Antonello Punturieri

Understanding the complexity of IgE-related phenotypes from childhood to young adulthood: a Mechanisms of the Development of Allergy (MeDALL) seminar.

Mechanisms of the Development of Allergy (MeDALL), a Seventh Framework Program European Union project, aims to generate novel knowledge on the mechanisms of initiation of allergy. Precise phenotypes of IgE-mediated allergic diseases will be defined in MeDALL. As part of MeDALL, a scientific seminar was held on January 24, 2011, to review current knowledge on the IgE-related phenotypes and to explore how a multidisciplinary effort could result in a new integrative translational approach. This article provides a summary of the meeting. It develops challenges in IgE-related phenotypes and new clinical and epidemiologic approaches to the investigation of allergic phenotypes, including cluster analysis, scale-free models, candidate biomarkers, and IgE microarrays; the particular case of severe asthma was reviewed. Then novel approaches to the IgE-associated phenotypes are reviewed from the individual mechanisms to the systems, including epigenetics, human inxa0vitro immunology, systems biology, and animal models. The last chapter deals with the understanding of the population-based IgE-associated phenotypes in children and adolescents, including age effect in terms of maturation, observed effects of early-life exposures and shift of focus from early life to pregnancy, gene-environment interactions, cohort effects, and time trends in patients with allergic diseases. This review helps to define phenotypes of allergic diseases in MeDALL.

Comparative effectiveness research in lung diseases and sleep disorders: recommendations from the National Heart, Lung, and Blood Institute workshop.

The Division of Lung Diseases of the National Heart, Lung, and Blood Institute (NHLBI) held a workshop to develop recommendations on topics, methodologies, and resources for comparative effectiveness research (CER) that will guide clinical decision making about available treatment options for lung diseases and sleep disorders. A multidisciplinary group of experts with experience in efficacy, effectiveness, implementation, and economic research identified (a) what types of studies the domain of CER in lung diseases and sleep disorders should include, (b) the criteria and process for setting priorities, and (c) current resources for and barriers to CER in lung diseases. Key recommendations were to (1) increase efforts to engage stakeholders in developing CER questions and study designs; (2) invest in further development of databases and other infrastructure, including efficient methods for data sharing; (3) make full use of a broad range of study designs; (4) increase the appropriate use of observational designs and the support of methodologic research; (5) ensure that committees that review CER grant applications include persons with appropriate perspective and expertise; and (6) further develop the workforce for CER by supporting training opportunities that focus on the methodologic and practical skills needed.

Chronic obstructive pulmonary disease: a view from the NHLBI.

The past decade has witnessed great progress in chronic obstructive pulmonary disease (COPD) research. New drugs have been developed and tested, indications for lung volume reduction surgery (LVRS) have been determined, and a growing base of scientific evidence now documents the efficacy of various therapies for symptoms and exacerbations. This advance in knowledge shatters the old conception of COPD as a hopelessly untreatable condition (1–4). It is clear that many patients with COPD can benefit from aggressive management, with a decrease in the frequency of hospitalizations and improvements in quality of life and survival. In addition, basic and clinical scientists have now identified cells, mechanisms, and molecules that appear to play key roles in disease pathogenesis. Additional novel treatments are on the horizon. The good news about COPD is getting out as many organizations are working effectively to increase awareness of the disease (5). n n nDespite advances in care, the COPD epidemic persists, causing more than 120,000 deaths per year in the United States alone. COPDs position as the fourth leading cause of death in the United States is ominous and the probability of the number of cases rising even further is disturbing. Population-based surveys show that as many as 24 million people in the United States have airflow limitation consistent with COPD and that half or more of these cases have not yet been diagnosed (6). Despite the availability of effective treatments for COPD, no existing therapy halts or reverses the progressive and accelerated decline in lung function that is characteristic of this condition. We are far from having a cure for COPD, and in fact, the most basic questions about this disease remain unanswered: n n nWhy do only a minority of smokers develop clinically significant COPD? n n nWhy is there great heterogeneity in the presentation of COPD? n n nWhich pathogenetic pathways are critical, and how can they be modulated therapeutically? n n nWhy does the disease continue to progress even after smoking cessation? n n nHow can the lung injury that characterizes COPD be reversed? n n n n nBetter means of preventing and treating COPD are urgently needed, but it is not entirely clear what studies should be done. The strategic decisions in COPD research—which investigative approaches to use, which hypotheses to test, which pathways to explore in detail, which basic findings to translate into human studies, and which therapeutic targets to test—are perhaps more difficult to make now than ever before. As opportunities for investigation in COPD have expanded, the pulmonary communitys task of choosing the most effective directions and approaches for COPD research has become even more complex, and wise choices are critical to secure future success. n nIn this essay, we encourage the pulmonary medical community to think about needs, opportunities, and the most productive approaches for research in COPD. We summarize new research directions and findings, how the disease itself is evolving, what research activities are currently underway, and how the infrastructure and organization of the research enterprise in the United States is adapting to new biological and technological challenges and advances that offer unprecedented opportunities for COPD research. We close with a call to action that presses the pulmonary community to widen its horizons and build interdisciplinary teams to better confront the problems of COPD.

American Thoracic Society/National Heart, Lung, and Blood Institute Asthma–Chronic Obstructive Pulmonary Disease Overlap Workshop Report

&NA; Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent chronic obstructive lung diseases with an associated high burden of disease. Asthma, which is often allergic in origin, frequently begins in infancy or childhood with variable airflow obstruction and intermittent wheezing, cough, and dyspnea. Patients with COPD, in contrast, are usually current or former smokers who present after the age of 40 years with symptoms (often persistent) including dyspnea and a productive cough. On the basis of age and smoking history, it is often easy to distinguish between asthma and COPD. However, some patients have features compatible with both diseases. Because clinical studies typically exclude these patients, their underlying disease mechanisms and appropriate treatment remain largely uncertain. To explore the status of and opportunities for research in this area, the NHLBI, in partnership with the American Thoracic Society, convened a workshop of investigators in San Francisco, California on May 14, 2016. At the workshop, current understanding of asthma‐COPD overlap was discussed among clinicians, pathologists, radiologists, epidemiologists, and investigators with expertise in asthma and COPD. They considered knowledge gaps in our understanding of asthma‐COPD overlap and identified strategies and research priorities that will advance its understanding. This report summarizes those discussions.

Reducing Health Inequities in the U.S.: Recommendations From the NHLBI's Health Inequities Think Tank Meeting

The National, Heart, Lung, and Blood Institute convened a Think Tank meeting to obtain insight and recommendations regarding the objectives and design of the next generation of research aimed at reducing health inequities in the United States. The panel recommended several specific actions, including: 1) embrace broad and inclusive research themes; 2) develop research platforms that optimize the ability to conduct informative and innovative research, and promote systems science approaches; 3) develop networks of collaborators and stakeholders, and launch transformative studies that can serve as benchmarks; 4) optimize the use of new data sources, platforms, and natural experiments; and 5) develop unique transdisciplinary training programs to build research capacity. Confronting health inequities will require engaging multiple disciplines and sectors (including communities), using systems science, and intervening through combinations of individual, family, provider, health system, and community-targeted approaches. Details of the panels remarks and recommendations are provided in this report.

A study of hydrogen exchange of monoclonal antibodies : specificity of the antigen-binding induced conformational stabilization

Amide-hydrogen exchange of three anti-yeast iso-1-cytochrome-c IgG monoclonal antibodies and the Fab, prepared from one of them, were studied by infrared spectrophotometry in the presence and absence of the deuterated immunogen and evolutionarily related species (the deuterated immunogen contained a population of a dimer. Each subunit of the dimer appeared to bind to the antibodies in a manner similar to the monomer). The number of hydrogens of the antibodies whose exchange was suppressed on binding to the immunogen was found to exceed that estimated for the residues shielded by the immunogen. Analysis of the data suggests that such suppression of hydrogen exchange occurs mainly for the Fab domains, but not for the Fc. One of the antibodies showed two distinct classes of amide-hydrogens. Class-1 hydrogens (approx. 36/site) exchange faster than class 2 (approx. 37/site). The exchange of class-1 hydrogens was suppressed by binding to the immunogen, but not to the evolutionarily related species. The exchange of class-2 hydrogens was suppressed by binding to the evolutionarily related species, as well as to the immunogen. Thus, the suppression of exchange of class-1 hydrogens appears to occur by some kind of conformational stabilization, the mechanism of which differentiates between the deuterated immunogen and the evolutionarily related species. Evidence suggests that the trans-interactions of the Fab domains may modulate the hydrogen exchange. If it is assumed that the antigen-binding strengthens the trans-interactions in such a way that the exchange of the slower exchanging hydrogens is suppressed, this could explain the suppression of exchange of class-2 hydrogens.

Perspectives from NHLBI Global Health Think Tank Meeting for Late Stage (T4) Translation Research

Almost three-quarters (74%) of all the noncommunicable disease burden is found within low- and middle-income countries. In September 2014, the National Heart, Lung, and Blood Institute held a Global Health Think Tank meeting to obtain expert advice and recommendations for addressing compelling scientific questions for late stage (T4) research-research that studies implementation strategies for proven effective interventions-to inform and guide the National Heart, Lung, and Blood Institutes global health research and training efforts. Major themes emerged in two broad categories: 1) developing research capacity; andxa02) efficiently defining compelling scientific questions within the local context. Compelling scientific questions included how to deliver inexpensive, scalable, and sustainable interventions using alternative health delivery models that leverage existing human capital, technologies and therapeutics, and entrepreneurial strategies. These broad themes provide perspectives that inform an overarching strategy needed to reduce the heart, lung, blood, and sleep disorders disease burden and global health disparities.

Female Sex and Gender in Lung/Sleep Health and Disease: Increased Understanding of Basic Biological, Pathophysiological and Behavioral Mechanisms Leading to Better Health for Female Patients with Lung Disease

Abstract Female sex/gender is an undercharacterized variable in studies related to lung development and disease. Notwithstanding, many aspects of lung and sleep biology and pathobiology are impacted by female sex and female reproductive transitions. These may manifest as differential gene expression or peculiar organ development. Some conditions are more prevalent in women, such as asthma and insomnia, or, in the case of lymphangioleiomyomatosis, are seen almost exclusively in women. In other diseases, presentation differs, such as the higher frequency of exacerbations experienced by women with chronic obstructive pulmonary disease or greater cardiac morbidity among women with sleep‐disordered breathing. Recent advances in ‐omics and behavioral science provide an opportunity to specifically address sex‐based differences and explore research needs and opportunities that will elucidate biochemical pathways, thus enabling more targeted/personalized therapies. To explore the status of and opportunities for research in this area, the NHLBI, in partnership with the NIH Office of Research on Womens Health and the Office of Rare Diseases Research, convened a workshop of investigators in Bethesda, Maryland on September 18 and 19, 2017. At the workshop, the participants reviewed the current understanding of the biological, behavioral, and clinical implications of female sex and gender on lung and sleep health and disease, and formulated recommendations that address research gaps, with a view to achieving better health outcomes through more precise management of female patients with nonneoplastic lung disease. This report summarizes those discussions.

A Decade of National Heart, Lung, and Blood Institute Programs Supporting COPD Research and Education

The past decade of research in chronic obstructive pulmonary disease (COPD) has seen a new age of understanding both pathogenic mechanisms and clinical manifestations of the disease. The National Heart, Lung, and Blood Institute (NHLBI) has helped guide this progress with a series of initiatives to stimulate COPD research in various ways. These initiatives were designed to promote a precision medicine approach to treating COPD, one that takes advantage of targeting particular molecular pathways and the individual pathobiologies of the diversity of COPD patients. This review describes the strategic objectives of these initiatives, as well as some of their observed and anticipated outcomes. In addition, we address parallel steps NHLBI has taken to promote COPD awareness among the public. As we look toward the immediate future of COPD research and education, we see a time of great progress in terms of understanding and treatment. Furthermore, while this remains a debilitating and disturbingly prevalent disease, as NHLBI looks even farther ahead, we envision emerging efforts toward COPD prevention.

Implementation Research to Address the United States Health Disadvantage: Report of a National Heart, Lung, and Blood Institute Workshop.

Four decades ago, U.S. life expectancy was within the same range as other high-income peer countries. However, during the past decades, the United States has fared worse in many key health domains resulting in shorter life expectancy and poorer health-a health disadvantage. The National Heart, Lung, and Blood Institute convened a panel of national and international health experts and stakeholders for a Think Tank meeting to explore the U.S. health disadvantage and to seek specific recommendations for implementation research opportunities for heart, lung, blood, and sleep disorders. Recommendations for National Heart, Lung, and Blood Institute consideration were made in several areas including understanding the drivers of the disadvantage, identifying potential solutions, creating strategic partnerships with common goals, and finally enhancing and fostering a research workforce for implementation research. Key recommendations included exploring why the United States is doing better for health indicators in a few areas compared with peer countries; targeting populations across the entire socioeconomic spectrum with interventions at all levels in order to prevent missing a substantial proportion of the disadvantage; assuring partnership have high-level goals that can create systemic change through collective impact; and finally, increasing opportunities for implementation research training to meet the current needs. Connecting with the research community at large and building on ongoing research efforts will be an important strategy. Broad partnerships and collaboration across the social, political, economic, and private sectors and all civil society will be critical-not only for implementation research but also for implementing the findings to have the desired population impact. Developing the relevant knowledge to tackle the U.S. health disadvantage is the necessary first step to improve U.S. health outcomes.