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Showing papers by "National Jewish Health published in 2013"


Journal ArticleDOI
01 Dec 2013-Thorax
TL;DR: It is demonstrated that elevated expression of cilium genes is associated with more extensive microscopic honeycombing and higher expression of both the airway mucin gene MUC5B and the metalloproteinase MMP7, a gene recently implicated in attenuating ciliated cell differentiation during wound repair.
Abstract: Background Idiopathic pulmonary fibrosis (IPF) is an untreatable lung disease with a median survival of only 3–5 years that is diagnosed using a combination of clinical, radiographic and pathologic criteria. Histologically, IPF is characterised by usual interstitial pneumonia (UIP), a fibrosing interstitial pneumonia with a pattern of heterogeneous, subpleural regions of fibrotic and remodelled lung. We hypothesised that gene expression profiles of lung tissue may identify molecular subtypes of disease that could classify subtypes of IPF/UIP that have clinical implications. Methods and findings We collected transcriptional profiles on lung tissue from 119 patients with IPF/UIP and 50 non-diseased controls. Differential expression of individual transcripts was identified using an analysis of covariance (ANCOVA) model incorporating the clinical diagnosis of each patient as well as age, gender and smoking status. Validation was performed in an independent cohort of 111 IPF/UIP and 39 non-diseased controls. Our analysis identified two subtypes of IPF/UIP based on a strong molecular signature associated with expression of genes previously associated with fibrosis (matrix metalloproteinases, osteopontin, keratins), cilium genes and genes with unknown function. We demonstrate that elevated expression of cilium genes is associated with more extensive microscopic honeycombing and higher expression of both the airway mucin gene MUC5B and the metalloproteinase MMP7, a gene recently implicated in attenuating ciliated cell differentiation during wound repair. Conclusions Expression of cilium genes appears to identify two unique molecular phenotypes of IPF/UIP. The different molecular profiles may be relevant to therapeutic responsiveness in patients with IPF/UIP.

192 citations


Journal ArticleDOI
TL;DR: A selection of 46 HLA DR, DQ, and DP specificities that provide worldwide population (phenotypic) coverage of almost 90 % at each locus, and account for over 66 % of all genes at eachlocus are described, to enable high throughput determination of HLA restriction.
Abstract: Classic ways to determine MHC restriction involve inhibition with locus-specific antibodies and antigen presentation assays with panels of cell lines matched or mismatched at the various loci of interest. However, these determinations are often complicated by T cell epitope degeneracy and promiscuity. We describe a selection of 46 HLA DR, DQ, and DP specificities that provide worldwide population (phenotypic) coverage of almost 90 % at each locus, and account for over 66 % of all genes at each locus. This panel afforded coverage of at least four HLA class II alleles in over 95 % of the individuals in four study populations of diverse ethnicity from the USA and South Africa. Next, a panel of single HLA class II-transfected cell lines, corresponding to these 46 allelic variants was assembled, consisting of lines previously developed and 15 novel lines generated for the present study. The novel lines were validated by assessing their HLA class II expression by FACS analysis, the in vitro peptide binding activity of HLA molecules purified from the cell lines, and their antigen presenting capacity to T cell lines of known restriction. We also show that these HLA class II-transfected cell lines can be used to rapidly and unambiguously determine HLA restriction of epitopes recognized by an individual donor in a single experiment. This panel of lines will enable high throughput determination of HLA restriction, enabling better characterization of HLA class II-restricted T cell responses and facilitating the development of HLA tetrameric staining reagents.

71 citations


Journal ArticleDOI
TL;DR: Elucidating DC functions, particularly in the lung, may then allow use of the inherent ability of these cells for enhanced vaccine strategies and therapeutics for pulmonary infections and diseases.
Abstract: Pulmonary dendritic cells (DCs) constantly sample the tissue and traffic inhaled antigens to the lung-draining lymph node where they normally orchestrate an appropriate immune response. The dynamic ability of these professional antigen-presenting cells to promote tolerance or immunity has been intensively studied by several groups, including ours. Distinct DC subsets in both lymphoid and non-lymphoid tissues have been described based on their surface molecule expression and location. Current efforts to unravel DC development and function are providing insight into the various roles each subset offers the immune system. Elucidating DC functions, particularly in the lung, may then allow use of the inherent ability of these cells for enhanced vaccine strategies and therapeutics for pulmonary infections and diseases.

44 citations


Journal ArticleDOI
TL;DR: T cell recognition of foreign peptide antigen and tolerance to self peptides is key to the proper function of the immune system, and particular MHC alleles are the most strongly associated, reflecting the key importance of MHC presentation of self peptide in autoimmunity.
Abstract: T cell recognition of foreign peptide antigen and tolerance to self peptides is key to the proper function of the immune system. Usually, in the thymus T cells that recognize self MHC + self peptides are deleted and those with the potential to recognize self MHC + foreign peptides are selected to mature. However there are exceptions to these rules. Autoimmunity and allergy are two of the most common immune diseases that can be related to recognition of self. Many genes work together to lead to autoimmunity. Of those, particular MHC alleles are the most strongly associated, reflecting the key importance of MHC presentation of self peptides in autoimmunity. T cells specific for combinations of self MHC and self peptides may escape thymus deletion, and thus be able to drive autoimmunity, for several reasons: the relevant self peptide may be presented at low abundance in the thymus but at high level in particular peripheral tissues; the relevant self peptide may bind to MHC in an unusual register, not present in the thymus but apparent elsewhere; finally the relevant self peptide may be post translationally modified in a tissue specific fashion. In some types of allergy, the peptide + MHC combination may also be fully derived from self. However the combination in question may be modified by the presence of other ligands, such as small drug molecules or metal ions. Thus these types of allergies may act like the post translationally modified peptides involved some types of autoimmunity.

41 citations


Journal ArticleDOI
TL;DR: It is suggested that IL-18-mediated endothelial cell death may contribute to vascular destruction and disappearance in SHS-induced COPD.
Abstract: Chronic second-hand smoke (SHS) exposure comprises the main risk factor for nonsmokers to develop chronic obstructive pulmonary disease (COPD). However, the mechanisms behind the chronic inflammation and lung destruction remain incompletely understood. In this study, we show that chronic exposure of Sprague-Dawley rats to SHS results in a significant increase of proinflammatory cytokine IL-18 and chemokine (C-C motif) ligand 5 in the bronchoalveolar lavage fluid (BALF) and a significant decrease of vascular endothelial growth factor (VEGF) in the lung tissue. SHS exposure resulted in progressive alveolar airspace enlargement, cell death, pulmonary vessel loss, vessel muscularization, collagen deposition, and right ventricular hypertrophy. Alveolar macrophages displayed a foamy phenotype and a decreased expression of the natural inhibitor of IL-18, namely, IL-18 binding protein (IL-18BP). Moreover, IL-18 down-regulated the expression of VEGF receptor-1 and VEGFR receptor-2, and induced apoptosis in pulmonary microvascular endothelial cells in vitro. We also observed a trend toward increased concentrations of IL-18 in the BALF of patients with COPD. Our findings suggest that IL-18-mediated endothelial cell death may contribute to vascular destruction and disappearance in SHS-induced COPD. Moreover, IL-18 and IL-18BP are potential new targets for therapeutics.

39 citations


Journal ArticleDOI
TL;DR: Polysomnography and CPC measures differentiated no from moderate to severe OSA groups and HFC ≥ 50 % discriminated successful from unsuccessful CPAP therapy, and showed clinical value in identifying sleep quality disturbance among CPAP users.
Abstract: The study compares polysomnography (PSG) and cardiopulmonary coupling (CPC) sleep quality variables in patients with (1) obstructive sleep apnea (OSA) and (2) successful and unsuccessful continuous positive airway pressure (CPAP) response. PSGs from 50 subjects (32 F/18 M; mean age 48.4 ± 12.29 years; BMI 34.28 ± 9.33) were evaluated. OSA patients were grouped by no (n = 16), mild (n = 13), and moderate to severe (n = 20) OSA (apnea–hypopnea index (AHI) ≤ 5, >5–15, >15 events/h, respectively). Outcome sleep quality variables were sleep stages in non-rapid eye movement, rapid eye movement sleep, and high (HFC), low (LFC), very low-frequency coupling (VLFC), and elevated LFC broad band (e-LFCBB). An AHI ≤ 5 events/h and HFC ≥ 50 % indicated a successful CPAP response. CPC analysis extracts heart rate variability and QRS amplitude change that corresponds to respiration. CPC-generated spectrograms represent sleep dynamics from calculated coherence product and cross-power of both time series datasets. T tests differentiated no and moderate to severe OSA groups by REM % (p = 0.003), HFC (p = 0.007), VLFC (p = 0.007), and LFC/HFC ratio (p = 0.038) variables. The successful CPAP therapy group (n = 16) had more HFC (p = 0.003), less LFC (p = 0.003), and e-LFCBB (p = 0.029) compared to the unsuccessful CPAP therapy group (n = 8). PSG sleep quality measures, except the higher arousal index (p = 0.038) in the unsuccessful CPAP group, did not differ between the successful and unsuccessful CPAP groups. HFC ≥ 50 % showed high sensitivity (77.8 %) and specificity (88.9 %) in identifying successful CPAP therapy. PSG and CPC measures differentiated no from moderate to severe OSA groups and HFC ≥ 50 % discriminated successful from unsuccessful CPAP therapy. The HFC ≥ 50 % cutoff showed clinical value in identifying sleep quality disturbance among CPAP users.

36 citations


Journal ArticleDOI
TL;DR: It is reported that CFA emulsified with PBS alone (without collagen) is sufficient to induce a strong response of Vγ4Vδ4+ cells in the draining lymph nodes of DBA/1 and C57BL/6 mice and that the TCRs of the elicited Vγ 4V γδ T cells in both strains heavily favor the canonical sequence.
Abstract: We previously reported a subset of γδ T cells in mice which preferentially responds following intradermal immunization with collagen in complete Freund's adjuvant (CFA). These cells express a nearly invariant "canonical" Vγ4Vδ4+ TCR. They are potent producers of IL-17A and promote the development of collagen-induced arthritis. In this study, we report that CFA emulsified with PBS alone (without collagen) is sufficient to induce a strong response of Vγ4Vδ4+ cells in the draining lymph nodes of DBA/1 and C57BL/6 mice and that the TCRs of the elicited Vγ4Vδ4+ cells in both strains heavily favor the canonical sequence. However, although both CFA and incomplete Freund's adjuvant (which lacks the killed mycobacteria present in CFA) induced Vγ4Vδ4+ γδ T cell to expand, only CFA stimulated them to express IL-17A. The route of immunization was also critical, since intraperitoneal CFA induced only a weak response by these cells, whereas intradermal or subcutaneous CFA strongly stimulated them, suggesting that the canonical CFA-elicited Vγ4Vδ4+ cells are recruited from Vγ4+ γδ T cells normally found in the dermis. Their IL-17A response requires the toll-like receptor adapter protein MyD88, and their activation is enhanced by IFNγ, although αβ T cells need not be present. The CFA-elicited Vγ4Vδ4+ γδ T cells show a cytokine profile different from that of other previously described IL-17-producing γδ T cells. Finally, the Vγ4Vδ4+ subset appears to promote the Th17 αβ T cell response, suggesting its importance in mounting an effective immune response against certain pathogens.

30 citations


Journal ArticleDOI
TL;DR: The disparate effects of type I and II IFNs on host resistance to certain intracellular bacterial infections are discussed and an overview of models that have been proposed to account for these disparate effects are provided.
Abstract: The type I and II interferons (IFNs) play important roles in regulating immune responses during viral and bacterial infections and in the context of autoimmune and neoplastic diseases. These two IFN types bind to distinct cell surface receptors that are expressed by nearly all cells to trigger signal transduction events and elicit diverse cellular responses. In some cases, type I and II IFNs trigger similar cellular responses, while in other cases, the IFNs have unique or antagonistic effects on host cells. Negative regulators of IFN signaling also modulate cellular responses to the IFNs and play important roles in maintaining immunological homeostasis. In this review, we provide an overview of how IFNs stimulate cellular responses. We discuss the disparate effects of type I and II IFNs on host resistance to certain intracellular bacterial infections and provide an overview of models that have been proposed to account for these disparate effects. Mechanisms of antagonistic cross talk between type I and II IFNs are also introduced.

27 citations


Journal ArticleDOI
TL;DR: This review provides an overview of rules that govern the B-cell labor roles, exceptions that break these rules, and models that have been used to define them.
Abstract: B lymphocytes are often considered a homogenous population. However, B cells in both mouse and humans are comprised of distinct subpopulations that differ in development, phenotype, function, and microenvironmental niches. Much of our understanding about how these different B-cells populations mount antibody responses has been derived from experimental findings in mouse models and based on the use of model antigens. These reductionist studies performed over decades have been invaluable in defining the parameters of the B-cell antibody response to different types of antigens. However, these antigens also are now known to differ in a significant manner from bona fide physiological pathogens, and precisely how these different B-cell subsets divide labor in the primary humoral immune defense of pathogens is less well understood. While there are no absolutes in this area, there are recurring themes that divide the roles of B-cell subsets to different arms of the antibody response. This review provides an overview of rules that govern the B-cell labor roles, exceptions that break these rules, and models that have been used to define them.

24 citations


Journal ArticleDOI
TL;DR: A simple, inquiry-based outreach lesson centered on a mouse dissection that stimulates interest in biology, personal health and careers in STEM fields, and enhances students' understanding of human organ systems.
Abstract: High school students in the United States are apathetic about science, technology, engineering and mathematics (STEM), and the workforce pipeline in these areas is collapsing. The lack of understanding of basic principles of biology means that students are unable to make educated decisions concerning their personal health. To address these issues, we have developed a simple, inquiry-based outreach lesson centered on a mouse dissection. Students learn key concepts in immunology and enhance their understanding of human organ systems. The experiment highlights aspects of the scientific method and authentic data collection and analysis. This hands-on activity stimulates interest in biology, personal health and careers in STEM fields. Here, we present all the information necessary to execute the lesson effectively with middle and high school students.

18 citations


Journal ArticleDOI
TL;DR: CT imaging findings in children with EC include right colonic wall thickening of variable extent downstream and absent or mild involvement of the terminal ileum, which should be considered in the differential diagnosis in children presenting with abdominal pain and bloody diarrhea.
Abstract: Background Eosinophilic colitis (EC) is a gastrointestinal disease of undetermined etiology whose clinical features overlap with those of the inflammatory bowel diseases To the best of our knowledge, the CT imaging features of EC have not been described in children

Journal ArticleDOI
01 Jan 2013
TL;DR: This review focuses specifically on the differentiation of innate effector cells, particularly the role of cytokine signaling in the differentiated cells of Bone marrow progenitors.
Abstract: Innate effector cells, including innate effector cells of myeloid and lymphoid lineages, are crucial components of various types of immune responses. Bone marrow progenitors differentiate into many subsets of innate effector cells after receiving instructional signals often provided by cytokines. Signal transducer and activator of transcription (STATs) have been shown to be essential in the differentiation of various types of innate effector cells. In this review, we focus specifically on the differentiation of innate effector cells, particularly the role of cytokine signaling in the differentiation of innate effector cells.

Journal ArticleDOI
TL;DR: It is found that SLAP−/− OT-1 mice have fewer CD8+ thymocytes but have increased CD5 expression and differences in α-chain repertoire are found, providing new insights into how TCR avidity during CD8- T cell development influences repertoire selection.
Abstract: How T cell receptor (TCR) avidity influences CD8+ T cell development and repertoire selection is not yet fully understood. To fill this gap, we utilized Src-like adaptor protein (SLAP)-deficient mice as a tool to increase TCR avidity on double positive (DP) thymocytes. We generated SLAP−/− mice with the transgenic MHC class I-restricted TCR (OT-1) and SLAP−/− Vβ5 mice, expressing only the β-chain of the TCR OT-1 transgene, to examine the effects of increased TCR surface levels on CD8+ T cell development and repertoire selection. In comparing SLAP−/− OT-1 and Vβ5 mice with wild-type controls, we performed compositional analysis and assessed thymocyte signaling by measuring CD5 levels. In addition, we performed tetramer and compositional staining to measure affinity for the cognate antigen, ovalbumin (OVA) peptide, presented by MHC. Furthermore, we quantified differences in α-chain repertoire in SLAP−/− Vβ5 mice. We have found that SLAP−/− OT-1 mice have fewer CD8+ thymocytes but have increased CD5 expression. SLAP−/− OT-1 mice have fewer DP thymocytes expressing Vα2, signifying increased endogenous α-chain rearrangement, and more non-OVA-specific CD8+ splenocytes upon tetramer staining. Our data demonstrate that SLAP−/− Vβ5 mice also have fewer OVA-specific cells and increased Vα2 usage in the peripheral Vβ5 CD8+ T cells that were non-OVA-specific, demonstrating differences in α-chain repertoire. These studies provide direct evidence that increased TCR avidity in DP thymocytes enhances CD8+ T cell negative selection deleting thymocytes with specificity for cognate antigen, an antigen the mature T cells may never encounter. Collectively, these studies provide new insights into how TCR avidity during CD8+ T cell development influences repertoire selection.

Journal ArticleDOI
TL;DR: How RNAi screens can be used to uncover critical growth and survival pathways and aid in the identification of novel therapeutic targets for improved treatment of hematological malignancies is discussed.
Abstract: Despite great advances in our understanding of the driving events involved in malignant transformation, only a small number of oncogenic drivers have been targeted and translated into tangible clinical benefit. Moreover, even when a targeted therapy can be shown to effectively inhibit an oncogenic driver, leading to cancer remission, disease persistence and/or relapse is typically inevitable. Reemergence of the cancer can result from either intrinsic or acquired resistance mechanisms that result in failure to eliminate all cancer cells. Intrinsic mechanisms of resistance include tumor heterogeneity and pathways that can compensate for the inhibition of the oncogenic driver. Acquired resistance mechanisms include mutation of the oncogenic driver to directly prevent drug-mediated inhibition and the activation of compensatory survival pathways. RNA interference (RNAi)-based screening provides a powerful approach for the interrogation of both intrinsic and acquired resistance mechanisms. The availability of short interfering (si)RNA libraries targeting all human and mouse genes has made it possible to perform large-scale unbiased screens to identify pathways that are specifically required in cancer cells of particular genotypes or following particular treatments, facilitating the design of potential new therapeutic strategies that may limit resistance mechanisms. In this review, we will discuss how RNAi screens can be used to uncover critical growth and survival pathways and aid in the identification of novel therapeutic targets for improved treatment of hematological malignancies.

Journal ArticleDOI
28 Feb 2013
TL;DR: In this paper, the authors discuss therapeutic options available for complicated diseases of the pleural space, including loculated malignant effusions, complicated pleural infections, hemothorax, nonexpanding lung, pleural thickening, and persistent bronchopleural fistulas.
Abstract: Clinicians frequently encounter patients with malignant and benign diseases involving the pleural space. Complications from these disease processes pose clinical challenges that often require a multi-disciplinary management approach. Here we discuss therapeutic options available for complicated diseases of the pleural space, including loculated malignant effusions, complicated pleural infections, hemothorax, nonexpanding lung, pleural thickening, and persistent bronchopleural fistulas. Our objective is to review current literature on management of these complex issues.

Journal ArticleDOI
TL;DR: Inflammation, the role of inflammation in disease, innate immune signal transduction pathways, and the use of spatiotemporal regulators of innate immunity as potential targets for discovery and therapeutics are discussed.
Abstract: The innate immune response plays a critical role in pathogen clearance. However, dysregulation of innate immunity contributes to acute inflammatory diseases such as sepsis and many chronic inflammatory diseases including asthma, arthritis, and Crohn’s disease. Pathogen recognition receptors including the Toll-like family of receptors play a pivotal role in the initiation of inflammation and in the pathogenesis of many diseases with an inflammatory component. Studies over the last 15 years have identified complex innate immune signal transduction pathways involved in inflammation that have provided many new potential therapeutic targets to treat disease. We are investigating several novel genes that exert spatial and in some cases temporal regulation on innate immunity signaling pathways. These novel genes include Tbc1d23, a RAB-GAP that inhibits innate immunity. In this review, we will discuss inflammation, the role of inflammation in disease, innate immune signal transduction pathways, and the use of spatiotemporal regulators of innate immunity as potential targets for discovery and therapeutics.

Journal ArticleDOI
TL;DR: Active engagement and monitoring of SDB and insomnia will often be necessary to achieve optimal outcomes, and aggressive treatment of insomnia prior to or in combination with SDB treatment may be particularly indicated in situations where insomnia is suspected to interfere with diagnosis or treatment.
Abstract: Sufficient evidence has accumulated to warrant conceptualization of comorbid insomnia and sleep disordered breathing (SDB) as a distinct clinical syndrome. As such, diagnostic and treatment approaches should be founded on an integrated and multidisciplinary approach with equivalent clinical attention and priority given to both insomnia and respiratory aspects of patients’ presenting complaints. Several well established and effective treatments exist for both insomnia and SDB. Although questions of optimal treatment combination and sequence remain to be examined, current evidence provides preliminary guidance regarding the sequential or concurrent management of insomnia and sleep disordered breathing when comorbid. Unsatisfactory response to pharmacotherapy or cognitive-behavioral therapy for chronic insomnia should trigger evaluation for comorbid sleep-related breathing disturbance prior to more aggressive or off label pharmacotherapy. Presence and course of insomnia symptoms should be monitored closely in SDB patients with persistence of insomnia symptoms following SDB treatment prompting targeted treatment of insomnia. Aggressive treatment of insomnia prior to or in combination with SDB treatment may be particularly indicated in situations where insomnia is suspected to interfere with diagnosis or treatment of SDB. Insomnia and sleep disordered breathing appear to uniquely contribute to the morbidity of patients with this comorbidity. With this in mind, active engagement and monitoring of SDB and insomnia will often be necessary to achieve optimal outcomes.

Journal ArticleDOI
TL;DR: The long distance interaction between the sites of allergic inflammation and the site of hematopoiesis in the bone marrow is reviewed, the characteristics of innate type-2 progenitors are studied, and the molecular mechanisms by which innatetype-2 effector cells acquire the capacity to produce type- 2 cytokines are focused on.
Abstract: Type-2 immune responses are the underlying cause of many allergic diseases and provide protection against parasitic infection. Effective type-2 immune responses are generated by type-2 helper CD4+ T cells (Th2) as well as type-2 innate effector cells. While we have learned a great deal about how CD4+ Th2 cells regulate their Th2 cytokine gene transcription, we still do not know how type-2 innate effector cells acquire their capacity to express Th2 cytokine genes. Furthermore, it remains poorly understood how Th2 cytokines regulate the differentiation of innate type-2 progenitor cells. In this review, we will focus on (1) the long distance interaction between the sites of allergic inflammation and the site of hematopoiesis in the bone marrow, (2) the characteristics of innate type-2 progenitors, and (3) the molecular mechanisms by which innate type-2 effector cells acquire the capacity to produce type-2 cytokines.

Journal ArticleDOI
05 Oct 2013
TL;DR: Inflammation of the distal airways is now realized as playing a greater role in asthma control, and newer techniques are available to assess the smaller airways.
Abstract: Airway inflammation is the basis for airway hyper-reactivity that results in the signs and symptoms of asthma. Great strides have been made in the past several decades to target airway inflammation using topical inhaled corticosteroids. In some cases, despite reported improvement in large airways indices on treatment, clinical control of asthma is not attained. Inflammation of the distal airways is now realized as playing a greater role in asthma control, and newer techniques are available to assess the smaller airways. Changes in formulations of inhaled corticosteroids and smaller particle size of medication allows for more effective targeting of the smaller airways.

Book ChapterDOI
01 Jan 2013
TL;DR: Clinical data regarding mechanisms by which obesity modifies asthma phenotype is reviewed, focusing on clinical and translational studies of response to controller therapies such as glucocorticoids and agents targeting leukotriene pathways.
Abstract: Asthma in obese adults is more severe than in lean individuals, and emerging data from clinical and translational studies suggest that obese patients are also less likely to respond to controller therapies, particularly inhaled corticosteroids. As a result, obese asthmatics receive complicated treatment regimens to which they are less likely to respond favorably. Given the high prevalence of both asthma and obesity, this interaction has significant potential to adversely impact both individual and population asthma burden. Despite this, no specific guidance currently exists in NIH or international guidelines as to the optimal therapeutic approach to the obese asthmatic. This chapter will review clinical data regarding mechanisms by which obesity modifies asthma phenotype, focusing on clinical and translational studies of response to controller therapies such as glucocorticoids and agents targeting leukotriene pathways.

Journal ArticleDOI
09 Nov 2013
TL;DR: Patients with idiopathic pulmonary fibrosis are at risk of both venous thromboembolic disease and coronary artery disease and treatment of these co-morbid processes may improve outcomes.
Abstract: Over the past decade, it has been increasingly recognized that patients with idiopathic pulmonary fibrosis (IPF) are at risk of both venous thromboembolic disease (VTE) and coronary artery disease (CAD). When present, these co-morbid conditions negatively affect outcomes. For this disease without effective therapy to improve survival, increased diagnosis and treatment of these co-morbid processes may improve outcomes. Better understanding of the mechanisms that place IPF patients at increased risk of VTE and CAD may also ultimately lead to novel therapeutic interventions.

Journal ArticleDOI
TL;DR: The Rocky Mountain region as a hub for immunology research began in the nineteenth and twenties with the arrival of tuberculosis patients sent for ‘‘clean air and sunshine’’ therapy, leading to remarkable growth of the Denver immunology group inseveral locations.
Abstract: Establishment of the Rocky Mountain region as a hub forimmunology research began in the nineteenth and twenti-eth centuries with the arrival of tuberculosis patients sentfor ‘‘clean air and sunshine’’ therapy. Gerald Webb, a pupilof Sir Almroth Wright—an early developer of typhoidvaccines and a strong proponent of immunization—movedto Colorado to be with his wife who had contractedtuberculosis and to complete his medical education at theUniversity of Denver. In June 1913, a small group ofdoctors from the United States and Canada, who hadtrained in London with Wright, met to consider thefounding of a society. Wright had famously said that ‘‘thephysician of the future will be an immunisator.’’ Webb,who had become a clinician–immunologist in ColoradoSprings, insisted that ‘‘immunologist’’ was a more inclu-sive term. Thus, Webb protected us from celebrating the100th birthday of the American Association of Immuni-sators in 2013. He was elected the first President of theAAI, a reflection of the prominence of the Colorado groupeven in the early history of American immunology [1].Many of the Colorado hospitals and research institutesbegan as tuberculosis sanatoria. The physicians who caredfor tuberculosis patients were impressed with how promi-nent a role the immune response played in both the controland the symptomatology of the disease. With the advent ofstreptomycin in the 1940s, the need for specialized sana-toria waned, and some of them were converted into hos-pitals for the treatment of another prominent pulmonaryimmunologic disease, asthma. National Jewish Hospital forConsumptives, the precursor of National Jewish Health,was founded in 1899. The Denver Sheltering Home forJewish Children, the precursor of the National AsthmaCenter, was established in 1907 as a home for the childrenof tuberculosis patients. These two sites merged in 1978and continue to lead in respiratory care and immunologyresearch today. This was where Kimishige and TerukoIshizaka identified IgE as the antibody isotype that medi-ates allergy in 1966 [2]. In that same year, Henry Claman atthe University of Colorado School of Medicine observedthe synergistic interaction between thymocytes and bonemarrow cells for the production of antibody, thus identi-fying for the first time the helper T cell and T-B collabo-ration [3].Both the Ishizakas and Claman were recruited to Col-orado by David Talmage, who was credited as the man whobrought modern immunology to Denver; he formulatedwhat became known as the clonal selection theory in 1957[4, 5]. Talmage arrived at the University of Colorado in1959. He encouraged the growth of immunology at all ofCU’s affiliated institutions, and began the process wherebynew recruits in these institutions would also be appointedas regular CU faculty. This policy of inclusiveness led toremarkable growth of the Denver immunology group inseveral locations, and the eventual separation of the dis-cipline from the Department of Microbiology and the for-mation of the Integrated Department of Immunology in1993. Kathryn Haskins was the founding interim Depart-ment Chair and John Cambier became its first permanentChair in 1999. They led us to many significant

Patent
05 Dec 2013
TL;DR: In this article, a method of treatment of airway obstruction associated with fibrin-containing cast formation by administering a fibrinolytic agent was proposed. But this method is not suitable for the treatment of lung cancer.
Abstract: The present invention is directed to methods of treatment of airway obstruction associated with fibrin-containing cast formation by administering a fibrinolytic agent.