ABSTRACT
Studies of asthma and allergy are generating increasing volumes of omics data for analysis and interpretation. The National Institute of Allergy and Infectious Diseases (NIAID) assembled a workshop comprising investigators studying asthma and allergic diseases using omics approaches, omics investigators from outside the field, and NIAID medical and scientific officers to discuss the following areas in asthma and allergy research: genomics, epigenomics, transcriptomics, microbiomics, metabolomics, proteomics, lipidomics, integrative omics, systems biology, and causal inference. Current states of the art, present challenges, novel and emerging strategies, and priorities for progress were presented and discussed for each area. This workshop report summarizes the major points and conclusions from this NIAID workshop. As a group, the investigators underscored the imperatives for rigorous analytic frameworks, integration of different omics data types, cross-disciplinary interaction, strategies for overcoming current limitations, and the overarching goal to improve scientific understanding and care of asthma and allergic diseases.
Subject(s)
Asthma , Hypersensitivity , United States , Humans , National Institute of Allergy and Infectious Diseases (U.S.) , Hypersensitivity/genetics , Asthma/etiology , Genomics , Proteomics , MetabolomicsABSTRACT
BACKGROUND: Allergen-specific IL-4+ and IL-13+ CD4+ cells (type 2 cells) are essential for helping B cells to class-switch to IgE and establishing an allergic milieu in the gastrointestinal tract. The role of T cells in established food allergy is less clear. OBJECTIVE: We examined the food allergen-specific T-cell response in participants of 2 food allergen immunotherapy trials to assess the relationship of the T-cell response to clinical phenotypes, including response to immunotherapy. METHODS: Blood was obtained from 84 participants with peanut allergy and 142 participants with egg allergy who underwent double-blind placebo-controlled food challenges. Peanut- and egg-responsive T cells were identified by CD154 upregulation after stimulation with the respective extract. Intracellular cytokines and chemokine receptors were also detected. The response to peanut epicutaneous immunotherapy (Peanut Epicutaneous Phase II Immunotherapy Clinical Trial [CoFAR6]; 49 participants receiving epicutaneous immunotherapy) and egg oral immunotherapy or a baked egg diet (Baked Egg or Egg Oral Immunotherapy for Children With Egg Allergy [CoFAR7]; 92 participants) was monitored over time. RESULTS: Peanut-specific type 2 and CCR6+ T cells were negatively correlated with each other and differently associated with immune parameters, including specific IgE level and basophil activation test result. At baseline, type 2 cells, but not CCR6+ cells, were predictive of clinical parameters, including a successfully consumed dose of peanut and baked egg tolerance. Exposure to peanut or egg immunotherapy was associated with a decrease in type 2 cell frequency. At baseline, high egg-specific type 2 cell frequency was the immune feature most predictive of oral immunotherapy failure. CONCLUSION: Food-specific type 2 T cells at baseline are informative of threshold of reactivity and response to immunotherapy.
Subject(s)
Egg Hypersensitivity , Food Hypersensitivity , Peanut Hypersensitivity , Administration, Oral , Allergens , Arachis , Desensitization, Immunologic , Egg Hypersensitivity/therapy , Food Hypersensitivity/therapy , Humans , Immunoglobulin E , Immunologic Factors , Peanut Hypersensitivity/therapyABSTRACT
BACKGROUND: Consortium for Food Allergy Research investigators previously reported 52-week outcomes from a randomized controlled trial of peanut epicutaneous immunotherapy, observing modest and statistically significant induction of desensitization, highest in children ages 4 to 11 years. OBJECTIVE: We sought to evaluate changes in efficacy, safety, and mechanistic parameters following extended open-label peanut epicutaneous immunotherapy. METHODS: Peanut-allergic participants (4-25 years) received 52 weeks of placebo (PLB), Viaskin Peanut 100 µg (VP100) or 250 µg (VP250), and then crossed over to VP250 for PLB (PLB-VP250) and VP100 (VP100-VP250) participants and continued treatment for VP250 participants (total = 130 weeks of active epicutaneous immunotherapy). Efficacy was assessed by double-blind, placebo-controlled food challenge (5044 mg peanut protein), and adherence, safety, and mechanistic parameters were evaluated. RESULTS: At week 130, desensitization success was achieved in 1 of 20 (5%) PLB-VP250, 5 of 24 (20.8%) VP100-VP250, and 9 of 25 (36%) VP250 participants, with median successfully consumed dose change from baseline of 11.5 mg, 141.5 mg, and 400 mg, respectively. Median age (years) for week 130 desensitization success was 6.2 years (interquartile range, 5.2-9.1) versus 9.4 years (interquartile range, 7.6-12.8) for failures (P < .001). Adherence was 96%. Adverse reactions were predominantly local patch-site reactions. Significant increases in peanut- and Ara h2-specific IgG4 observed at week 52 persisted to week 130. By a post hoc analysis, there were no statistically significant increases from week 52 to week 130 in either desensitization success or successfully consumed dose. CONCLUSIONS: Extended treatment with VP250 was well tolerated, and desensitization observed at week 52 persisted between weeks 52 and 130. Treatment success was observed predominantly in younger participants, with younger age at initiation of active therapy an important predictor of success.
Subject(s)
Age Factors , Immunotherapy/methods , Peanut Hypersensitivity/immunology , 2S Albumins, Plant/immunology , Adolescent , Adult , Antigens, Plant/immunology , Arachis/immunology , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Immunoglobulin G/blood , Injections, Subcutaneous , Male , Peanut Hypersensitivity/diagnosis , Peanut Hypersensitivity/therapy , Prognosis , Young AdultABSTRACT
Atopic dermatitis (AD) affects up to 20% of children worldwide and is an increasing public health problem, particularly in developed countries. Although AD in infants and young children can resolve, there is a well-recognized increased risk of sequential progression from AD to other atopic diseases, including food allergy (FA), allergic rhinitis, allergic asthma, and allergic rhinoconjunctivitis, a process referred to as the atopic march. The mechanisms underlying the development of AD and subsequent progression to other atopic comorbidities, particularly FA, are incompletely understood and the subject of intense investigation. Other major research objectives are the development of effective strategies to prevent AD and FA, as well as therapeutic interventions to inhibit the atopic march. In 2017, the Division of Allergy, Immunology, and Transplantation of the National Institute of Allergy and Infectious Diseases sponsored a workshop to discuss current understanding and important advances in these research areas and to identify gaps in knowledge and future research directions. International and national experts in the field were joined by representatives from several National Institutes of Health institutes. Summaries of workshop presentations, key conclusions, and recommendations are presented herein.
Subject(s)
Hypersensitivity, Immediate , Skin Diseases , Animals , Biomarkers , Humans , Hypersensitivity, Immediate/etiology , Hypersensitivity, Immediate/microbiology , Hypersensitivity, Immediate/prevention & control , Hypersensitivity, Immediate/therapy , Microbiota , Skin Diseases/etiology , Skin Diseases/microbiology , Skin Diseases/prevention & control , Skin Diseases/therapyABSTRACT
BACKGROUND: Egg allergy is phenotypically heterogeneous. A subset of patients with egg allergy can tolerate egg in an extensively heated form. Inclusion of baked egg (BE) into the diet accelerates resolution of egg allergy. Conversely, BE reactivity is associated with persistent disease. The immune basis of this clinical heterogeneity is unknown. OBJECTIVES: We sought to study egg-specific antibody, basophil, and T-cell responses in children with reactivity or tolerance to BE. METHODS: All participants underwent double-blind, placebo-controlled challenges to BE, and those who tolerated BE were challenged with unheated egg white protein to confirm clinical egg reactivity. Laboratory studies included serum antibody measurements, basophil activation tests, and CD154-based detection of egg-responsive T cells by using flow cytometry. RESULTS: Of the 129 children studied, BE-reactive participants had significantly greater levels of egg-, ovalbumin-, and ovomucoid-specific IgE; lower ratios of egg-specific IgG4/IgE; and increased basophil activation in response to egg. Among all participants, CD154-based profiling revealed egg-responsive T cells producing IL-4 and IL-13 but little IL-10 or IFN-γ, as well as the presence of egg-responsive Foxp3+CD25+CD127low regulatory T cells. Egg-responsive T cells expressed CCR4, CCR6, and CXCR5, indicating capacity for homing to the skin, mucosa, and B-cell follicles. However, neither the frequency nor phenotype of egg-responsive T cells was different in those with tolerance or reactivity to BE. CONCLUSIONS: Egg-specific antibody and basophil responses, but not T-cell responses, are greater in those with reactivity versus tolerance to BE. Egg-specific antibody and T-cell responses were highly heterogeneous in this cohort. The clinical implications of this immune heterogeneity will need to be studied longitudinally.
Subject(s)
Basophils/immunology , Egg Hypersensitivity/immunology , Immunoglobulin E/immunology , T-Lymphocytes/immunology , Adolescent , Child , Child, Preschool , Cooking , Double-Blind Method , Egg Proteins/immunology , Female , Humans , Immune Tolerance/immunology , Immunoglobulin E/blood , Male , PhenotypeABSTRACT
BACKGROUND: The contribution of phenotypic variation of peanut-specific T cells to clinical allergy or tolerance to peanut is not well understood. OBJECTIVES: Our objective was to comprehensively phenotype peanut-specific T cells in the peripheral blood of subjects with and without peanut allergy (PA). METHODS: We obtained samples from patients with PA, including a cohort undergoing baseline peanut challenges for an immunotherapy trial (Consortium of Food Allergy Research [CoFAR] 6). Subjects were confirmed as having PA, or if they passed a 1-g peanut challenge, they were termed high-threshold subjects. Healthy control (HC) subjects were also recruited. Peanut-responsive T cells were identified based on CD154 expression after 6 to 18 hours of stimulation with peanut extract. Cells were analyzed by using flow cytometry and single-cell RNA sequencing. RESULTS: Patients with PA had tissue- and follicle-homing peanut-responsive CD4+ T cells with a heterogeneous pattern of TH2 differentiation, whereas control subjects had undetectable T-cell responses to peanut. The PA group had a delayed and IL-2-dependent upregulation of CD154 on cells expressing regulatory T (Treg) cell markers, which was absent in HC or high-threshold subjects. Depletion of Treg cells enhanced cytokine production in HC subjects and patients with PA in vitro, but cytokines associated with highly differentiated TH2 cells were more resistant to Treg cell suppression in patients with PA. Analysis of gene expression by means of single-cell RNA sequencing identified T cells with highly correlated expression of IL4, IL5, IL9, IL13, and the IL-25 receptor IL17RB. CONCLUSIONS: These results demonstrate the presence of highly differentiated TH2 cells producing TH2-associated cytokines with functions beyond IgE class-switching in patients with PA. A multifunctional TH2 response was more evident than a Treg cell deficit among peanut-responsive T cells.
Subject(s)
Peanut Hypersensitivity/immunology , T-Lymphocyte Subsets/immunology , Th2 Cells/immunology , Adult , Female , Humans , Male , Randomized Controlled Trials as Topic , Young AdultABSTRACT
BACKGROUND: Peanut allergy is common, life-threatening, and without therapeutic options. We evaluated peanut epicutaneous immunotherapy (EPIT) by using Viaskin Peanut for peanut allergy treatment. OBJECTIVE: We sought to evaluate the clinical, safety, and immunologic effects of EPIT for the treatment of peanut allergy. METHODS: In this multicenter, double-blind, randomized, placebo-controlled study, 74 participants with peanut allergy (ages 4-25 years) were treated with placebo (n = 25), Viaskin Peanut 100 µg (VP100; n = 24) or Viaskin Peanut 250 µg (VP250; n = 25; DBV Technologies, Montrouge, France). The primary outcome was treatment success after 52 weeks, which was defined as passing a 5044-mg protein oral food challenge or achieving a 10-fold or greater increase in successfully consumed dose from baseline to week 52. Adverse reactions and mechanistic changes were assessed. RESULTS: At week 52, treatment success was achieved in 3 (12%) placebo-treated participants, 11 (46%) VP100 participants, and 12 (48%) VP250 participants (P = .005 and P = .003, respectively, compared with placebo; VP100 vs VP250, P = .48). Median change in successfully consumed doses were 0, 43, and 130 mg of protein in the placebo, VP100, and VP250 groups, respectively (placebo vs VP100, P = .014; placebo vs VP250, P = .003). Treatment success was higher among younger children (P = .03; age, 4-11 vs >11 years). Overall, 14.4% of placebo doses and 79.8% of VP100 and VP250 doses resulted in reactions, predominantly local patch-site and mild reactions (P = .003). Increases in peanut-specific IgG4 levels and IgG4/IgE ratios were observed in peanut EPIT-treated participants, along with trends toward reduced basophil activation and peanut-specific TH2 cytokines. CONCLUSIONS: Peanut EPIT administration was safe and associated with a modest treatment response after 52 weeks, with the highest responses among younger children. This, when coupled with a high adherence and retention rate and significant changes in immune pathways, supports further investigation of this novel therapy.
Subject(s)
Allergens/administration & dosage , Desensitization, Immunologic/methods , Peanut Hypersensitivity/therapy , Transdermal Patch , Adolescent , Adult , Child , Child, Preschool , Double-Blind Method , Female , Humans , Male , Young AdultABSTRACT
Background: Food allergy (FA) and atopic dermatitis (AD) are common conditions that often present in the first year of life. Identification of underlying mechanisms and environmental determinants of FA and AD is essential to develop and implement effective prevention and treatment strategies. Objectives: We sought to describe the design of the Systems Biology of Early Atopy (SunBEAm) birth cohort. Methods: Funded by the National Institute of Allergy and Infectious Diseases (NIAID) and administered through the Consortium for Food Allergy Research (CoFAR), SunBEAm is a US population-based, multicenter birth cohort that enrolls pregnant mothers, fathers, and their newborns and follows them to 3 years. Questionnaire and biosampling strategies were developed to apply a systems biology approach to identify environmental, immunologic, and multiomic determinants of AD, FA, and other allergic outcomes. Results: Enrollment is currently underway. On the basis of an estimated FA prevalence of 6%, the enrollment goal is 2500 infants. AD is defined on the basis of questionnaire and assessment, and FA is defined by an algorithm combining history and testing. Although any FA will be recorded, we focus on the diagnosis of egg, milk, and peanut at 5 months, adding wheat, soy, cashew, hazelnut, walnut, codfish, shrimp, and sesame starting at 12 months. Sampling includes blood, hair, stool, dust, water, tape strips, skin swabs, nasal secretions, nasal swabs, saliva, urine, functional aspects of the skin, and maternal breast milk and vaginal swabs. Conclusions: The SunBEAm birth cohort will provide a rich repository of data and specimens to interrogate mechanisms and determinants of early allergic outcomes, with an emphasis on FA, AD, and systems biology.
ABSTRACT
PURPOSE: Altered fractionation radiotherapy with concomitant boost (AFRT-CB) may be considered an alternative treatment for patients not appropriate for chemoradiation (CRT). As functional outcomes following AFRT-CB have been minimally reported, this exploratory paper describes the outcomes of patients managed with AFRT-CB or CRT at 6 months post-treatment. METHODS: Using a cross-sectional analysis design, functional outcomes of 14 AFRT-CB and 17 CRT patients with T1-T3 oropharyngeal cancers were explored at 6 months post-treatment. Clinical and instrumental swallow assessments, weight and nutritional status, and the functional impact of treatment were examined. RESULTS: Inferior outcomes were observed for the CRT patients on the RBHOMS (p = 0.03) which was reflected in diet and fluid restrictions with 18% of the CRT group requiring modified fluids and diets. Although a trend (p = 0.07) was noted for increased lingual deficits and aspiration risk for fluids in the CRT group, no other significant differences were observed. Both groups experienced an average of 10 kg weight loss and reported reduced general and swallowing-related function. CONCLUSIONS: These preliminary data suggest functional outcomes following AFRT-CB and CRT were largely comparable at 6 months post-treatment. Treatment intensification in any form may contribute to impaired function which requires multidimensional intervention. Larger cohort investigations with systematic methodology are needed to further examine these initial findings.
Subject(s)
Chemoradiotherapy , Deglutition , Nutritional Status , Oropharyngeal Neoplasms/therapy , Self Report , Adult , Aged , Aged, 80 and over , Cross-Sectional Studies , Deglutition/drug effects , Deglutition/radiation effects , Dose Fractionation, Radiation , Female , Follow-Up Studies , Humans , Male , Middle Aged , Oropharyngeal Neoplasms/pathology , Outcome Assessment, Health Care , Queensland , Radiotherapy, ConformalABSTRACT
Altered fractionation radiotherapy for head and neck cancer has been associated with improved locoregional control, overall survival, and heightened toxicity compared with conventional treatment. Swallowing, nutrition, and patient-perceived function for altered fractionation radiotherapy with concomitant boost (AFRT-CB) for T1-T3 oropharyngeal squamous cell carcinoma (SCC) have not been previously reported. Fourteen consecutive patients treated with AFRT-CB for oropharyngeal SCC were recruited from November 2006 to August 2009 in a tertiary hospital in Brisbane, Australia. Swallowing, nutrition, and patient-perceived functional impact assessments were conducted pretreatment, at 4-6 weeks post-treatment, and at 6 months post-treatment. Deterioration from pretreatment to 4-6 weeks post-treatment in swallowing, nutrition, and functional impact was evident, likely due to the heightened toxicity associated with AFRT-CB. There was significant improvement at 6 months post-treatment in functional swallowing, nutritional status, patient-perceived swallowing, and overall function, consistent with recovery from acute toxicity. However, weight and patient perception of physical function and side effects remained significantly worse than pretreatment scores. The ongoing deficits related to weight and patient-perceived outcomes at 6 months revealed that this treatment has a long-term impact on function possibly related to the chronic effects of AFRT-CB.
Subject(s)
Carcinoma, Squamous Cell/radiotherapy , Deglutition Disorders/etiology , Deglutition/radiation effects , Nutritional Status/radiation effects , Oropharyngeal Neoplasms/radiotherapy , Radiation Injuries/etiology , Radiotherapy/adverse effects , Aged , Aged, 80 and over , Deglutition Disorders/diagnostic imaging , Dose Fractionation, Radiation , Female , Fluoroscopy , Humans , Male , Middle Aged , Prospective Studies , Recovery of Function , Surveys and Questionnaires , Treatment OutcomeABSTRACT
With no long-term data available in published research to date, this study presents details of the swallowing outcomes as well as barriers to and facilitators of oral intake and weight maintenance at 2 years after altered fractionation radiotherapy with concomitant boost (AFRT-CB). Twelve patients with T1-T3 oropharyngeal cancer who received AFRT-CB were assessed at baseline, 6 months, and 2 years post-treatment for levels of dysphagia and salivary toxicity, food and fluid tolerance, functional swallowing outcomes, patient-reported function, and weight. At 2 years, participants were also interviewed to explore barriers and facilitators of oral intake. Outcomes were significantly worse at 2 years when compared to baseline for late toxicity, functional swallowing, and patient-rated physical aspects of swallowing. Most patients (83%) tolerated a full diet pretreatment, but the rate fell to 42% (remainder tolerated soft diets) at 2 years. Multiple barriers to oral intake that impacted on activity and participation levels were identified. Participants lost 11 kg from baseline to 2 years, which was not regained between 6 months and 2 years. Global, social, and emotional domains of patient-reported function returned to pretreatment levels. At 2 years post AFRT-CB, worsening salivary and dysphagia toxicity, declining functional swallowing, and multiple reported ongoing barriers to oral intake had a negative impact on participants' activity and participation levels relating to eating. These ongoing deficits contributed to significant deterioration in physical swallowing functioning determined by the MDADI. In contrast, patients perceived their broader functioning had improved at 2 years, suggesting long-term adjustment to ongoing swallowing deficits.
Subject(s)
Carcinoma, Squamous Cell/rehabilitation , Deglutition Disorders/physiopathology , Deglutition/physiology , Oropharyngeal Neoplasms/radiotherapy , Recovery of Function , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/complications , Carcinoma, Squamous Cell/diagnosis , Deglutition Disorders/etiology , Dose Fractionation, Radiation , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Staging , Oropharyngeal Neoplasms/complications , Oropharyngeal Neoplasms/diagnosis , Quality of Life , Time Factors , Treatment OutcomeABSTRACT
Background: Food allergy is common and causes substantial morbidity and even mortality. Safe and effective treatments for food allergy would therefore be highly desirable, especially for individuals with multiple food allergies. Objectives: Our aim was to describe a phase 3 study on treatment of patients with multiple food allergies with omalizumab. Methods: The study was developed as a collaboration between the Consortium for Food Allergy Research, the National Institute of Allergy and Infectious Diseases, and 2 industry sponsors (Genentech and Novartis). Results: The study is currently under way, enrolling participants from age 1 year to age 55 years who are allergic to peanut and at least 2 other foods (including milk, egg, wheat, cashew, hazelnut, and walnut). The study is designed to address 3 major questions. First, stage 1 will study the potential value of omalizumab for the treatment of patients with peanut allergy and at least 2 other common food allergens. Second, stage 2 will directly compare treatment of patients with multifood allergies using omalizumab as monotherapy versus treatment with omalizumab-facilitated multiallergen oral immunotherapy in which omalizumab is used as an adjunctive treatment. Third, stage 3 will address the longer-term outcomes following these treatment approaches, including the introduction of dietary forms of the study foods to induce or maintain desensitization. Conclusions: This phase 3 study will provide important information on the potential of omalizumab to treat patients with multiple food allergies.
ABSTRACT
Deaf students often lag behind hearing peers in numerical and mathematical abilities. Studies of hearing children with mathematical difficulties highlight the importance of estimation skills as the foundation for formal mathematical abilities, but research with adults is limited. Deaf and hearing college students were assessed on the Number-to-Position task as a measure of estimation, and completed standardised assessments of arithmetical and mathematical reasoning. Deaf students performed significantly more poorly on all measures, including making less accurate number-line estimates. For deaf students, there was also a strong relationship showing that those more accurate in making number-line estimates achieved higher scores on the math achievement tests. No such relationship was apparent for hearing students. Further insights into the estimation abilities of deaf individuals should be made, including tasks that require symbolic and non-symbolic estimation and which address the quality of estimation strategies being used.
ABSTRACT
Germline mutations in Fas and Fasl induce nonmalignant T cell hyperplasia and systemic autoimmunity and also greatly increase the risk of B cell neoplasms. B lymphomas occurring in Fasl mutant (gld) mice usually are immunoglobulin (Ig) isotype switched, secrete Ig, and are plasmacytoid in appearance but lack Myc translocations characteristic of other plasma cell (PC) neoplasms. Here, we explore the relationship between B cell autoreactivity and transformation and use gene expression profiling to further classify gld plasmacytoid lymphomas (PLs) and to identify genes of potential importance in transformation. We found that the majority of PLs derive from antigen-experienced autoreactive B cells producing antinuclear antibody or rheumatoid factor and exhibit the skewed Ig V gene repertoire and Ig gene rearrangement patterns associated with these specificities. Gene expression profiling revealed that both primary and transplanted PLs share a transcriptional profile that places them at an early stage in PC differentiation and distinguishes them from other B cell neoplasms. In addition, genes were identified whose altered expression might be relevant in lymphomagenesis. Our findings provide a strong case for targeted transformation of autoreactive B cells in gld mice and establish a valuable model for understanding the relationship between systemic autoimmunity and B cell neoplasia.
Subject(s)
Autoimmunity , Cell Transformation, Neoplastic , Lymphoma, B-Cell/etiology , Membrane Glycoproteins/physiology , Plasma Cells/pathology , Animals , Antibody Specificity , B-Lymphocytes/immunology , Fas Ligand Protein , Gene Expression Profiling , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Lymphoma, B-Cell/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C3HABSTRACT
Hydrocephalus is a common and potentially devastating birth defect affecting the CNS, and its relationship with G protein-coupled receptors (GPCRs) is unknown. We have expressed 2, 4, or 6 copies of a GPCR--the human PAC1 receptor with a 130-kb transgene in the mouse nervous system in a pattern closely resembling that of the endogenous gene. Consistent with PAC1 actions, PKA and PKC activity were elevated in the brains of Tg mice. Remarkably, Tg mice developed dose-dependent hydrocephalus-like characteristics, including enlarged third and lateral ventricles and reduced cerebral cortex, corpus callosum, and subcommissural organ (SCO). Neuronal proliferation and apoptosis were implicated in hydrocephalus, and we observed significantly reduced neuronal proliferation and massively increased neuronal apoptosis in the developing cortex and SCO of Tg embryos, while neurite outgrowth and neuronal migration in vitro remain uncompromised. Ventricular ependymal cilia are crucial for directing cerebrospinal fluid flow, and ependyma of Tg mice exhibited disrupted cilia with increased phospho-CREB immunoreactivity. These data demonstrate that altered neuronal proliferation/apoptosis and disrupted ependymal cilia are the main factors contributing to hydrocephalus in PAC1-overexpressing mice. This is the first report to our knowledge demonstrating that misregulation of GPCRs can be involved in hydrocephalus-related neurodevelopmental disorders.
Subject(s)
Brain/abnormalities , Hydrocephalus/metabolism , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/genetics , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism , Animals , Apoptosis , Brain/embryology , Brain/metabolism , Cell Movement , Cell Proliferation , Cilia/metabolism , Ependyma/cytology , Ependyma/metabolism , Gene Dosage , Humans , Hydrocephalus/pathology , Mice , Mice, Transgenic , Neurons/cytology , Neurons/physiology , Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism , Protein Processing, Post-TranslationalABSTRACT
We have compared histologic features and gene expression profiles of newly identified plasmacytomas from NFS.V(+) congenic mice with plasmacytomas of IL6 transgenic, Fasl mutant, and SJL-beta2M(-/-) mice. NFS.V(+) tumors comprised an overlapping morphologic spectrum of high-grade/anaplastic, intermediate-grade/plasmablastic, and low-grade/plasmacytic cases with similarities to subsets of human multiple myeloma and plasmacytoma. Microarray and immunohistochemical analyses of genes expressed by the most prevalent tumors, plasmablastic plasmacytomas, showed them to be most closely related to immunoblastic lymphomas, less so to plasmacytomas of Fasl mutant and SJL mice, and least to plasmacytic plasmacytomas of IL6 transgenic mice. Plasmablastic tumors seemed to develop in an inflammatory environment associated with gene signatures of T cells, natural killer cells, and macrophages not seen with plasmacytic plasmacytomas. Plasmablastic plasmacytomas from NFS.V(+) and SJL-beta2M(-/-) mice did not have structural alterations in Myc or T(12;15) translocations and did not express Myc at high levels, regular features of transgenic and pristane-induced plasmacytomas. These findings imply that, as for human multiple myeloma, Myc-independent routes of transformation contribute to the pathogenesis of these tumors. These findings suggest that plasma cell neoplasms of mice and humans exhibit similar degrees of complexity. Mouse plasmacytomas, previously considered to be homogeneous, may thus be as diverse as their human counterparts with respect to oncogenic mechanisms of plasma cell transformation. Selecting specific types of mouse plasmacytomas that relate most closely to subtypes of human multiple myeloma may provide new opportunities for preclinical testing of drugs for treatment of the human disease.
Subject(s)
B-Lymphocytes/pathology , Plasmacytoma/pathology , Animals , B-Lymphocytes/immunology , Cell Differentiation/physiology , Cell Lineage , Gene Expression Profiling , Genes, myc , Humans , Immunohistochemistry , Interleukin-6/genetics , Mice , Mice, Inbred BALB C , Mice, Knockout , Mice, Transgenic , Neoplasm Staging , Plasmacytoma/genetics , Plasmacytoma/immunology , Plasmacytoma/metabolismABSTRACT
BACKGROUND: Egg allergy is one of the most common food allergies of childhood. There is a lack of information on the immunologic basis of egg allergy beyond the role of IgE. OBJECTIVE: To use transcriptional profiling as a novel approach to uncover immunologic processes associated with different phenotypes of egg allergy. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from egg-allergic children who were defined as reactive (BER) or tolerant (BET) to baked egg, and from food allergic controls (AC) who were egg non-allergic. PBMCs were stimulated with egg white protein. Gene transcription was measured by microarray after 24 h, and cytokine secretion by multiplex assay after 5 days. RESULTS: The transcriptional response of PBMCs to egg protein differed between BER and BET versus AC subjects. Compared to the AC group, the BER group displayed increased expression of genes associated with allergic inflammation as well as corresponding increased secretion of IL-5, IL-9 and TNF-α. A similar pattern was observed for the BET group. Further similarities in gene expression patterns between BER and BET groups, as well as some important differences, were revealed using a novel Immune Annotation resource developed for this project. This approach identified several novel processes not previously associated with egg allergy, including positive associations with TLR4-stimulated myeloid cells and activated NK cells, and negative associations with an induced Treg signature. Further pathway analysis of differentially expressed genes comparing BER to BET subjects showed significant enrichment of IFN-α and IFN-γ response genes, as well as genes associated with virally-infected DCs. CONCLUSIONS: Transcriptional profiling identified several novel pathways and processes that differed when comparing the response to egg allergen in BET, BER, and AC groups. We conclude that this approach is a useful hypothesis-generating mechanism to identify novel immune processes associated with allergy and tolerance to forms of egg.
Subject(s)
Egg Hypersensitivity/genetics , Gene Expression Profiling , Phenotype , Adolescent , Child , Child, Preschool , Cytokines/biosynthesis , Egg Hypersensitivity/immunology , Egg Hypersensitivity/metabolism , Female , Humans , Male , Molecular Sequence Annotation , Ovum/immunologyABSTRACT
BACKGROUND & AIMS: There are few well-designed studies evaluating the effect of oral nutrition supplements in patients with cancer cachexia. The aim of this study, in a posthoc analysis, was to examine the effect of dietary compliance on intake and body composition in patients with unresectable pancreatic cancer. METHODS: Two hundred patients were randomised to receive 2 cans/day of a protein and energy dense, oral nutrition supplement+/-n-3 fatty acids in an international, multi-centre randomised trial over 8 weeks. Dietary compliance was defined a priori as consumption of a minimum of 1.5 cans/day of either supplement. Body composition, dietary intake and quality of life were measured at baseline, 4 and 8 weeks. RESULTS: On average, there were significant differences in energy intake (501 kcal), protein intake (25.4 g) and weight (1.7 kg) between patients who were compliant with the nutrition prescription compared to noncompliant patients controlling for n-3 fatty acid randomisation, baseline weight and quality of life. Over the 8-week period, there was significant improvement in weight only. There was no significant difference in the energy intake from meals of the total group over the 8 weeks. CONCLUSIONS: Compliance with the prescription of 1.5 cans of a protein and energy dense, oral nutrition supplement +/-n-3 fatty acids improved nutrition related outcomes in untreated pancreatic cancer patients. This level of supplement intake does not inhibit meal intake.
Subject(s)
Body Composition/drug effects , Energy Intake/physiology , Fatty Acids, Omega-3/administration & dosage , Food, Formulated , Pancreatic Neoplasms/therapy , Patient Compliance , Aged , Body Weight/drug effects , Cachexia/therapy , Dietary Proteins/administration & dosage , Double-Blind Method , Energy Intake/drug effects , Female , Humans , Male , Quality of Life , Treatment OutcomeABSTRACT
BACKGROUND & AIMS: Cancer-induced weight loss is associated with poor outcomes and is common in pancreatic cancer. The aims were to determine whether stabilising weight loss for patients with unresectable pancreatic cancer was associated with improved survival and quality of life (QoL) and to identify determinants of weight stabilisation. METHODS: A post hoc analysis was performed using data from 107 patients in a multicentre trial. Patients were categorised as weight losing (> 1 kg lost) or weight stable (< or = 1 kg lost) after an 8 week nutrition intervention period. Group survival duration (Kaplan Meier) and QoL (EORTC QLQ-C30) were compared. Predictors of weight stability were determined using logistic regression analysis. RESULTS: Patients with weight stabilisation survived longer from baseline (log rank test 5.53, P = 0.019). They also reported higher QoL scores (P = 0.037) and a greater mean energy intake (P <0.001) at Week 8 than those who continued to lose weight. The absence of nausea and vomiting (OR 6.5, P =0.010) and female gender (OR 5.2, P = 0.020) were independent determinants of weight stabilisation. CONCLUSIONS: Weight stabilisation over an 8 week period in weight-losing patients with unresectable pancreatic cancer was associated with improved survival duration and QoL.
Subject(s)
Body Weight , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/therapy , Quality of Life , Aged , Double-Blind Method , Energy Intake , Female , Humans , Logistic Models , Male , Middle Aged , Survival Rate , Weight LossABSTRACT
Nutrition issues facing people with cancer are significant. The role of nutrition therapy is often assumed to be less important than pharmacologic interventions as outcomes are less clear in the literature. Especially important has been the focus on traditional outcomes such as morbidity and mortality rather than adopting a more patient-centered approach and including quality of life as a key outcome. There is a general failure to recognize weight loss early enough and to implement nutrition interventions, which are effective. The nutrition intervention should be composed of both a prescription and an implementation method. To achieve compliance, the nutrition therapy should be implemented in an aggressive manner. Data show that when compliance is achieved, outcomes in the form of improved quality of life and functional capacity can be achieved. For people with cancer and their care-givers, outcomes such as quality of life have meaning, and for patients with poor prognoses, this may hold more meaning than mortality and morbidity outcomes. Clinicians need to implement triage systems to identify patients for early intervention and focus on nutrient combinations. They need to be confident that with the right prescription and implementation, nutrition therapy can be successful and bring real benefit to patients with cancer.