T H E   N I H    C A T A L Y S T      N O V E M B E R   –  D E C E M B E R   2003


Organized According to Government Performance and Results Act Goals


Goal A: Add to the body of knowledge about normal and abnormal biological functions and behavior

Identification of disease genes

n Identification of Vang12 as a gene important for the correct organization of stereocilia within the sensory cells of the inner ear, the appropriate movement of which is the first step in the detection of sound (NIDCD, NCI)

n Identification of the gene responsible for the ability to taste phenylthiocar bamide contributes to understanding phenotypic variations in bitter taste sensitivities, with implications for clinical interventions related to diet and behaviors such as smoking (NIDCD)

n Identification of a novel mutation of PCDH15 that accounts for a large proportion of cases of type 1 Usher syndrome among Ashkenazi Jews (NIDCD)

n Identification of genetic defects in two drug-metabolizing enzymes, CYP2C9 and CYP2C19, offering the prospect of genetic testing to customize drug prescriptions; among drugs metabolized by these enzymes are anticoagulant, anticonvulsant, antidiabetic, antihypertensive, antiinflammatory, antiulcer, and antianxiety agents (NIEHS)

n Discovery of a gene involved in congenital hydrocephalus in mice—Rfx4—which establishes a model system to study genetic and environmental causes of hydrocephalus in humans and lays the groundwork for developing screening assays for defects in the Rfx4 human gene (also cloned) (NIEHS)

n Identification of the gene HRPT2, whose inactivation predisposes to hyperparathyroidism–jaw tumor (HPT-JT) syndrome (NHGRI, NIDDK)

n Identification of SUFU as a susceptibility gene for medulloblastoma (NCI)

n Discovery of mutations in a novel kidney cancer gene (BHD) that lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with Birt-Hogg-Dubé syndrome (NCI)

n Identification of the genetic basis for Hutchinson-Gilford progeria syndrome, which may shed light on the general phenomenon of human aging (NHGRI)

n Identification of the genetic basis for Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V, a finding that could have implications for other inherited neuropathies and motor neuron diseases as well (NHGRI, NINDS)

n Identification of de novo CIAS1 mutations in about 50 percent of clinically recognized neonatal-onset multisystem inflammatory disease, a pyrin-associated autoinflammatory disease, with implications for IL-1 receptor blockade treatment (NIAMS, NIAID)

n Identification of H2AX, a core histone component, as a tumor-suppressor gene in mice that works in concert with p53; the absence of even one allele increases tumor formation in the absence of p53 (NCI)

n Identification of the human chromosomal regions that contain allelic variants that predispose to addiction vulnerability (NIDA)

n Mutation in a gene that encodes the largest subunit of the axonal transport protein dynactin found to cause motor neuron disease characterized by muscle weakness and vocal fold paralysis (NINDS, NIDCD)

n Identification of a novel ubiquitin ligase as a new Fanconi anemia gene—the first of the Fanconia anemia genes found to encode a product, PHF9, with catalytic activity that might serve as a target for new therapeutic modalities (NIA)

n Correlation of an amino-acid–altering polymorphism in the BDNF (brain-derived neurotrophic factor) gene with ability to remember past experiences, measures of hippo-campal neuronal activity, and hippocampal activation patterns (as seen on functional MRI), findings that advance the study of Alzheimer’s disease, depression, and normal aging (NIMH, NIAAA, NCI, NICHD)

n First demonstration in humans of a genetic basis (COMT gene variations) for individual differences in the brain’s response to amphetamine, suggesting that COMT genotype be taken into consideration in managing such disorders as depression, schizophrenia, Parkinson’s disease, attention deficit disorder, and traumatic brain injury (NIMH)

Important new animal models

n Claudin 14 knockout mice, a model for autosomal recessive deafness DFNB29, tracks the rapid degeneration of cochlear hair cells during the second and third weeks of life, when hearing function in mice is being established (NIDCD, VRP)

n Mouse models of mutations in the A-type lamins—structural proteins in the nucleus associated with congenital forms of muscular dystrophy, cardiomyopathy, peripheral motor neuropathy, lipodystrophy, and premature aging—cast light on how nuclear organization relates to cell function in developmental and disease processes (NCI)

n A pyrin-truncation mouse model of familial Mediterranean fever exhibits heightened sensitivity to endotoxin, suggesting that in affected humans, transient bacteremias might provoke systemic inflammatory response and pointing to potential treatments involving recombinant IL-1 receptor antagonist and pharmacologically manipulated pyrin (NIAMS, NHGRI)

n A chemokine receptor mutant that resulted in impaired adhesive function is found to be associated with reduced risk of atheroslerotic cardiovascular disease in humans; a mouse model demonstrated the mutation’s effect on the development of atherosclerosis (NIAID, NHLBI, NICHD)

n A new mouse model for S-Ag–induced uveitis supports an etiological role for retinal antigens and facilitates development of antigen-specific therapies tailored to particular HLA haplotypes; the model presents a vehicle to engineer the development of autoimmunity (NEI)

n Discovery that the regulation of epidermal factors controlling the skin’s permeability barrier depends on a kruppel-like transcription factor leads to the development of a mouse model for studying how to accelerate the process of barrier acquisition in premature infants (NHGRI)


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

n Study of the interaction of cadherin 23, and accelerating alleles in mice, sheds more light on predisposition to age-related hearing loss and noise-induced hearing loss in humans and informs the exploration of stem cell treatment strategies (NIDCD)

n The actin cytoskeletal core that supports the stereocilia within the inner ear sensory cells is not rigid, as previously thought, but undergoes dynamic renewal in about the same time it takes to recover from temporary noise-induced hearing loss (NIDCD)

n Single-cell mutational analysis of the c-kit gene demonstrates that systemic mastocytosis is a clonal disorder of a pluripotential hematopoietic progenitor cell; the study establishes the precision of the single-cell PCR technique and also suggests that the development of mastocytosis may require two lesions of the c-kit gene (NIAID, NIAMS)

n The finding that cell-free hemoglobin limits nitric oxide availability in sickle cell disease suggests the potential benefit of therapies that accelerate cell-free ferrous hemoglobin oxidation (NIDDK, CC, NHLBI)

n Individuals with risk factors for coronary artery disease have reduced numbers of circulating endothelial progenitor cells, which may contribute to impaired angiogenesis and ventricular remodeling in myocardial ischemia (NHLBI)

n Reduction of nitrite to nitric oxide by deoxyhemoglobin in the circulation leads to vasodilation of blood vessels (NHLBI)

n A novel cytokine-receptor–binding aminopeptidase (ARTS-1) may regulate inflammation by promoting release of three families of soluble cytokine receptors: type I tumor necrosis factor, type II interleukin-1, and interleukin-6 receptor-a (NHLBI)

n The chromatin-binding protein HMGb3 is required to prevent differentiation of hematopoietic stem cells and must be down-regulated to enable differentiation of myeloid and B cells; HMGb3 deficiency causes a functional loss in stem cell activity (NHGRI)

n Elucidation of the aggregation of a-1-proteinase inhibitor (PI) deficiency and associated liver disease may improve the manufacture of a-1-PI augmentation products (CBER, NIDDK)

n A new type of prion, based on autoacti-vation in trans rather than amyloid formation, is discovered (NIDDK)

n Continuing studies of the pathogenesis of HIV infection suggest that integrin avb3 (the vibronectin receptor) plays a role in HIV infection of peripheral blood monocyte-derived macrophages and may be a CD4 cofactor in promoting viral entry into cells (CBER, NIDCR)

n Recognition that the synuclein gene locus is triplicated in Parkinson’s disease, with a concomitant increase in the production of synuclein mRNA and protein, advances understanding of Parkinson’s mechanisms and informs treatment strategies (NIA, NINDS, NHGRI)

n A single treatment of recombinant humanized erythropoietin after coronary artery ligation in rats dramatically reduces the extent of myocardial infarction (MI) and left ventricular functional decline that occurs in untreated animals, a finding that supports the initiation of clinical studies in MI patients (NIA)

n Animal studies show that nitric oxide signaling and brain-derived neurotrophic factor (BDNF) together regulate neurogenesis in the mammalian brain and that dietary restriction increases neurogenesis, apparently by stimulating production of BDNF; drug and dietary strategies to prevent or treat human neurodegenerative disorders might be entertained (NIA)

n Dietary restriction (intermittent fasting) in huntingtin mutant mice, an animal model for Huntington’s disease, increases levels of BDNF and the protein chaperone heat-shock protein-70, slows the progression of neuropathological, motor, and metabolic abnormalities, and extends lifespan, suggesting that dietary intervention may suppress the disease process in humans who carry the mutant huntingtin gene (NIA)

n In a study for the first time linking two signaling pathways—b-1 adrenergic receptor (AR) and the Ca2+/calmodulin kinase II—sustained b1AR stimulation precipitates cardiac myocyte apoptosis, suggesting signaling-selective receptor stimulation in the management of cardiovascular disease–for example, selective b1AR blockade with concurrent b2AR activation as a potential approach to chronic heart failure (NIA)

n HuR, an RNA-binding protein whose depletion via AMP-activated protein kinase activity is associated with cell senescence, is found to play a major role in enhancing p53 translation in response to ultraviolet irradiation, suggesting that it has a broad role in cellular response to toxic agents (NIA)

n Ovarian cancer cells engineer resistance to cisplatin by remodeling the extracellular matrix through upregulation of COL6A3, increasing tumor cell collagen VI expression; strategies to inhibit ECM-tumor interactions may enhance chemotherapy (NIA, NHGRI)

n The role of receptor channels in mediating calcium signaling leading to the secretion of pituitary hormones essential for normal breast development, lactation, and reproductive function is elucidated (NICHD)

n Demonstration of a physical association between anaphylatoxins and the constant region of immunoglobulin (F9ab)2 fragment suggests a strategy for interference with the inflammatory process (NINDS, NICHD, NIAID, NHLBI, CBER)

n Discovery of a mechanism for the development of AIDS-related lipodystrophy and insulin resistance in successfully treated AIDS patients—two small proteins encoded by HIV that are produced by the patient’s cells and usurp the normal proteins that regulate hormone actions and gene transcription—suggests a therapeutic role for antagonists to these two viral proteins (NICHD, NCI)

n Glial cell-line–derived neurotrophic factor and neurturin are demonstrated to be new neuromodulators that regulate the development of the neuromuscular synapse through both pre- and postsynaptic mechanisms (NICHD, NCI)

n Elucidation of the immune-suppressing mechanisms of human herpesvirus 6, a HIV co-pathogen, provides the first evidence in a physiologically relevant model (human lymphoid tissue) that HHV-6 can severely affect the physiology of secondary lymphoid organs through direct infection of T lymphocytes and modulation of key membrane receptors and chemokines (NICHD)

n Structural and functional studies of glutamate receptors, including high-resolution X-ray structures of glutamate receptor agonists, provide detailed insight into the molecular basis of ligand-receptor subtype specificity that may aid in the design of selective agonists to manage stroke damage and other CNS disorders associated with dysfunctional glutamate receptor activity (NICHD)

n Development of a new method for culturing Plasmodium falciparum at high erythrocyte concentrations demonstrates that P. falciparum can replicate at packed densities and offers a new approach to studying the pathogenesis of cerebral malaria (NICHD)

n The mechanism by which anthrax lethal toxin suppresses normal protective anti-inflammatory response—by repressing certain nuclear hormone receptors—can aid in the development of new treatments and prevention of the toxic effects of anthrax (NIMH, NIAID, NIDDK)

n Elucidation of the mechanism by which IL-2 adjunctive therapy expands peripheral CD4+ T cells in HIV-infected patients is elucidated (CC, NIAID)

n The DNA polymerase, DnaE2, is found to contribute to the survival and emergence of drug resistance in Mycobacterium tuberculosis, suggesting a potential new target for therapeutic intervention (NIAID)

n Intravenous immunoglobulins are found to neutralize the pro-inflammatory effects of complement fragments C3a and C5a—potent anaphylatoxins—in a mouse model of asthma and a pig model of cardiopulmonary distress, suggesting a possible expansion of the clinical applications of therapeutic doses of immunoglobulins (NINDS, NICHD, NIAID, NHLBI, CBER)

n Animal studies of scrapie transmission into a resistant species produces subclinical infection with underlying persistence, replication, and adaptation of infectivity, suggesting that subclinical infection of humans exposed to bovine spongiform encephalophy (mad cow disease) could lead to dangerous transmission in the future (NIAID)

n Discovery of elevated levels of IL-6 in patients with mastocytosis has implications for therapy (NIAID)

n Studies in yeast and human cell extracts demonstrate that cadmium acts as an environmental mutagen and carcinogen by inhibiting the DNA mismatch repair system, rather than by direct DNA damage (NIEHS)

n Elucidation of the molecular mechanism by which chelation therapy effects methyl-mercury excretion after mercury-induced renal damage suggests that variations in organic anion transporters may explain individual susceptibility to methylmercury toxicity (NIEHS)

n Mesoamerican Mestizos and North American Caucasians with idiopathic inflammatory myopathy display differing patterns of clinical manifestations, autoantibodies, and immunoglobulins, suggesting that expression of this condition is modulated by different genes and environmental exposures around the world (NIEHS)

n Postpartum uterine tissue remodeling appears to be the mechanism by which parity confers protection from uterine fibroids (NIEHS)

n A polymorphism in the COMT (catechol-O-methyltransferase) gene affects opioid m-receptor mediated responses to pain and was found to be associated with anxiety disorder among Caucasian and Plains American Indian women (NIAAA)

n Demonstration of impaired synaptic plasticity in the brain and well-defined functional consequences of prolonged marijuana use (NIDA)

n Description of the ascending pathway from the primate brainstem to the cortex sets the stage for tracking other ascending pathways, and the impaired feedback is thought to contribute to such conditions as acquired nystagmus, spasmodic torticollis, Parkinson’s disease, and schizophrenia (NEI)

n Identification of a cellular phenotype characteristic of Lowe syndrome provides a model system to test possible interventions in the disease process (NHGRI)

n The results of a 10-year imaging study show that although children and adolescents with attention deficit hyperactivity disorder have smaller brain volumes than healthy controls (whether previously medicated or not), their brain development throughout childhood and adolescence is similar to controls, evidence that stimulant drugs do not disturb brain development (NIMH, NINDS)

n Elucidation of the process by which inhibitory synaptic neuronal endings absorb glutamate, which leads to the production of GABA and may prevent seizures resulting from excess glutamate, advances understanding and control of epilepsy (NINDS)

n Neurocognitive effects of chronic marijuana, cocaine, and alcohol use are found to persist after 28 days of abstinence, with severity related to dose; multiple drug use produces additive negative effects (NIDA)

n The finding that T cells reactive to myelin basic protein contribute to disease activity in multiple sclerosis points to a more specific target in future therapeutic trials (NINDS)

n Discovery of second-site, function-restoring mutations in Wiskott-Aldrich syndrome suggests that such genetic reversions may take place more frequently than generally believed and that identification and characterization of the mechanisms underlying back mutations can aid in the development of new therapeutic strategies for genetic disorders (NHGRI, NCI)

n The potential for blood-cell–associated prion proteins to transmit transmissible spongiform encephalopathies through blood transfusion is elucidated (NHLBI, CBER)

n Embryonic epithelial branching in the morphogenesis of salivary glands depends on regulation by the extracellular matrix protein fibronectin, just as do lung and kidney development (NIDCR)


Goal B: Develop new or improved instruments and technologies for use in research and medicine

n Use of more relevant computed tomography measures to determine visceral adipose tissue (VAT) volume, which refutes findings in other studies that sex differences documented in other racial groups do not apply to African Americans (NIDDK, NICHD, CC)

n Design and manufacture of a unique acupuncture needle with a microdialysis probe that enables the recovery of biological agents from the tissue surrounding the needle tip (DBEPS, CC)

n Development of fine-bore immunoaffinity capillary electrophoresis enabling multiple analyte analysis on collected samples (DBEPS, NINDS, NICHD)

n Development of a 3-D anatomically correct computational model of the human spinal cord to model drug delivery and tissue distribution, with the aim of studying this system to treat chronic pain (DBEPS, NIDCR, NINDS)

n Development of a variant of green fluorescent protein that allows selective marking of proteins through photoactivation (PA-GFP), a labeling method preferable to photo-bleaching for studying temporal and spatial dynamics of proteins and addressing fundamental questions in cell and developmental biology (NICHD)

n Measurement of the kinetics of folding of a single protein molecule (NIDDK)

n Delineation of a molecular structural model of amyloid fibrils formed by the 40-residue b-amyloid peptide associated with Alzheimer’s disease (NIDDK)

n High-resolution microscopy, high-throughput imaging, and computer simulations to study the positioning of entire chromosomes and gene loci within the nucleus and their rearrangements during differentiation and tumorigenesis, which enhances understanding of how spatial organization affects genome expression and could lead to new diagnostic and analytic cytogenetic tests based on interphase genome organization (NCI)

n Human lymphoid tissue studies to elucidate the dynamics of HIV-1 variants, which show that the later-stage CXCR4-utilizing variant upregulates CC-chemokines that suppress the replication of early-stage CCR5, ushering in accelerated progression to AIDS; development of a real-time PCR-based assay to evaluate the replication of HIV variants and the R5-to-X4 switch (NICHD)

Advances in imaging

n A novel real-time MRI system for guiding intramyocardial injections of therapeutic agents affords better visualization of the target tissue than traditional X-ray fluoroscopy and the ability to monitor drug effects immediately (NHLBI)

n An MRI system that allows physicians the ability to visualize 3-D volumes inside a patient in real-time, rather than individual slices, is particularly useful for tracking interven-tional devices; a method to obtain maps of the blood flow in the cardiac chambers enables evaluation of pressure differences in different locations in the heart and great vessels and assessment of the severity of certain types of cardiovascular disease (NHLBI)

n Combining electron tomography with energy-filtered electron microscopy yields high-resolution images of 3-D distributions of specific chemical elements in cells; this technique will be useful for elucidating the organization of DNA in the nucleus because the intrinsic image contrast mechanism clearly distinguishes between protein and nucleic acid (DBEPS)

n The use of semiconductor-based nanocrystals as a nontoxic angiographic contrast agent is explored (DBEPS, NICHD, NCI)

n The first radiolabeled nonpeptide ligand for the corticotropin releasing hormone type 1 receptor that can be used for PET scanning is designed and synthesized (NIDDK)

n Stem cells labeled with magnetic particles are amenable to magnetic resonance imaging, which has been used to track mesenchymal stem cells injected directly into the left ventricle (NHLBI, NINDS)

Advances in bioinformatics

n Launching of the Cohort Consortium—an interdisciplinary public-private, intramural-extramural collaboration—to facilitate subset data analysis and the examination of gene-gene and gene-environment interactions in cancer, diabetes, and cardiovascular, neurological, and other complex diseases (NCI)

Advances in biotechnology

n The finding that over a lifetime the mitochondrial DNA of single bone-marrow progenitor cells accumulates multiple mutations has implications for the aging process, forensic identifications, and anthropological conclusions based on mitochondrial DNA sequence (NHLBI)

n The finding of sequence-based bias in the integration of murine leukemia virus and human immunodeficiency virus-1 into the human genome has ramifications for gene therapy (NHGRI)

n Generation and analysis of a phylogenetically diverse set of genomic sequences from 12 vertebrate species is accomplished, as well as the demonstration of how comparative sequence analysis can be used to identify small genomic regions that are highly conserved across multiple species (NHGRI)

n A new, highly specific molecular tracking technique—T-cell clonotype tracking—allows ex vivo determination of clonal frequency without prior in vitro expansion that can aid in the study of pathogenesis of neurological immune disorders and in designing therapeutic interventions in such conditions as multiple sclerosis, HTLV-1—associated myelopathy/tropical spastic paraparesis, and chronic Lyme neuroborreliosis (NINDS)

n Description for the first time of the global differences between expression profiles of the two stem cell lineages—embryonic and trophoblastic—derived from the early embryo, and identification of genes expressed specifically in TS and ES cells, sets the stage for further study of the differences between the lineage-committed and pluripotent stem cells and their genes (NIA)

n Buccal epithelial cells collected from women who had received male-to-female bone marrow transplant show the Y phenotype in the overwhelming majority of cells—with no evidence of fusion—supporting the idea that adult stem cells retain plasticity and have a role in regenerative medicine (NIDCR, NHGRI. NHLBI, NIMH, NINDS)

n Engineering of an anthrax toxin activated by urokinase plasminogen activator transforms this toxin into a potent suppressor of a broad array of malignant tumors, eradicating established tumors without damaging normal cells (NIDCR)


Goal C: Develop new or improved approaches for preventing or delaying the onset or progression of disease and disability

n Neither estrogen nor prolactin exposure is found to be related to the risk of developing systemic lupus erythematosus, but breastfeeding is associated with reduced risk in a population-based, case-control study (NIEHS)

n Continuing post-trial follow-up of the Finnish ATBC (a-tocopherol, b-carotene cancer prevention) trial reveals no new findings that would alter the recommendation that smokers should not take supplemental b-carotene (NCI)

n Continuing very long-term follow-up of sibling patients with gyrate atrophy show that the earlier in life an arginine-restricted diet is begun, the greater the protection against retinal lesions that ultimately lead to blindness (NEI)

n Epidemiologic studies indicate that DDT use for malaria control in sub-Saharan Africa is accompanied by an increase in infant mortality from DDT toxicity equal to a decrease in infant mortality attributable to malaria prevention, suggesting that other means to control malaria be used (NIEHS)

n Analysis of data from the Breast Cancer Detection Demonstration Trial shows that the risk of ovarian cancer is increased in women who use estrogen-only replacement therapy and increases with duration, especially beyond 10 years (NCI)

n The risk of breast cancer after successful treatment for Hodgkin’s disease increases with radiation dosage to the breast and is ameliorated by the degree of damage to ovarian function from radiation or alkylating agents; the risk of lung cancer is associated with both radiation exposure and alkylating agents; these risks persist for decades, supporting the need for long-term follow-up of these patients (NCI)

n Data generated from the ALTS Cervical Cancer Screening Study demonstrate that human papilloma virus testing helps distinguish women with equivocal cytological findings who have potentially precancerous lesions from those whose abnormalities are not life threatening (NCI)

n Circulating free testosterone levels correlates with specific measures of cognitive performance among men 50–90 years old in the Baltimore Longitudinal Study of Aging, a finding that could lead to study of the safety and efficacy of testosterone supplementation to prevent or attenuate cognitive loss in healthy aging men (NIA, NCCAM)

n Differences in characteristics of African American and non-African American teenagers suggest the need for ethnoculturally sensitive treatment strategies for smoking cessation in adolescents—and the need to be mindful that the number of cigarettes smoked daily may reflect nicotine clearance rate rather than degree of dependence and addiction (NIDA)

n Skipping meals (without calorie reduction or weight loss) was found to have beneficial effects on resistance to diabetes, cardiovascular risk factors and response to stress, and nerve cell integrity in mice; a controlled trial to test the effect of reducing meal frequency in humans is in development (NIA)

n Synthetic p53 inhibitors improves behavioral outcome in a mouse model of Parkinson’s disease and may have clinical implications (NIA)

Vaccine development

n A recombinant hepatitis E vaccine is highly immunogenic and efficacious in preventing hepatitis and even infection in rhesus macaques after I.V. challenge with three different genotypes of hepatitis E virus, strongly suggesting it will prove highly efficacious in preventing hepatitis E in an ongoing field trial in Nepal (NIAID)

n A phase I multiclade HIV-1 DNA plasmid vaccine trial is underway (VRC)

n A phase I/II clinical trial of modified vaccinia virus Ankara is being tested against Dryvax challenge in vaccinia-naïve individuals (VRC)

n A phase I study of a lipooligosaccharide-based conjugate vaccine against nontypeable Haemophilus influenzae, the cause of about one-third of cases of purulent pediatric otitis media and a common cause of adult pulmonary infection, proved safe and immunogenic in adults and is now being planned for evaluation in a phase II trial in children (NIDCD)

n A single injection of a conjugate vaccine containing Staphylococcus aureus type 5 and type 8 capsular polysaccharides is safe and immunogenic and provides some protection for approximately 40 weeks against S. aureus bacteremia in patients with end-stage renal disease, an immunocompromised population at especially high risk for S. aureus bacteremia; testing of booster doses is suggested (NICHD)

n Isolation and characterization of two glycolipid surface antigens of Borrelia burgdorferi advances the study of immunity to this pathogen and the quest for an effective vaccine against Lyme disease (NICHD)

n Persistence of antibodies and efficacy against typhoid fever is documented for up to four years follow-up in children 2 to 5 years old vaccinated with conjugate Salmonella typhi vaccine (Vi capsular polysaccharide bound to a recombinant mutant Pseudo-monas exotoxin) (NICHD, NIDDK)

n Development and testing of conjugate shigella and cholera vaccines and purification of Campylobacter jejuni and Mycobacterium tuberculosis polysaccharides continues (NICHD, NIDDK)

n An improved anthrax vaccine that induced capsular antibodies in mice expands the immunity conferred by available anthrax vaccines and could prove to provide more protection against the greater number of spores that might be released in a deliberate anthrax attack (NICHD, NIDDK, NIAID)

n Studies showing that Brucella abortus interacts with two different toll-like receptors to trigger the release of both TNF and IL-12 inform the use of bacteria in designing adjuvants and/or carriers for vaccines and immunotherapy (CBER, NIAID, NCI)


Goal D: Develop new or improved methods for diagnosing disease and disability

n A computer-aided detection algorithm identifies large polyps missed by CT in patients at risk for colorectal cancer (CC)

n Establishment of the best predictors of fibrosis progression in chronic hepatitis enables the safe deferral of treatment for patients with normal aminotransferase levels and mild liver histology (NIDDK, NCI, CC)

n The uncovering of three immunogenetic markers provides additional evidence for linkage disequilibrium in familial Hodgkin’s disease (NCI)

n High-throughput microarray genetic testing and novel imaging techniques with image-analysis software improves early identification of neovascularization in patients with age-related macular degeneration (NEI, CIT)

n MRI proves more accurate than cardiac risk factors, ECG, and troponin assays in detecting acute coronary syndrome in patients arriving at the emergency room with chest pain (NHLBI)

n Only one-third of children with Smith-Magenis syndrome are found to have a normal lipid profile, suggesting that hypercholesterolemia can be an early marker of the syndrome in children younger than 4 or 5, the age when the disease is usually diagnosed (NHGRI)

n New hepatitis B surface antigen assays proves superior to currently licensed tests for detecting hepatitis B virus in blood donations; two of the newer tests were subsequently licensed; work continues on developing nucleic acid tests to assay for HBV DNA (CBER, NHLBI)

n Sequential evaluation of changes in visual memory test scores are predictive of Alz-heimer’s disease up to 15 years later in a study involving more than 1,400 people enrolled in the Baltimore Longitudinal Study of Aging, providing a tool for early identification of increased risk and lengthening the window of opportunity for preventive measures (NIA)

n Cerebrospinal fluid levels of b-amyloid and tau proteins appear to be early biomarkers of Alzheimer’s disease that offer a tool more reliable than current methods to prospectively track changes in people at risk for the disease; long-term studies to evaluate this potential are now underway (NIMH)

Gene expression patterns

n Gene expression profiling proves to be the most precise prognostic index yet described for mantle cell lymphoma and suggests that therapeutic modulation of the cell cycle has the potential to significantly prolong life (NCI)

n The Clinical Proteomics Program pioneers the use of serum proteomic patterns to detect early-stage ovarian cancer, achieving 100 percent sensitivity in identifying all stages of ovarian cancer—including stage 1—and 95 percent specificity; serum proteomic patterns also correctly predict 95 percent of prostate cancers and 78 percent of benign prostatic conditions; specificity for men with marginally elevated PSA levels is 71 percent, suggesting that this assay become an adjunct to PSA in deciding whether to biopsy men with marginally elevated PSA levels (NCI, CBER)

n The Clinical Proteomics Program has produced more than 20 publications in the past year elaborating on signal pathway analysis of metastasis models and human cancers and proteomic pattern diagnostics, with particular reference to prostate, ovarian, and colon cancers (CBER, NCI)

n Gene expression profiling demonstrates for the first time that the transcription defect in Werner’s syndrome (WS) is specific to certain genes and that transcription alterations in WS are strikingly similar to those in normal aging, identifying which genes are important in the aging process and supporting the use of WS as an aging model (NIA)

n Gene expression patterns in the postmortem cortex of cocaine abusers reveals cocaine-regulated transcripts associated with an array of signaling mechanisms, neuronal plasticity, and oligodendrocyte function, including alteration in the extracellular signal–regulated kinase (MEK/ERK) pathway (NIDA)

n Ex vivo gene expression profiles differ among multiple sclerosis patients according to responsiveness to interferon-b, a finding that can elucidate the mechanism of action of IFN-b in relation to different disease patterns and lead to optimized therapy; profiling after short-term treatment may enable prediction of long-term treatment response (NINDS, NCI, CC)


Goal E: Develop new or improved approaches for treating disease and disability

n Cyclophosphamide and glucocorticoids for induction and methotrexate for maintaining remission prove an effective and well-tolerated regimen in patients with active Wegener’s granulomatosis (NIAID)

n Itraconazole proves effective in preventing fungal infection in patients with chronic granulomatous disease; recurrent infections in patients with CGD are most likely reinfections, not relapses (NIAID, CC, NCI)

n Pretreatment of fatty donor livers with IL-6 in vitro dramatically improves the take of such livers in liver transplantation, a finding with major clinical implications because one-third of all donor livers are fatty and at high risk of transplantation failure (NIAAA)

n Endocannabinoids acting on cannabinoid receptor 1 (CB1) in the brain have a major role in regulating alcohol preference in mice and also in the age-dependent decline in alcohol preference, findings that support the planned use of CB1 antagonists in the treatment of alcoholism (NIAAA)

n Recombinant leptin-replacement therapy improves glycemic control and decreases triglyceride levels in patients with lipodystrophy and severe insulin resistance (NIDDK, CC)

n Maintenance therapy with ribavirin alone in patients with chronic hepatitis C maintains biochemical improvements obtained with combination interferon-ribavirin but with lower incidence of necroinflammatory changes in the liver (NIDDK, NCI)

n Safety is established for nonmyeloablative allotransplantation in HIV patients with hematologic malignancies (NIDDK, NIAID, NHGRI, CC, NHLBI, NCI)

n Melanoma patients offered nonmyeloab-lative conditioning followed by adoptive transfer of antitumor lymphocytes specific for the MART-1 melanocyte differentiation antigen experience both the destruction of metastatic tumors and an autoimmune attack on normal tissues that express the MART-1 antigen; these results support the efficacy of this new approach in melanoma treatment and suggest that normally expressed "self-antigens" can be useful as targets for human tumor immunotherapy in other settings if the autoimmune consequences of such treatment are acceptable, as may be the case in prostate, breast, ovary, or thyroid cancer (NCI, NEI)

n A Phase I trial involving patients with a variety of solid tumors at advanced stages and prior treatment histories establishes a safe dose for further clinical trials of an epothilone B analog—a member of a novel class of nontaxane microtubule-stabilizing agents that has shown promise in vitro (NCI)

n Bevacizumab (anti-VEGF antibody) prolongs time to progression in patients with metastatic renal cancer in a randomized controlled trial (NCI)

n In the most favorable outcome yet documented for this incurable disease, treatment of aplastic anemia with immunosuppression results in remission and a favorable long-term response (NHLBI)

n Autologous lymphocyte-depleted peripheral blood stem cells mitigates the myelosup-pressive effects of high-dose cyclophosphamide in the treatment of refractory chronic autoimmune thrombocytopenia (NHLBI, CC)

n Different "trajectories of dying" and degrees of dependency during what turned out to be the last year of life are observed in elderly individuals who died of cancer, of organ failure, suddenly, or in a frail state, underscoring the need to create more-tailored programs of care for elderly patients (NIA)

n A short course of humanized anti-CD40 ligand antibody improves serologic activity and decreased hematuria in a pilot study involving patients with proliferative lupus glomerulonephritis, but the potential for increased risk of thrombotic events needs study (NIAMS, NIDDK)

n A new clinical program for the study of allograft tolerance introduces four novel immunomodulation regimens, including Campath-1H, a humanized CD52-specific monoclonal antibody (alemtuzumab) (NIDDK, NCI)

n High daily doses of sublingual buprenor-phine significantly reduces both cocaine and opiate use in outpatients dependent on both substances—the first direct demonstration of this agent’s efficacy in treating dual dependence (NIDA)

n Immunological tolerization to E-selectin, an adhesion molecule on endothelial cells, provides protection against development of ischemic and hemorrhagic strokes in animal studies; plans for human trials using this approach are underway under a CRADA with industry (NINDS)

n Dopamine D3 receptor antagonists show promise as anti-addiction and anti-relapse agents (NIDA)

n Methadone treatment induces attenuation of cerebrovascular deficits associated with prolonged cocaine and heroine abuse (NIDA)

n Enzyme replacement therapy improves peripheral nervous system function, corrects abnormal cerebral perfusion, and improves quality of life in a controlled clinical trial involving patients with Fabry disease (NINDS, NHLBI)

n Long-term follow-up of patients in the Early Treatment Diabetic Retinopathy Study shows that 15 to 20 years after laser photocoagulation therapy and despite progression of other diabetic complications, retinopathy remains largely stabilized, with 80 percent still having good vision and no patient becoming blind. (NEI)

n Elucidation of the role of ocular surface inflammation in Sjögren’s syndrome helps secure the approval of cyclosporine-A eye drops in the treatment of dry eye (NEI)

n In vitro studies demonstrated that accelerated programmed cell death of the retinal pigment epithelial cells, a major cause of blindness in age-related macular degeneration, is not related to the caspase-dependent system of proteins but to an apoptosis-inducing factor, the effects of which can be prevented by treatment of RPE cells with hepatocyte growth factor/scatter factor—the first observation of a potential therapy of this form of AMD (NEI)

n Antibody therapy (humanized monoclonal antibody directed against the a-chain of the interleukin-2 receptor–daclizumab) continues to be safe and effective in the treatment of uveitis in a cohort of patients with the longest history of use of this agent in the world (up to four years); clinical trials are being planned to test expanded uses in uveitis and in other autoimmune diseases (NEI, NCI)

n Daclizumab is not only well tolerated in multiple sclerosis patients unresponsive to standard therapy but also dramatically inhibits inflammatory activity in a phase II clinical trial that establishes the drug as a promising candidate for immunomodulatory treatment of MS (NINDS, NCI)

n Primate studies showing that adenovirus-induced thrombocytopenia is the result of a reversible increase in platelet clearance rather than bone marrow suppression may inform the design of safer gene-therapy delivery methods (CBER, OAR)

n Small clinical studies in which exendin-4, an amino acid found in the saliva of the Gila monster and an agonist of glucagon-like peptide-1 (GLP-1) receptor in humans, is well tolerated and a potent, long-acting insulin-releasing agent in patients with type 2 diabetes, setting the stage for larger phase III clinical trials (NIA)

n GLP-1 agonists are shown to be neurotrophic and neuroprotective in cell cultures subjected to toxic insults emulating stroke and Alzheimer’s disease and to be effective in well-established animal models of neurodegenerative conditions; novel GLP-1 analogs are synthesized and patented and are being assessed for use as experimental drugs in humans with a wide array of neurodegenerative diseases (NIA)

n A potential therapeutic agent for spinal muscular atrophy is identified (NINDS)

n Deacetylase inhibitors reduce the toxicity associated with the mutant polyglutamine that underlies many hereditary neurodegen-erative disorders and are being considered for clinical trials in Huntington’s disease, spinal muscular atrophy, and other diseases associated with polyglutamate expansion and aberrant histone acetylation (NINDS)

n Identification of a drug that drastically reduces the toxic homogentisic acid produced by alkaptonuria patients suggests moving toward long-term safety and efficacy studies (NHGRI, NICHD, CC)

n Generated under a CRADA with industry, a new class of immunosuppressive drugs that inhibit JAK3 proves effective against allograft rejection in nonhuman primates and is of likely use in the treatment of autoimmune and inflammatory disorders as well; human trials are anticipated (NIAMS)


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