensitivity to lower auditory frequencies, a finding that could lead to improved design of cochlear implants (NIDCD, DBEPS)

n Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors, pointing to the use of such agents in the treatment of muscular dystrophy in humans (NIAMS)

n Discovery of novel biological actions of the nutritional supplement DHEA in stimulating the production of nitric oxide and endothelin-1 from the lining of blood vessels, elucidating why DHEA supplementation may be helpful for metabolic health in some diseases and circumstances, but not in others (NCCAM)

n Discovery of a new molecular mechanism for thyroid hormone action, providing new insight into the role of thyroid hormone in human brain, heart, lipid, and neuronal matters and underscoring concerns about agricultural chemicals that interfere with thyroid hormone activities and such public-health problems as learning disorders, cardiovascular disease, obesity, and depression (NIEHS)

n Demonstration that SHPRH, a putative tumor-suppressor gene, is the human orthologue of the yeast Rad5, the most significant factor in yeast DNA repair and the prevention of genomic instability during replication, providing a new mechanism for understanding and potentially treating several types of cancers (NHGRI)

n Demonstration in mice that an impaired epidermal barrier can promote an inflammatory response, suggesting that the most effective treatments for inflammatory skin disorders might concomitantly suppress the immune response and enhance epidermal differentiation to restore the barrier (NHGRI, NEI, NICHD)

n Discovery of a novel endogenous lipid, N-arachidonoyl-l-serine, and its vasodilator activity at a novel endothelial receptor, with implications for the dynamics of an endogenous vascular protective agent (NIAAA)

n Demonstration that dopamine-related disorders, such as Parkinson's disease, may not stem from changes in the overall levels of cortical activity, but from dysfunctional coordination of corticostriatal circuitries (NIAAA)

n Discovery of the pathway in the brain that may underlie human stable visual perception in spite of continual shifts in the retinal image resulting from rapid eye movements (NEI)

n Demonstration in mice of key roles for sphingosine-1-phosphate signaling in immunity (NIAMS, NIDDK, NIAID)

n Design and synthesis of new nucleotide derivatives that interact with P2 nucleotide receptors that induce cardioprotection in an ischemic heart model, with potential value in preventing platelet aggregation and reducing cardiomyopathy (NIDDK)

n Identification of novel isoforms of protocadherin-15 as components of the tip-link complex of hair cell stereocilia, further elucidating the mechanism of transduction in sensory cells of the inner ear (NIDCD, NHGRI)

n Elucidation of the role of p53 in mitochondrial respiration and the ascendancy of the glycolytic pathway as the energy source for cancer cells (NHLBI, NIDDK)

n Discovery that the behavior of oxidatively modified RNA may, in part, explain age-related changes in protein modification and thermostability and the accumulation of protein aggregates in neurodegenerative diseases (NHLBI)

n Discovery that resveratrol induces in obese mice on a high-fat diet a variety of metabolic and physiologic effects associated with caloric restriction and extended lifespan, raising the possibility that longevity in humans may be pharmacologically enhanced without severe dietary restriction (NIA)

n Identification of a link between circulating endothelial microparticles and ischemic stroke with regard to severity, lesion volume, and outcome (NINDS, CBER-FDA)

n Identification of the neutralization epitope responsible for the hepatitis B virus subtype-specific protection in chimpanzees (CC, CBER-FDA)

n Quantification of hepatitis B virus genomes and infectivity in human sera (NIAID, CBER-FDA)

n Finding that natural regulatory T lymphocytes (T-regs) can be activated through their innate immunity receptors to prevent autoimmune uveitis in a mouse model and that T-regs not specific only to the retina can offer protection, with implications for the development of T-reg–based therapies for humans, where the triggering ocular antigens are often unidentified (NEI)

n Elucidation of the role of neuron location—in the striate or extrastriate cortex—in choice-related activity in macaques (NEI)

n Structural analysis of DNA strand slippage that generates deleterious mutations underlying disease, supporting a decades-old but yet-unproven idea (NIEHS)

n TLR4 gene found to protect against tumor development in mice, suggesting that targeting the innate immune system may be useful in fighting human diseases, including cancer (NIEHS)

n Discovery of a retinal synapse that triggers neurotransmitter release by calcium influx through glutamate receptor channels (NINDS)

n Demonstration that Notch receptor activation promotes the survival in vitro of human embryonic neural stem cells and, in vivo, generates increased precursor cells and improved motor skills in adult rats with ischemic brain injury, with implications for the field of regenerative medicine (NINDS)

n Global expression profiling of mouse embryonic stem cells and adult neural stem/progenitor cells revealing three distinct phases—undifferentiated ESCs, primitive ectoderm-like cells, and neural progenitor cells—defining a developmental path to neural fate and providing a scale for the degree of commitment/differentiation (NIA)

n Elucidation of the mechanism of IL-21 regulation of CD8+ T lymphocytes, suggesting ways to exercise control over this cytokine (NHLBI)

n Finding that children with bipolar disorder display greater limbic activation and misread neutral facial expressions as hostile when asked to rate degree of hostility than do unaffected children, implicating this face-processing deficit in the poor social skills characteristic of this disorder (NIMH)

n Findings on MRI that children with high IQs show more rapid cortical thickening during childhood and peak later than in age peers, perhaps reflecting a longer developmental window for higher-level thinking circuitry and consistent with fMRI findings that levels of prefrontal activationcorrelate with IQ (NIMH)

n Identification of the first novel Birt-Hogg-Dubé binding protein–folliculin interacting protein—and further elucidation of the molecular mechanisms involved in kidney cancer formation, suggesting that tumor growth may be partly controlled by molecular agents that target the mTOR pathway (NCI)

n Demonstration in clinical studies in patients with pediatric sarcoma that interleukin-2 therapy significantly expands suppressive regulatory T cells, indicating that new T-cell growth factors that do not induce this expansion should be studied for use in cancer immunotherapy and that therapeutics that induce in vivo depletion of suppressive T cells would likely augment antitumor immunity (NCI, CC, VRC)

n Elucidation of changes in chromatin structure and mobility in living cells at sites of DNA double-strand breaks, further elaborating the mechanism by which DNA breaks are detected and repaired and informing the design of drugs to potentiate this response (NCI)

n Elucidation of the effect of ionizing radiation on unhit neighboring bystander cells and of differences between hit and unhit cells in the formation of DNA double-strand breaks, a better understanding of which may lead to improved cancer radiation treatment (NCI, CC)

n Reversal of age-related defects associated with truncated lamin A protein in both normally aged cells and the cells of patients with progeria, identifying a novel molecular mechanism in human aging, establishing progeria as a useful model to study human aging, demonstrating the reversibility of the cellular aging process, and providing an experimental system to study the molecular basis for the absence of tumors in the cells of progeria patients and the link between aging and cancer at the molecular level (NCI)

n Findings that an iron-sulfur protein regulates mitochondrial iron homeostasis and that compromised iron-sulfur cluster assembly results in mitochondrial overload as a result of abnormal mitochondrial-to-nuclear signaling, with implications for the study of Friedreich’s ataxia (NICHD)

n Crystallographic and functional analysis of glutamate receptor ligand complexes, elucidating the differences between kainite and AMPA receptors, with implications for understanding the gating mechanism of glutamate receptor ion channels and the suggestion that glutamate receptors are capable of much larger movements than previously thought (NICHD)

n Characterization of the previously unknown ligand-binding selectivity of the NMDA receptor NR3A subunit, expressed widely in the embryonic and early postnatal nervous system of mammals, paving the way for crystallographic analysis and better understanding of the functional role of this subunit (NICHD)

n Elucidation of distinct mechanisms for acute and long-term synaptic modulation by neurotrophin-3, and the tracking of two parallel but distinct molecular pathways to elicit long-term changes in synaptic function and structure, with implications for understanding cell biological mechanisms underlying synapse development and plasticity (NICHD)

n First localization of brain sites—in the ventral tegmental area and the nucleus accumbens—within which cannabinoids have rewarding actions, linking cannabis reward regions to the brain regions involved in the rewarding actions of cocaine, amphetamine, heroin, and nicotine (NIDA)

n Demonstration for the first time that selective dopamine D3 receptor antagonism constitutes a new and promising pharmacotherapeutic approach to the treatment of nicotine dependence (NIDA)

n Establishment by event-related functional MRI that two largely distinct neural networks mediate stimulus-driven (bottom-up) and intentionally driven (top-down) control of visuospatial selective attention (NIDA)

n Discovery that administration of MDMA and methamphetamine to rats increases plasma serotonin to levels high enough to stimulate mitogenic responses in pulmonary artery smooth muscle cells, suggesting that these abused stimulants may increase the risk of developing idiopathic pulmonary arterial hypertension (NIDA)

n Design and synthesis of noncompetitive metabotropic glutamate receptor subtype 5 antagonists and their evaluation in animal models of drug abuse and anxiety (NIDA)


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

Advances in imaging

n Findings via fluorescence resonance energy transfer in living cells of dynamic membrane changes–conformational change in the B-cell receptor and a dynamic reorganization of the local membrane lipid environment–providing a new view of B-cell activation in live cells that may lead to novel targets for enhancing or dampening B-cell responses (NIAID)

n Development of a powerful nuclear magnetic resonance method, based on paramagnetic relaxation enhancement, to detect and visualize transient, low-population encounter complexes in macromolecular protein-protein and protein-nucleic acid interactions, enabling study of such dynamics as the search for specific binding sites by transcription factors diffusing along DNA (NIDDK)

n Development of quantitative MRI techniques for in vivo pharmacokinetic analysis of drug transport in the eye, with implications for clinical applications (NEI, DBEPS, NINDS)

n Development of fluorine-18 radiochemically labeled protein for PET imaging of HER2 receptor, with potential use in breast-cancer diagnosis (NIBIB, NCI).

n Real-time MRI successfully guided recanalization of total arterial occlusions in animals, laying the groundwork for future studies of image-guided opening of blocked arteries as an alternative to surgery in humans (NHLBI)

n Solid-state NMR examination of the structure of amyloid fibrils formed in vitro from purified recombinant Sup35, elucidating the [PSI(+)] prion phenomenon (NIDDK)

n New insights into the structure of influenza virus via cryoelectron tomography suggesting the existence of an alternative pathway for the budding of nascent virions from host cells in which matrix protein is minimally involved, with possible implications for vaccine design (NIAMS)

n PET studies in awake monkeys showing that species-specific vocalizations evoke robust activity in homologues of human perisylvian language areas, hinting at the key neural mechanisms of the last common ancestor of macaques and humans that may have been recruited during the evolution of language (NIDCD, NIMH)

n Development of two new fluorescent protein techniques: 1) a high-resolution microscopy technique—photoactivated localization microscopy—that is capable of optical resolutions beyond the limit imposed by diffraction, and 2) fluorescence protease protection, an assay that enables determination of a protein’s topology in living cells via a fluorescent readout before and after trypsin-induced destruction of green fluorescent protein attached to a protein of interest (NICHD)

Advances in bioinformatics

n Development of the Clinical Study Information System to support efficient management and analysis of clinical data to better inform clinical decisionmaking, currently used in the study of a-galactosidase activity in Fabry disease (CIT, NINDS)

n Development and enhancement of tools (PubMatrix SE) for the storage, retrieval, and mining of genetic-associations data in the biomedical literature, using natural language processing and statistical methods to assess the strength of associations among various entities (CIT, NIA)

n Development of tools to query, process, quantify, and visualize data–including behavioral, genomic, imaging, video, dysmorphology, and clinical-trial research data—from the National Database for Autism Research, serving to expedite autism research (CIT, NIMH, NICHD, NINDS, NIEHS, NIDCD)

n The production and public release of high-density genotype data throughout the human genome in a series of 270 individuals with Parkinson's disease and 270 neurologically normal individuals, providing access to the largest collection of publicly available genotypes in a case-control cohort and facilitating research on Parkinson's and other neurodegenerative disorders (NIA, NINDS; see <https://queue.coriell.org/Q/snp_index.asp>

n Development of an integrative computational framework to study human macronutrient metabolism and body-composition regulation (NIDDK)

n Creation of a model of biological charge transfer to study the electric current through a chain of single-file water molecules using sophisticated computer-simulation techniques. (CIT, NIDDK)

n Determination of the genomic landscape of major histone modifications in human T cells, showing a correlation of modification patterns with transcriptional regulatory elements and suggesting that the combination of these patterns with comparative genomics is an efficient strategy of annotating the human genome (NHLBI)

Advances in biotechnology

n Development of a unified theory of force-induced molecular transitions for single-molecule pulling experiments, with application to DNA unzipping (CIT, NIDDK)


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

n Development of a model (<http://dceg.cancer.gov/melanomarisktool>) for use during a routine physical exam to estimate the five-year absolute risk of a first primary melanoma among whites between 20 and 70 years old (NCI)

n Findings that long-term survivors of pediatric sarcoma are at increased risk of persistent psychological distress, musculoskeletal impairments, cardiovascular disease, and infertility, suggesting long-term management approaches (NCCAM, NCI, CC, NICHD, NHLBI)

n The finding that, separate from their antioxidant effects, polyphenolic compounds from blueberries prolong the lifespan of Caenorhabditis elegans by 20 percent, demonstrating for the first time that these compounds have beneficial effects on whole animals as well as cells and suggesting that fruits and vegetables containing polyphenolic compounds may promote human longevity (NIA)

n Long-term dietary energy restriction, whether by intermittent fasting or a low-calorie diet, found to produce changes in heart rate, blood pressure, and heart rate variability in rats opposite those associated with aging, suggesting the study of dietary energy restriction in humans as another means to achieve cardiovascular fitness effects typically associated with aerobic exercise (NIA)

n First-time prevalence estimates for BRCA1 and BRCA2 mutations in a population-based case-control study of black and white American women ages 35 to 64, yielding also significant predictors of each mutation (NHGRI, NCI, NICHD)

n Finding that overweight and obese men have decreased fertility, with a 20-pound increase yielding a 10 percent increase in infertility risk (NIEHS)

n Launching of three major intramural clinical studies—the first product of a new integrated focus on autism—to define the characteristics of different subtypes of autism spectrum disorders; to examine the effectiveness of the antibiotic minocycline in treating regressive autism; and to address the widespread but unproven theory that autism may be treated successfully by chelation therapy to remove heavy metals from the blood (NIMH)

n Demonstration that oral glucosamine does not cause or significantly worsen insulin resistance or endothelial dysfunction in either lean or obese people and that steady-state glucosamine levels do not change with oral dosing, a finding that will aid in evaluating future studies of glucosamine's efficacy (NCCAM)

n Launching of a randomized, prospective clinical trial to compare the efficacy of tai chi chuan, a mind-body practice, with aerobic exercise in improving the cardiovascular and psychological status of adult cancer survivors (NCCAM)

n Finding from the first cohort study addressing the 1986 Chernobyl accident that children and adolescents exposed to the radioactive iodine experienced a large increase in thyroid cancer (NCI, NIDDK)

n Finding from a population-based study that excess risk of acute myeloid leukemia following treatment for Hodgkin's lymphoma was higher among patients who received chemotherapy in addition to radiotherapy, those over 35 at the time of treatment, and those treated before 1984 (NCI)

n TNF and IL-10 polymorphisms, separately and even more so in combination, found to confer increased risk of non-Hodgkin's lymphoma, especially diffuse large B-cell lymphoma, based on data from the International Lymphoma Epidemiology Consortium (NCI)

n Excess body weight during midlife, including overweight as well as obesity (as defined by body-mass index) found to be associated with an increased risk of death from all causes in otherwise-healthy people who had never smoked (NCI, NIA)

n Women with prenatal exposure to diethylstilbestrol found to have an increased risk of breast cancer after age 40, according to results of the first prospective study on the subject (NCI)

n First report from ongoing genetic analysis of complex cardiovascular and personality traits among individuals living in the relatively isolated populations of Sardinia to identify the impact of genetic influences on risk factor variations, with the aim of identifying targets for intervention to prevent the development of cardiovascular disease (NIA)

n Design of clinical studies to test the hypothesis that specific spectral photoprotective filters—vermilion sunglasses that reduce both rod activation in bright ambient light and the accumulation of toxic photoproducts like A2E in the retinal pigment epithelium—will lessen A2E levels and stymie progression of both early and moderate age-related macular degeneration following cataract surgery and intraocular lens implantation and in young patients with Stargardt’s macular dystrophy (NICHD, NEI)

Vaccine development

n Development and testing of the second component of a live attenuated tetravalent dengue virus vaccine, which was found to be safe and highly immunogenic in healthy adult volunteers (NIAID)

n Development of an H5 DNA influenza vaccine, built on existing VRC DNA plasmid platform technology, now being tested in a Phase I clinical trial to evaluate safety and immunogenicity in adult volunteers (VRC)

n Testing of a single-shot adenovirus Ebola vaccine in a Phase 1 vaccine trial to evaluate safety and immunogenicity in adult volunteers (VRC)

n Testing of a second-generation West Nile virus DNA vaccine for humans, using an improved expression vector expressing WNV proteins, in a Phase 1 vaccine trial to evaluate safety and immunogenicity in adult volunteers (VRC)

n Achievement of long-lasting and transmission-blocking activity of antibodies to Plasmodium falciparum in mice administered immunogenic protein conjugates of surface protein Pfs25, with implications for the development of a malaria vaccine (NICHD)


Development of new or improved ways to diagnose disease and disability

n Development of a microbore static tissue-sampling needle combined with a flow immunoassay lab-on-a-chip for the assessment of in situ tissue inflammation in muscle and skin disease (DBEPS, NCI, CC, NIAMS)

Gene expression patterns

n Development of an antibody-based microarray assay for small RNA detection that eliminates the need to manipulate RNA, thereby improving reproducibility and sensitivity of microarrays for these key regulators of gene expression (NIAID)

n Development of a loss-of-function RNA interference screen for molecular targets in cancer, an "Achilles heel" methodology that uncovers a key signaling component in diffuse large B-cell lymphoma and can be used to classify cancers based on which regulatory proteins and pathways promote proliferation or prevent cell death (NCI, CIT)

n Demonstration that gene expression profiling distinguishes the more aggressive Burkitt lymphoma from diffuse large B-cell lymphoma when current methods of pathological diagnosis fail to do so, leading to intensive chemotherapy regimens and superior survival for patients with this molecular diagnosis of Burkitt lymphoma (NCI, CIT)


Development of new or improved ways to treat disease and disability

n Development of monoclonal antibodies to vaccinia virus B5 protein that neutralize vaccinia and smallpox viruses, protect mice against vaccinia virus, and may also be useful for protection against other pox viruses, such as monkeypox virus (NIAID, ORS)

n Discovery of the mode of action of PA-824, a drug that may shorten the duration of tuberculosis treatment regimens and is now in early-stage clinical trials, with implications for improved drug design and accelerated TB drug development (NIAID)

n Anakinra, a recombinant soluble interleukin-1 receptor antagonist, found to rapidly and dramatically reduce systemic inflammation in patients with neonatal-onset multisystem inflammatory disease, a devastating inherited autoinflammatory disorder refractory to other therapies (NIAMS, NEI, NIDCD, NINDS, CC, NCI, NIAID, NIDDK)

n Finding that having two copies of the less-common version of a gene encoding the serotonin 2A receptor increases the odds of a favorable response to antidepressants and that this version is more than six times more prevalent in white than in black patients, helping explain racial differences in treatment outcome and supporting the importance of the serotonin receptor in the mechanism of antidepressant action (NIAAA, NIMH)

n Symptom relief achieved in as little as two hours for patients with treatment-resistant depression following a single I.V. dose of ketamine in a preliminary randomized study, a major improvement over the typical eight weeks or more for a treatment effect from current antidepressants (NIMH)

n Establishment of safety and suggestion of efficacy in a Phase 1 clinical trial of ciliary neurotrophic factor, delivered by encapsulated intraocular implants, in the treatment of retinal neurodegeneration, raising the possibility of also using this approach to deliver therapeutic proteins in retinal diseases not caused by genetic mutations (NEI, NIDCD)

n New insights into the immune recovery process after allogeneic stem-cell transplantation in leukemia patients, pointing to the importance of natural killer cell recovery and strategies to boost the graft-vs.-leukemia effect in the first month post-transplant (NHLBI, CC)

n Discovery that carrageenan, an inexpensive polysulfated carbohydrate found in many consumer products, including some over-the-counter sexual lubricants, is an extremely potent inhibitor of genital herpesvirus infection (NCI)

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