Oxidative Stress and Air Pollution: Its Impact on Chronic Respiratory Diseases.

Redox regulation participates in the control of various aspects of metabolism. Reactive oxygen and nitrogen species participate in many reactions under physiological conditions. When these species overcome the antioxidant defense system, a distressed status emerges, increasing biomolecular damage and leading to functional alterations. Air pollution is one of the exogenous sources of reactive oxygen and nitrogen species. Ambient airborne particulate matter (PM) is important because of its complex composition, which includes transition metals and organic compounds. Once in contact with the lungs' epithelium, PM components initiate the synthesis of inflammatory mediators, macrophage activation, modulation of gene expression, and the activation of transcription factors, which are all related to the physiopathology of chronic respiratory diseases, including cancer. Even though the pathophysiological pathways that give rise to the development of distress and biological damage are not fully understood, scientific evidence indicates that redox-dependent signaling pathways are involved. This article presents an overview of the redox interaction of air pollution inside the human body and the courses related to chronic respiratory diseases.

Current Insights on the Impact of Proteomics in Respiratory Allergies.

Respiratory allergies affect humans worldwide, causing extensive morbidity and mortality. They include allergic rhinitis (AR), asthma, pollen food allergy syndrome (PFAS), aspirin-exacerbated respiratory disease (AERD), and nasal polyps (NPs). The study of respiratory allergic diseases requires new technologies for early and accurate diagnosis and treatment. Omics technologies provide the tools required to investigate DNA, RNA, proteins, and other molecular determinants. These technologies include genomics, transcriptomics, proteomics, and metabolomics. However, proteomics is one of the main approaches to studying allergic disorders' pathophysiology. Proteins are used to indicate normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. In this field, the principal goal of proteomics has been to discover new proteins and use them in precision medicine. Multiple technologies have been applied to proteomics, but that most used for identifying, quantifying, and profiling proteins is mass spectrometry (MS). Over the last few years, proteomics has enabled the establishment of several proteins for diagnosing and treating respiratory allergic diseases.

Subcutaneous Allergen-Specific Immunotherapy Is Safe in Pediatric Patients with Allergic Rhinitis.

INTRODUCTION: Subcutaneous allergen-specific immunotherapy (SCIT) is one of the main cornerstones in the treatment of allergic rhinitis in pediatric patients. It has demonstrated symptoms and quality of life improvement, but it is not exempt from adverse reactions (ADVrs). Nevertheless, there are a few reports that have evaluated their safety. Our objective was to evaluate the ADVr to SCIT in pediatric patients. METHODS: We reviewed 786 clinical records with SCIT from 2005 to 2018, comparing the clinical characteristics of patients with ADVrs with SCIT versus a group of a similar number of patients who completed SCIT (control group, CG). The analysis of ADVrs was according to the World Allergy Organization (WAO) 2010 grading system by frequency analysis, survival curve, and log rank. RESULTS: Of 786 patients, 106 (13.4%) presented ADVrs, and the patients with ADVr had sensitivity and immunotherapy with at least 2 allergens versus CG p < 0.001, containing a combination of standardized and nonstandardized allergens (p = 0.003). The ADVrs were in the buildup phase (p < 0.001). The survival curve showed that 50% had some reaction at 12 weeks of SCIT. The most frequent ADVr was grade 1 in 73/106 patients (68.8%) and grade 2 in 33/106 (31.1%). The log-rank analysis between the grades of the WAO grading system showed a statistically significant difference (p = 0.02). CONCLUSIONS: The SCIT is safe in pediatric patients. The ADVrs are infrequent, grade 1 being the most reported; however, at >12 weeks, the risk of ADVrs that involve 2 organs systems increases.

New Insights into the Role of PD-1 and Its Ligands in Allergic Disease.

Programmed cell death 1 (PD-1) and its ligands PD-L1 and PD-L2 are receptors that act in co-stimulatory and coinhibitory immune responses. Signaling the PD-1/PD-L1 or PD-L2 pathway is essential to regulate the inflammatory responses to infections, autoimmunity, and allergies, and it has been extensively studied in cancer. Allergic diseases include asthma, rhinoconjunctivitis, atopic dermatitis, drug allergy, and anaphylaxis. These overactive immune responses involve IgE-dependent activation and increased CD4+ T helper type 2 (Th2) lymphocytes. Recent studies have shown that PD-L1 and PD-L2 act to regulate T-cell activation and function. However, the main role of PD-1 and its ligands is to balance the immune response; however, the inflammatory process of allergic diseases is poorly understood. These immune checkpoint molecules can function as a brake or a kick-start to regulate the adaptive immune response. These findings suggest that PD-1 and its ligands may be a key factor in studying the exaggerated response in hypersensitivity reactions in allergies. This review summarizes the current understanding of the role of PD-1 and PD-L1 and PD-L2 pathway regulation in allergic diseases and how this immunomodulatory pathway is currently being targeted to develop novel therapeutic immunotherapy.

Overview of New Treatments with Immunotherapy for Breast Cancer and a Proposal of a Combination Therapy.

According to data from the U.S. National Cancer Institute, cancer is one of the leading causes of death worldwide with approximately 14 million new cases and 8.2 million cancer-related deaths in 2018. More than 60% of the new annual cases in the world occur in Africa, Asia, Central America, and South America, with 70% of cancer deaths in these regions. Breast cancer is the most common cancer in women, with 266,120 new cases in American women and an estimated 40,920 deaths for 2018. Approximately one in six women diagnosed with breast cancer will die in the coming years. Recently, novel therapeutic strategies have been implemented in the fight against breast cancer, including molecules able to block signaling pathways, an inhibitor of poly [ADP-ribose] polymerase (PARP), growth receptor blocker antibodies, or those that reactivate the immune system by inhibiting the activities of inhibitory receptors like cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death protein 1 (PD-1). However, novel targets include reactivating the Th1 immune response, changing tumor microenvironment, and co-activation of other components of the immune response such as natural killer cells and CD8+ T cells among others. In this article, we review advances in the treatment of breast cancer focused essentially on immunomodulatory drugs in targeted cancer therapy. Based on this knowledge, we formulate a proposal for the implementation of combined therapy using an extracorporeal immune response reactivation model and cytokines plus modulating antibodies for co-activation of the Th1- and natural killer cell (NK)-dependent immune response, either in situ or through autologous cell therapy. The implementation of "combination immunotherapy" is new hope in breast cancer treatment. Therefore, we consider the coordinated activation of each cell of the immune response that would probably produce better outcomes. Although more research is required, the results recently achieved by combination therapy suggest that for most, if not all, cancer patients, this tailored therapy may become a realistic approach in the near future.

Study of the hard-disk system at high densities: the fluid-hexatic phase transition.

Integral equations of uniform fluids have been considered unable to predict any characteristic feature of the fluid-solid phase transition, including the shoulder that arises in the second peak of the fluid-phase radial distribution function, RDF, of hard-core systems obtained by computer simulations, at fluid densities very close to the structural two-step phase transition. This reasoning is based on the results of traditional integral approximations, like Percus-Yevick, PY, which does not show such a shoulder in hard-core systems, neither in two nor three dimensions. In this work, we present results of three Ansätze, based on the PY theory, that were proposed to remedy the lack of PY analytical solutions in two dimensions. This comparative study shows that one of those Ansätze does develop a shoulder in the second peak of the RDF at densities very close to the phase transition, qualitatively describing this feature. Since the shoulder grows into a peak at still higher densities, this integral equation approach predicts the appearance of an orientational order characteristic of the hexatic phase in a continuous fluid-hexatic phase transition.

Interleukin 16 and CCL17/thymus and activation-regulated chemokine in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Interleukin (IL) 16 and thymus and activation-regulated cytokine (TARC) are chemoattractant cytokines for eosinophils and TH2 cells. Differential levels of these components in aspirin-exacerbated respiratory disease (AERD) and allergic rhinitis with asthma (ARwA) may be related to a different inflammatory response in both asthma phenotypes. OBJECTIVE: To assess the nasal lavage immunoreactivity of IL-16 and TARC cytokines. METHODS: We used multienzyme-linked immunosorbent assays to detect IL-5, IL-13, IL-16, IL-33, I-309/CCL1, TARC/CCL17, monocyte-derived chemokine/CCL22, periostin, and eosinophil cationic protein levels in nasal lavages from patients with AERD and patients with ARwA. RESULTS: The IL-13, IL-16, TARC, and periostin levels were significantly higher in patients with AERD compared with those of patients with ARwA. Correlation analysis of mediator levels in AERD revealed a possible role of IL-16 and TARC in eosinophil recruitment and activation. CONCLUSION: IL-16, TARC, and periostin distinguish between patients with AERD and those with ARwA. These mediators, taken together rather than individually, may comprise good specific nasal markers in patients with AERD. The effects of IL-16 and TARC on TH1, TH2, and T-regulatory cell functions in AERD cannot be disregarded.

Physiopathology and genetics in aspirin-exacerbated respiratory disease.

INTRODUCTION: Aspirin-exacerbated respiratory disease (AERD) is a clinical entity characterized by hypersensitivity to aspirin leading to asthma and chronic rhinosinusitis with nasosinusal polyposis. The pathophysiology of the disease involves disruption at the level of arachidonic acid metabolism. Therefore, genetic association studies have been focused on the genes coding this pathway. As other mechanisms involved in the genesis of the disease were elucidated, the corresponding genes were also explored. AIM: To describe the association reported in the literature between gene polymorphisms involved in the pathophysiology or therapeutic processes of AERD. RESULTS: There is a genetic association between polymorphisms of genes involved in the synthesis of proteins related to arachidonic acid metabolism (LTC4S, ALOX5), antigen presentation (HLA), inflammation (IL5, IL17), and aspirin metabolism (CYP2C19). CONCLUSIONS: Genetic association research in AERD has evaluated studies of SNPs in metabolic pathways related to arachidonic acid. Recently, whole genome analysis strategies have allowed the detection of new genetic variants that were previously not considered. Furthermore, these studies have identified SNPs that are associated with inflammatory processes, which could serve as diagnostic markers or predictors of the therapeutic response.

Association of TRPM3 Polymorphism (rs10780946) and Aspirin-Exacerbated Respiratory Disease (AERD).

INTRODUCTION: Aspirin-exacerbated respiratory disease (AERD) refers to the combination of asthma rhinosinusitis and poliposis; ingestion of aspirin or other non-steroid anti-inflammatory drugs exacerbate asthma-like symptoms. The pathogenesis of AERD is unknown, and genetic and environmental factors contribute to the disease. Our objective is identifying polymorphisms associated with susceptibility in a Mexican mestizo population. METHODS: Primarily we performed custom Illumina goldengate array-based genotyping of 1512 SNPs, carefully selected from a variety of acute/chronic inflammatory lung conditions previously reported. Four SNPs in TRPM3 gene showed the lowest p-values (rs10780946, rs7025694, rs1889915, and rs7047645). We further selected rs10780946 and rs7025694 for validation using Taqman genotyping (n = 743; 288 AERD, 272 ATA, and 183 HC). RESULTS: rs10780946 showed association when compared between AERD and ATA groups under co-dominant (p = 0.006), dominant (p = 0.002), overdominant (p = 0.01), and log-additive (p = 0.03) genetic models. AERD showed increased heterozygous TC (rs10780946-rs7025694) haplotype compared to ATA and HC (p < 0.05). We could not confirm any association between rs7025694 and AERD. CONCLUSION: rs10780946 TRPM3 polymorphism is associated with AERD susceptibility.

Respiratory proteomics: from descriptive studies to personalized medicine.

Respiratory diseases are highly prevalent and affect humankind worldwide, causing extensive morbidity and mortality with the environment playing an important role. Given the complex structure of the airways, sophisticated tools are required for early diagnosis; initial symptoms are nonspecific, and the clinical diagnosis is made frequently late. Over the past few years, proteomics has made high technological progress in mass-spectrometry-based protein identification and has allowed us to gain new insights into disease mechanisms and identify potential novel therapeutic targets. This review will highlight the contributions of proteomics toward the understanding of the respiratory proteome listing potential biomarkers and its potential application to the clinic. We also outline the contributions of proteomics to creating a personalized approach in respiratory medicine.

Identification of Ligustrum lucidum pollen allergens using a proteomics approach.

BACKGROUND: Ligustrum spp. are members of the Oleaceae family, one of the most prominent allergic families worldwide. The genus Ligustrum contains approximately fifty species, including Ligustrum lucidum, which have been widely cultivated as ornamental plants, and its pollen is a source of inhalant allergens associated with respiratory allergic diseases. Little is known about the presence of allergenic proteins in L. lucidum. METHODS: The L. lucidum pollen proteins were extracted by a modified phenolic extraction method. A pool of four sera from mono sensitive patients was analyzed by 2DE immunoblotting and mass spectrometric analysis was performed on 6 immunoreactive protein spots. RESULTS: SDS-PAGE of L. lucidum pollen extract revealed proteins in ranges of 15-150 kDa. The 2DE gel profile of the L. lucidum pollen protein extract showed approximately 180 spots, and the 2DE immunoblots obtained using sera from Ligustrum monosensitive patients as the source of IgE antibodies revealed six allergen protein spots, corresponding to Profilin, Enolase, Fra e 9.01 (ß-1,3-glucanase), Pollen-specific Polygalacturonases, Alanine aminotransferase, and two ATP synthase beta subunits. CONCLUSION: We report for the first time the identification of IgE-reactive proteins from L. lucidum.

Rapid generation of an RBL cellular model to study proteins that cause allergenic reactions in vitro.

Allergic diseases affect nearly 30% of people worldwide. There is a wide range of allergen sources, such as animal dander, food, venom, dust mites, and pollen. The skin prick test is the predominant technique used to identify allergenic sensitivity in vivo; the main problem is that it can be imprecise as many of the allergen extracts are made of mixtures of allergic and nonallergic components, making it difficult to identify the disease-eliciting allergen. An alternative to solve this problem is employing cellular models in vitro that may allow allergen identification, allergy diagnosis, and testing of novel potential compounds that can be used in immunotherapeutics. For example, rat basophilic leukemia (RBL) cells are a well-suited model for studying allergies. Unfortunately, cells generated from RBL cells are not commercially available. Therefore, we developed an RBL model with a degranulation gene reporter capable of recognizing human IgE involved in allergenic sensitivity using commercial plasmids. Employing this model, we successfully evaluated the capacity of union between IgE from allergic patients to allergenic proteins from Oleaceae tree pollen. This RBL cell model can be used as a diagnostic method for sensitivity to any allergens from different sources in vitro.

[DRESS syndrome induced by anti-TB drugs]. / Síndrome de DRESS inducido por fármacos antituberculosos.

OBJETIVE: To describe the phenotype of DRESS syndrome induced by antituberculosis drugs. METHODS: Descriptive study, withdrawn from the review of the records of patients with DRESS syndrome, identified in the interconsultation of the Department of Research in Immunogenetics and Allergy, of the Insti-tuto Nacional de Enfermedades Respiratorias (INER) Ismael Cosío Villegas, among 2014 and 2020. Frequency analysis was performed. The associations between biomarkers and latency are calculated with the χ2 test and log-rank, and the evaluation of the change in the biomarkers with the Wilcoxon test. The value of p < 0.05 is considered statistically significant. For data analysis, the SPSS v.21 program was obtained. RESULTS: 15 patients were identified; represented by 0.02% of total cases treated in the Department for so-meimmuno-allergic condition (15/7052); the main symptomatology were: rash (100%), eosinophilia (93%), fe-ver (80%), adenomegaly (60%), kidney damage (40%), liver damage (33%), and latency of 21 days. Liver damage was associated with prolonged latency (p = 0.02). After treatment, the total levels of eosinophils (p < 0.001) and liver and kidney biomarkers (p < 0.04) decreased. DRESS syndrome induced by antituberculosis drugs is not associated with the number of drugs prescribed or with the pattern of resistance of Mycobacterium tuberculosis. CONCLUSIONS: DRESS syndrome induced by antituberculosis drugs is an atypical clinical reaction, similar to other types of DRESS syndrome that respond favorably to systemic corticosteroids.

OBJETIVO: Describir el fenotipo del síndrome de DRESS inducido por fármacos antituberculosos. MÉTODOS: Estudio descriptivo efectuado a partir de la revisión de los expedientes de pacientes con síndrome de DRESS, identificados en la interconsulta del Departamento de Investigación en Inmunogénetica y Alergia, del Instituto Nacional de Enfermedades Respiratorias (INER) Ismael Cosío Villegas, entre 2014 y 2020. Se realizó análisis de frecuencias. Las asociaciones entre biomarcadores y latencia se calcularon con la prueba de χ2 y log-rank, y la evaluación del cambio en los biomarcadores con la prueba de Wilcoxon. Se consideró esta-dísticamente significativo el valor de p < 0.05. Para el análisis de los datos se utilizó el programa SPSS v.21. RESULTADOS: Se identificaron 15 pacientes, que representaron el 0.2% de los casos atendidos en el Departa-mento por algún padecimiento inmuno-alérgico (15/7052); las principales manifestaciones fueron: exantema (100%), eosinofilia (93%), fiebre (80%), adenomegalia (60%), daño renal (40%), daño hepático (33%) y latencia de 21 días. El daño hepático se asoció con latencia prolongada (p = 0.02). Posterior al tratamiento disminu-yeron las concentraciones totales de eosinófilos (p < 0.001) y biomarcadores hepáticos y renales (p < 0.04). El síndrome de DRESS inducido por fármacos antituberculosos no se asoció con la cantidad de fármacos prescritos ni con el patrón de resistencia de Mycobacterium tuberculosis. CONCLUSIONES: El síndrome de DRESS inducido por fármacos antituberculosos es una reacción clínica atípica, similar a otros tipos de síndrome de DRESS que responden favorablemente a corticosteroides sisté-micos.

A Novel Approach for Optimization of Soft Material Constitutive Model Parameters Based on a Genetic Algorithm and Drucker's Stability Criterion.

The growing interest in soft materials to develop flexible devices involves the need to create accurate methodologies to determine parameter values of constitutive models to improve their modeling. In this work, a novel approach for the optimization of constitutive model parameters is presented, which consists of using a genetic algorithm (GA) to obtain a set of solutions from data of uniaxial tensile tests, which are later used to simulate the mechanical test using finite element analysis (FEA) software to find an optimal solution considering Drucker's stability criterion. This approach was applied to the elastomer Ecoflex 00-30 considering the Warner and Yeoh models and Rivlin's phenomenological theory. The correlation between the experimental and the predicted data by the models was determined using the root mean squared error (RMSE), where the found parameter sets provided a close fit to the experimental data with RMSE values of 0.022 (ANSYS) and 0.024 (ABAQUS) for Warner's model, while for Yeoh's model were 0.014 (ANSYS) and 0.012 (ABAQUS). It was found that the best parameter values accurately follow the experimental material behavior using FEA. The proposed GA not only optimizes the material parameters but also has a high reproducibility level with average RMSE values of 0.024 for Warner's model and 0.009 for Yeoh's model, fulfilling Drucker's stability criterion.

Lung Function and Asthma Clinical Control in N-ERD Patients, Three-Year Follow-Up in the Context of Real-World Evidence.

Purpose: To describe the lung function and clinical control of asthma in patients with N-ERD during three years of medical follow-up using GINA guidelines. Methods: We evaluated 75 N-ERD and 68 asthma patients (AG). Clinical control, lung function, and asthma treatment were evaluated according to GINA-2014. We compared all variables at baseline and one, two, and three years after treatment. Results: At baseline, the N-ERD group had better basal lung function (LF) than the AG group (p<0.01), and the AG group used higher doses of inhaled corticosteroids than the N-ERD group (52.4% vs 30.5%, p=0.01) and short-term oral corticosteroid (OCS) use (52.4% vs 30.5%, p<0.01). Instead, N-ERD patients needed more use of leukotriene receptor antagonists (LTRA) (29.3% vs 5.9%, p<0.01). This group had better clinical control than the AG group (62.1% vs 34.1%, p<0.01). During the medical follow-up, the LF of the N-ERD group remained at normal values; however, these parameters improved in AG from one year (p<0.01). Likewise, there was a diminished use of high doses of ICS (52.4% vs 33%, p<0.05) and short-term OCS (67.6% vs 20.6%, p<0.01) in asthma patients. However, N-ERD patients still needed more use of LTRAs (p<0.02) during the study. In this context, one-third of N-ERD patients had to use a combination of two drugs to maintain this control. From the second year on, clinical control of asthma was similar in both groups (p>0.05). Conclusion: According to GINA guidelines, only one-third of patients with N-ERD can gradually achieve adequate lung function and good asthma control with a high ICS dosage. Only a very small portion of patients will require the continued use of a second medication as an LTRA to keep their asthma under control.

Biologic Therapies for Asthma and Allergic Disease: Past, Present, and Future.

The discovery of the mechanism underlying allergic disease, mouse models of asthma, and bronchoscopy studies provided initial insights into the role of Th2-type cytokines, including interlukin (IL)-4, IL-5 and IL-13, which became the target of monoclonal antibody therapy. Omalizumab, Benralizumab, Mepolizumab, Reslizumab, and Tezepelumab have been approved. These biologicals have been shown to be good alternative therapies to corticosteroids, particularly in severe asthma management, where they can improve the quality of life of many patients. Given the success in asthma, these drugs have been used in other diseases with type 2 inflammation, including chronic rhinosinusitis with nasal polyps (CRSwNP), atopic dermatitis, and chronic urticaria. Like the Th2-type cytokines, chemokines have also been the target of novel monoclonal therapies. However, they have not proved successful to date. In this review, targeted therapy is addressed from its inception to future applications in allergic diseases.

Air pollution: impact and prevention.

Air pollution is becoming a major health problem that affects millions of people worldwide. In support of this observation, the World Health Organization estimates that every year, 2.4 million people die because of the effects of air pollution on health. Mitigation strategies such as changes in diesel engine technology could result in fewer premature mortalities, as suggested by the US Environmental Protection Agency. This review: (i) discusses the impact of air pollution on respiratory disease; (ii) provides evidence that reducing air pollution may have a positive impact on the prevention of disease; and (iii) demonstrates the impact concerted polices may have on population health when governments take actions to reduce air pollution.

Allergen Immunotherapy: Current and Future Trends.

Allergen immunotherapy (AIT) is the sole disease-modifying treatment for allergic rhinitis; it prevents rhinitis from progressing to asthma and lowers medication use. AIT against mites, insect venom, and certain kinds of pollen is effective. The mechanism of action of AIT is based on inducing immunological tolerance characterized by increased IL-10, TGF-ß, and IgG4 levels and Treg cell counts. However, AIT requires prolonged schemes of administration and is sometimes associated with adverse reactions. Over the last decade, novel forms of AIT have been developed, focused on better allergen identification, structural modifications to preserve epitopes for B or T cells, post-traductional alteration through chemical processes, and the addition of adjuvants. These modified allergens induce clinical-immunological effects similar to those mentioned above, increasing the tolerance to other related allergens but with fewer side effects. Clinical studies have shown that molecular AIT is efficient in treating grass and birch allergies. This article reviews the possibility of a new AIT to improve the treatment of allergic illness.

Feature selection reveal peripheral blood parameter's changes between COVID-19 infections patients from Brazil and Ecuador.

The investigation of conventional complete blood-count (CBC) data for classifying the SARS-CoV-2 infection status became a topic of interest, particularly as a complementary laboratory tool in developing and third-world countries that financially struggled to test their population. Although hematological parameters in COVID-19-affected individuals from Asian and USA populations are available, there are no descriptions of comparative analyses of CBC findings between COVID-19 positive and negative cases from Latin American countries. In this sense, machine learning techniques have been employed to examine CBC data and aid in screening patients suspected of SARS-CoV-2 infection. In this work, we used machine learning to compare CBC data between two highly genetically distinguished Latin American countries: Brazil and Ecuador. We notice a clear distribution pattern of positive and negative cases between the two countries. Interestingly, almost all red blood cell count parameters were divergent. For males, neutrophils and lymphocytes are distinct between Brazil and Ecuador, while eosinophils are distinguished for females. Finally, neutrophils, lymphocytes, and monocytes displayed a particular distribution for both genders. Therefore, our findings demonstrate that the same set of CBC features relevant to one population is unlikely to apply to another. This is the first study to compare CBC data from two genetically distinct Latin American countries.