Report of the Working Group on Integrated Translational Research in DNA Repair.

On September 28-29, 2006, the National Institute of Environmental Health Sciences led a team from the National Institutes of Health in hosting a Working Group on Integrated Translational Research in DNA Repair, in Berkeley, CA. In recognition of the far-reaching goals for this area of investigation, the Working Group was charged with conceiving a vision to facilitate projects that would apply the lessons of DNA Repair research to clinical application and public health. The participants included basic and physician scientists working in the various areas of DNA Repair and genome stability, as well as agency representatives of the National Cancer Institute and the National Institute of General Medical Sciences. In constructing this vision of practical research recommendations, the Working Group was asked to identify roadblocks to progress, suggest enabling technologies, and to consider areas that are ripe for translation. This report summarizes the rationale for this initiative and the recommendations that emerged.

Recent advances and opportunities in research on lupus: environmental influences and mechanisms of disease.

OBJECTIVES: In this review we summarize research on mechanisms through which environmental agents may affect the pathogenesis of lupus, discuss three exposures that have been the focus of research in this area, and propose recommendations for new research initiatives. DATA SOURCES AND SYNTHESIS: We examined studies pertaining to key mechanistic events and specific exposures. Apoptosis leading to increased production or decreased clearance of immunogenic intracellular self-antigens and defective apoptosis of autoreactive immune cells both have been implicated in the loss of self-tolerance. The adjuvant or bystander effect is also needed to produce a sustained autoimmune response. Activation of toll-like receptors is one mechanism through which these effects may occur. Abnormal DNA methylation may also contribute to the pathogenesis of lupus. Each of the specific exposures we examined--Epstein-Barr virus, silica, and trichloroethylene--has been shown, in humans or in mice, to act upon one or more of these pathogenic steps. Specific recommendations for the continued advancement of our understanding of environmental influences on lupus and other autoimmune diseases include the development and use of mouse models with varying degrees of penetrance and manifestations of disease, identification of molecular or physiologic targets of specific exposures, development and use of improved exposure assessment methodologies, and multisite collaborations designed to examine understudied environmental exposures in humans. CONCLUSIONS: The advances made in the past decade concerning our understanding of mechanisms involved in the development of lupus and the influence of environmental agents on this process provide a strong foundation for further developments in this field.

Meeting report: the role of environmental lighting and circadian disruption in cancer and other diseases.

Light, including artificial light, has a range of effects on human physiology and behavior and can therefore alter human physiology when inappropriately timed. One example of potential light-induced disruption is the effect of light on circadian organization, including the production of several hormone rhythms. Changes in light-dark exposure (e.g., by nonday occupation or transmeridian travel) shift the timing of the circadian system such that internal rhythms can become desynchronized from both the external environment and internally with each other, impairing our ability to sleep and wake at the appropriate times and compromising physiologic and metabolic processes. Light can also have direct acute effects on neuroendocrine systems, for example, in suppressing melatonin synthesis or elevating cortisol production that may have untoward long-term consequences. For these reasons, the National Institute of Environmental Health Sciences convened a workshop of a diverse group of scientists to consider how best to conduct research on possible connections between lighting and health. According to the participants in the workshop, there are three broad areas of research effort that need to be addressed. First are the basic biophysical and molecular genetic mechanisms for phototransduction for circadian, neuroendocrine, and neurobehavioral regulation. Second are the possible physiologic consequences of disrupting these circadian regulatory processes such as on hormone production, particularly melatonin, and normal and neoplastic tissue growth dynamics. Third are effects of light-induced physiologic disruption on disease occurrence and prognosis, and how prevention and treatment could be improved by application of this knowledge.

Meeting report: Structural determination of environmentally responsive proteins.

The three-dimensional structure of gene products continues to be a missing lynchpin between linear genome sequences and our understanding of the normal and abnormal function of proteins and pathways. Enhanced activity in this area is likely to lead to better understanding of how discrete changes in molecular patterns and conformation underlie functional changes in protein complexes and, with it, sensitivity of an individual to an exposure. The National Institute of Environmental Health Sciences convened a workshop of experts in structural determination and environmental health to solicit advice for future research in structural resolution relative to environmentally responsive proteins and pathways. The highest priorities recommended by the workshop were to support studies of structure, analysis, control, and design of conformational and functional states at molecular resolution for environmentally responsive molecules and complexes; promote understanding of dynamics, kinetics, and ligand responses; investigate the mechanisms and steps in posttranslational modifications, protein partnering, impact of genetic polymorphisms on structure/function, and ligand interactions; and encourage integrated experimental and computational approaches. The workshop participants also saw value in improving the throughput and purity of protein samples and macromolecular assemblies; developing optimal processes for design, production, and assembly of macromolecular complexes; encouraging studies on protein-protein and macromolecular interactions; and examining assemblies of individual proteins and their functions in pathways of interest for environmental health.

Understanding the epidemiology and progression of systemic lupus erythematosus.

OBJECTIVES: This review examines the burden and patterns of disease in systemic lupus erythematosus (SLE) and the influence and interactions of gender, ethnicity, age, and psychosocial attributes with respect to disease progression, focusing on issues relevant to clinical practice and research. METHODS: PubMed literature search complemented by review of bibliographies listed in identified articles. RESULTS: An increased risk among reproductive age women is clearly seen in African Americans in the United States. However, in other populations, a different pattern is generally seen, with the highest age-specific incidence rates occurring in women after age 40 years. The disease is 2 to 4 times more frequent, and more severe, among nonwhite populations around the world and tends to be more severe in men and in pediatric and late-onset lupus. SLE patients now experience a higher than 90% survival rate at 5 years. The less favorable survival experience of ethnic minorities is possibly related to socioeconomic status rather than to ethnicity per se, and adequate social support has been shown to be a protective factor, in general, in SLE patients. Discordance between physician and patient ratings of disease activity may affect quality of care. CONCLUSIONS: Our understanding of ways to improve outcomes in SLE patients could benefit from patient-oriented research focusing on many dimensions of disease burden. Promising research initiatives include the inclusion of community-based patients in longitudinal studies, use of self-assessment tools for rating disease damage and activity, and a focus on self-perceived disease activity and treatment compliance.

Recent advances and opportunities in research on lupus: environmental influences and mechanisms of disease.

We summarize research on mechanisms through which environmental agents may affect the pathogenesis of lupus, discuss three exposures that have been the focus of research in this area, and propose recommendations for new research initiatives. We examined studies pertaining to key mechanistic events and specific exposures. Apoptosis leading to increased production or decreased clearance of immunogenic intracellular self-antigens and defective apoptosis of autoreactive immune cells both have been implicated in the loss of self-tolerance. The adjuvant or bystander effect is also needed to produce a sustained autoimmune response. Activation of toll-like receptors is one mechanism through which these effects may occur. Abnormal DNA methylation may contribute to the pathogenesis of lupus. Each of the specific exposures has been shown, in humans or in mice, to act upon one or more of these pathogenic steps. Specific recommendations for the continued advancement of our understanding of environmental influences on lupus and other autoimmune diseases include the development and use of mouse models with varying degrees of penetrance and manifestations of disease, identification of molecular or physiologic targets of specific exposures, development and use of improved exposure assessment methodologies, and multisite collaborations designed to examine understudied environmental exposures in humans.

Employment and disability issues in systemic lupus erythematosus: a review.

OBJECTIVE: To summarize research pertaining to work disability in lupus patients, discuss challenges patients face applying for federal disability assistance in the US, and make recommendations for clinical and health policy research. METHODS: We searched Medline for articles on work or disability in lupus patients and gathered information from the Social Security Administration and the National Organization of Social Security Claimants' Representatives. RESULTS: We found 12 publications with employment-related data; 6 included analysis of predictors of work status. The prevalence of inability to work or cessation of work was 15-51% in these studies (3-15 years after diagnosis); 20-32% of patients received disability benefits. Lower education level, higher disease activity, higher disease damage, older age, and higher physical job strain were independent predictors of work disability or work cessation in at least 2 studies. Lupus patients may be less successful than patients with other diseases when applying for federal disability assistance, possibly because medical records may not accurately reflect functional limitations. In addition, symptoms contributing to work disability (e.g., fatigue, pain, neurocognitive dysfunction) may be difficult to assess and quantify. CONCLUSION: Work disability in lupus patients is common. Additional research on risk factors for work disability in lupus patients and on strategies for reducing the impact of these factors on work-related activities is needed. The development of better measures and rating scales for the symptoms responsible for work disability in lupus patients and studies of factors influencing the success of obtaining federal disability benefits would also be useful.

Recovery from heart failure with circulatory assist: a working group of the National, Heart, Lung, and Blood Institute.

BACKGROUND: Over the past decade, mechanical circulatory support has been beneficial as a bridge to cardiac transplantation, and anecdotal evidence suggests that heart failure patients fitted with mechanical assist devices experience direct cardiac benefits. Moreover, recent trials on limited numbers and subpopulations of patients--notably the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH)--support earlier observations of improved cardiac function and point towards the use of assist devices as destination therapy. Methods and results To investigate this phenomenon, on August 2-3, 2001, the National Heart, Lung, and Blood Institute convened the working group, "Recovery from Heart Failure with Circulatory Assist" in Bethesda, Maryland. The team included cardiac surgeons, cardiologists, and experts in experimental research. The goal was to prioritize recommendations to guide future programs in: (1). elucidating the mechanisms leading to reverse remodeling associated with a left ventricular assist device (LVAD); (2). exploring advanced treatments, including novel pharmacologies, tissue engineering, and cell therapies, to optimize recovery with LVAD therapy; and (3). identifying target genes, proteins, and cellular pathways to focus on for production of novel therapies for myocardial recovery and cardiovascular disease. CONCLUSIONS: The working group also made research and clinical recommendations to eventually translate findings into improved therapeutic strategies and device design: (1). support collaborations among clinical and basic scientists with an emphasis on clinical/translational research that might eventually lead to clinical trials; (2). identify candidate patients most likely to benefit from LVAD as a destination therapy; (3). explore potential biomarkers indicating when patients could most successfully be weaned from devices; and (4). promote clinical and experimental study of mechanically assisted organs and the tissue derived from them.

Recent advances and opportunities in research on lupus: environmental influences and mechanisms of disease / Avanços e oportunidades atuais na pesquisa sobre lúpus: influências ambientais e mecanismos da doença

We summarize research on mechanisms through which environmental agents may affect the pathogenesis of lupus, discuss three exposures that have been the focus of research in this area, and propose recommendations for new research initiatives. We examined studies pertaining to key mechanistic events and specific exposures. Apoptosis leading to increased production or decreased clearance of immunogenic intracellular self-antigens and defective apoptosis of autoreactive immune cells both have been implicated in the loss of self-tolerance. The adjuvant or bystander effect is also needed to produce a sustained autoimmune response. Activation of toll-like receptors is one mechanism through which these effects may occur. Abnormal DNA methylation may contribute to the pathogenesis of lupus. Each of the specific exposures has been shown, in humans or in mice, to act upon one or more of these pathogenic steps. Specific recommendations for the continued advancement of our understanding of environmental influences on lupus and other autoimmune diseases include the development and use of mouse models with varying degrees of penetrance and manifestations of disease, identification of molecular or physiologic targets of specific exposures, development and use of improved exposure assessment methodologies, and multisite collaborations designed to examine understudied environmental exposures in humans.

Resumimos uma pesquisa sobre os mecanismos pelos quais agentes ambientais podem afetar a patogenia do lúpus. Discutimos três exposições, foco de pesquisa na área, e propomos recomendações para novas iniciativas de pesquisa. Examinamos estudos relativos a eventos mecanicistas e exposições relativas. A apoptose que resulta no aumento da produção ou diminuição da menor depuração de auto-antígenos imunogênicos intracelulares e de apoptoses defeituosas de células imunes auto-reativas sofre implicações com a perda da auto-tolerância. Foi necessário um adjuvante ou efeito do observador para gerar uma resposta autoimune sustentável. A ativação de receptores toll-like é um dos mecanismos através do qual esses efeitos podem ocorrer. A metilação anormal do DNA também pode contribuir à patogenia de lúpus. Cada exposição mostrou, em humanos e camundongos, que age conforme um ou mais desses passos patogênicos. Recomendações específicas ao contínuo progresso do conhecimento sobre as influências ambientais no lúpus e outras doenças autoimunes compreendem o desenvolvimento e utilização de modelos de camundongos com graus variados de penetrância e manifestações da doença, identificação de alvos moleculares ou fisiológicos de exposições específicas, desenvolvimento e uso de melhores metodologias de avaliação de exposição e colaborações multisite para examinar exposições ambientais sobre os humanos menos estudados.