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Biomedical subjects

Mario Castro

Publications and source records attributed to Mario Castro.

At least 19 recordsLinked to original sources
PubMed2026

Aberrant mucin expression and keratinization distinguishing severe from mild asthma revealed by interpretable machine learning.

Type 2 (T2) immune cells dominate the airways of patients with mild-moderate asthma (MMA) with a more complex type 1 (T1)-T2 mixed immune response evident in treatment-refractory severe asthma (SA). We hypothesized that comparing the transcriptomes of the airway epithelium of patients with SA and MMA would reveal molecular signatures associated with more severe disease in the context of a complex immune response. Using our interpretable machine learning tool, SLIDE, meaningful latent factors (context-specific gene co-expression networks) were revealed that distinguished SA from MMA. Unexpectedly, an aberrant high expression of normally host-protective, membrane-tethered, and IFN-inducible mucins, MUC1 and MUC4, was identified in SA. Gene networks in the significant latent factors discriminating SA from MMA corresponded to enrichment of a keratinization program in SA airways. Keratinization was marked by increased expression of the stress keratin KRT16, signifying squamous metaplasia suggesting adaptive reprogramming of the airway epithelium in response to chronic stress. These mucins and KRT16 were inversely associated with lung function in 2 separate asthma cohorts. Imaging of endobronchial biopsies revealed significantly higher KRT16 protein expression in SA compared with MMA that strongly correlated with MUC1 protein expression. Our study identifies dysregulated host-protective and maladaptive repair responses in SA distinguishing from MMA.

Humans↗
PubMed2026

A cross-sectional study of oxidative stress pathway genotypes and their interactions with environmental pollutant levels identifies associations with gene expression and lung function.

BACKGROUND: Asthma is a heterogeneous disease influenced by genetic and environmental factors. Fine particulate matter (PM2.5) exacerbates asthma, likely through oxidative stress pathways, but whether genetic variation modifies this effect remains unclear. METHODS: We analysed data on 948 adults with asthma from the Severe Asthma Research Program (SARP), linking ZIP-code-level PM2.5 exposure with whole-genome sequencing data. We tested 4337 single nucleotide polymorphisms (SNPs) in 120 oxidative stress pathway genes for gene-environment (GxE) interactions with PM2.5 on lung function (forced expiratory volume in 1 s [FEV1] % predicted) using weighted linear regression. Gene expression data from bronchial epithelial cells (n = 170) were used to assess cis-expression quantitative trait loci (eQTLs). FINDINGS: Higher PM2.5 exposure was associated with lower FEV1% predicted (β per μg/m3 = -0.7, p = 0.01). We identified 20 SNPs across seven genes (OXSR1, PXDN, TPO, LRRK2, APP, MSRA, MSRB2) with significant GxE interactions after multiple-testing correction. Five SNPs were also eQTLs, linking PM2.5-modified gene expression to lung function. Minor alleles in OXSR1 and PXDN were associated with reduced gene expression and worsened FEV1% under high PM2.5 exposure. Conversely, TPO variants were associated with higher baseline expression and lower lung function, but under increasing PM2.5 exposure, minor allele carriers showed suppressed TPO expression and improved FEV1%. INTERPRETATION: This study identified 20 SNPs in oxidative stress pathway genes that modify the effect of PM2.5 on lung function in asthma. These findings highlight the importance of integrating environmental context in genetic studies and suggest potential therapeutic targets for pollution-sensitive asthma phenotypes. FUNDING: Supported by NIH grants.

Cross-Sectional Studies↗
PubMed2025

α1-Antitrypsin Gene Variation Associates With Asthma Exacerbations and Related Health Care Utilization.

BACKGROUND: α1-Antitrypsin deficiency is caused by rare pathogenic variants in SERPINA1, the strongest genetic risk factor for chronic obstructive pulmonary disease. Few studies have evaluated the effects of SERPINA1 variation on asthma severity accounting for critical gene-by-environment interactions with smoking. OBJECTIVE: To characterize the influence of SERPINA1 variation on asthma severity. METHODS: DNA samples from 847 non-Hispanic White and 446 African American participants from the Severe Asthma Research Program underwent SERPINA1 resequencing to identify rare variants. An independent population of 1955 individuals with asthma and α1-antitrypsin concentrations from a Cleveland Clinic Health System (CCHS) database were evaluated for severity measures. RESULTS: In White participants, a history of minimum smoking significantly interacted with SERPINA1 low-to-rare frequency variation to determine risk for asthma-related health care utilization. This was attributed to protease inhibitor type Z heterozygotes (MZ, N = 11), who had a higher frequency of emergency department (ED) visits (6 [54.5%] MZ heterozygotes, odds ratio [OR] = 7.60, 95% confidence interval [CI] = 1.71-39.7, P = .010), hospitalization (5 [45.5%], OR = 16.1, 95% CI = 2.64-150.4, P = .0050) in the past year, and lifetime intensive care unit (ICU) admissions (6 [54.5%], OR = 12.5, 95% CI = 2.44-75.6, P = .0032) compared with 146 individuals without SERPINA1 variants (30 [20.5%] reporting ED visits, 17 [11.6%] hospitalization, and 15 [10.3%] ICU admission). SERPINA1 variant-by-ever smoking interactions in African American participants for ED visits (P = .069) were related to 4 of 6 compound heterozygotes reporting an ED visit. In CCHS, α1-antitrypsin concentrations were inversely associated with moderate-to-severe asthma risk (OR = 0.97 per 10 mg/dL increase in α1-antitrypsin, 95% CI = 0.94-0.99, P = .010) and exacerbations (OR = 0.84 per 10 mg/dL, 95% CI = 0.76-0.94, P = .002). CONCLUSIONS: SERPINA1 variation and α1-antitrypsin concentrations impact asthma severity through gene-environment interactions with minimum smoking.

Adult↗
PubMed2006

IL4R alpha mutations are associated with asthma exacerbations and mast cell/IgE expression.

BACKGROUND: Severe asthma has been associated with severe exacerbations, lower lung function and greater tissue inflammation. Previous studies have suggested that mutations in interleukin-4 receptor alpha (IL4Ralpha) are associated with lower lung function, higher IgE, and a gain in receptor function. However, an effect on exacerbations and tissue inflammation has not been shown. HYPOTHESIS: Allelic substitutions in IL4Ralpha are associated with asthma exacerbations, lower lung function, and tissue inflammation, in particular to mast cells and IgE. METHODS: Two well-characterized cohorts of subjects with severe asthma were analyzed for five single nucleotide polymorphisms (SNPs) in IL4Ralpha. These polymorphisms were compared with the history of severe asthma exacerbations and lung function. In the primary (National Jewish) cohort, these polymorphisms were also compared with endobronchial tissue inflammatory cells and local IgE. RESULTS: In both cohorts, the presence of the minor alleles at E375A and Q551R, which were more common in African Americans, was associated with a history of severe exacerbations and lower lung function. In the National Jewish cohort, the C allele at E375A was associated with higher tissue mast cells and higher levels of IgE bound to mast cells. The significance for most of these associations remained when whites (the larger racial subgroup) were analyzed separately. CONCLUSIONS: SNPs in IL4Ralpha, which are more common in African Americans, are associated with severe asthma exacerbations, lower lung function, and increased mast cell-related tissue inflammation. Further studies of the impact of these mutations in African Americans and on receptor function are indicated.

Adult↗
PubMed2006

Predicting episodes of poor asthma control in treated patients with asthma.

BACKGROUND: Asthma exacerbations are dangerous, expensive, and difficult to anticipate. OBJECTIVE: To characterize patients with asthma who had asthma episodes and exacerbations during 4 weeks of observation. METHODS: A total of 2032 volunteers with asthma (age, 3-64 years; 62% female subjects) were studied over two 2-week intervals after flu vaccine and placebo. Baseline data, including several asthma questionnaires, were analyzed for prediction of subsequent asthma events as recorded on diaries detailing peak flow, medication use, and health care use. RESULTS: During 28 days of diary collection, 43.2% of participants had at least 1 episode of poor asthma control. Most episodes were characterized by increased use of rescue medications or reductions in peak flow, but nearly 15% of participants had exacerbations characterized by use of systemic corticosteroids, unscheduled health care visits, or both. Episode frequency was highest in children <10 years of age. Additional risk factors were smoking, African American ethnicity, low lung function, and past history of severe asthma. The best predictors were symptom questionnaires, and a simple questionnaire concerning the preceding 2 weeks worked as well as more complex questionnaires or those reflecting longer periods. In regression analyses, questionnaire results, smoking, lung function, ethnicity, and asthma history all were associated with asthma episodes in people older than 10 years, whereas only asthma history was predictive in those <10 years. CONCLUSION: Symptom questionnaires are predictive of subsequent asthma episodes in people older than age 10 years, but not in younger people. CLINICAL IMPLICATIONS: Simple assessments may be helpful in identifying patients most at risk for future asthma episodes.

Adolescent↗
PubMed2006

IL-12 p80 is an innate epithelial cell effector that mediates chronic allograft dysfunction.

RATIONALE: Bronchiolitis obliterans syndrome is the leading cause of chronic lung allograft dysfunction. We have demonstrated that respiratory viral infection is a bronchiolitis obliterans syndrome risk factor and virus-dependent injury induces expression of innate airway epithelial genes belonging to the interleukin (IL)-12 family. Thus, we hypothesized that epithelial cell IL-12 family members could mediate lung allograft dysfunction. OBJECTIVES: We used mouse and human allograft specimens to evaluate the role of epithelial cell IL-12 family members in allograft dysfunction associated with and without viral infection. METHODS: Murine and human IL-12 family members were characterized and manipulated in allografts and then correlated with epithelial cell injury, immune cell accumulation, and collagen deposition. RESULTS: In a mouse model of lung transplantation, concurrent viral infection and allogeneic transplantation increased epithelial injury and this was followed by exaggerated accumulation of macrophages and collagen deposition. This virus-driven allograft dysfunction was associated with an epithelial innate response manifested by a synergistic increase in the production of the macrophage chemoattractant IL-12 p80 (p80), but not IL-12 or IL-23. Blockade or overexpression of donor epithelial p80 resulted in a corresponding abrogation or enhancement of macrophage accumulation and allograft dysfunction. We extended these findings to human recipients with viral infection and transplant bronchitis and again observed excessive epithelial p80 expression that correlated with increased macrophage accumulation. CONCLUSIONS: These experiments support a role for an enhanced epithelial innate response as a central process in allograft dysfunction and identify the macrophage chemoattractant p80 as an innate epithelial effector of disease progression.

Animals↗
PubMed2006

Nonlinear ripple dynamics on amorphous surfaces patterned by ion beam sputtering.

Erosion by ion-beam sputtering (IBS) of amorphous targets at off-normal incidence frequently produces a (nanometric) rippled surface pattern, strongly resembling macroscopic ripples on aeolian sand dunes. A suitable generalization of continuum descriptions of the latter allows us to describe theoretically for the first time the main nonlinear features of ripple dynamics by IBS, namely, wavelength coarsening and nonuniform translation velocity, that agree with similar results in experiments and discrete models. These properties are seen to be the anisotropic counterparts of in-plane ordering and (interrupted) pattern coarsening in IBS experiments on rotating substrates and at normal incidence.

Journal Article↗
PubMed2006

Brief communication: Molecular characterization of O alleles at the ABO locus in Chilean Aymara and Huilliche Indians.

A molecular characterization of alleles O1, O1variant (O1v), and the mutation G542A of the ABO blood group was performed in two Amerindian populations of Chile, the Aymara (n = 84) and the Huilliche (n = 75). In addition, a sample of 82 individuals of Santiago belonging to the mixed Chilean population was typed for comparative purposes. The polymorphisms which allow for molecular differentiation of different alleles of the O blood group were studied in genomic DNA. The mutations G188, G261-, G542A, T646A, and C771T, described for alleles O1, O1v, and G542A, were determined using the PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) technique. All individuals studied were group O homozygotes for the deletion G261-, which defines the O1 alleles. Results obtained indicate that allele O1v exhibits frequencies of 0.65, 0.81, and 0.60 in Aymara, Huilliche, and Santiago populations, respectively. The frequencies of allele O1(G542A) were 0.119, 0.113, and 0.079 in the same populations. Frequencies for alleles O1 and O1v obtained in the Chilean populations studied concur with the results obtained by other authors, respecting the greater frequency of allele O1v as well as with its heterogeneous distribution in aboriginal South American populations. In Chilean populations, Allele G542A exhibits lower frequencies than those described for indigenous populations from Brazil and may be used as an Amerind admixture marker.

ABO Blood-Group System↗
PubMed2006

The C523A beta2 adrenergic receptor polymorphism associates with markers of asthma severity in African Americans.

Our goal was to explore associations between ss2 adrenergic receptor polymorphisms and markers of asthma severity in African American and Caucasian patients with asthma. Polymorphisms at loci -1023, -654, -47, 46, 79, 491, and 523 were genotyped and haplotypes were imputed in 143 African Americans and 336 Caucasians. C523A genotype associated with percentage of African Americans (but not of Caucasians) having an asthma exacerbation: AA, AC, and CC genotypes were 17, 29, and 40%, respectively (p = 0.018). Symptom scores, pulmonary function, and rescue inhaler use paralleled exacerbation prevalence. We conclude the 523 A allele modifies asthma severity in African Americans.

Adult↗
PubMed2006

Asthma status and severity affects missed school days.

Excessive school absence disrupts learning and is a strong predictor of premature school dropout. School-aged children with asthma are absent more often compared to their healthy peers without asthma; yet, the causes are inadequately documented. We sought to determine the difference in mean absence days between children with and without asthma, the relationship between asthma severity and missed days from school, and if incident absences were due to asthma in a predominantly African American urban school district in the Midwestern United States. A cross-sectional analysis was conducted of 9014 students (grades K-12) followed for absenteeism over the 2002-2003 academic year. A subset of 543 students with asthma was assessed for asthma severity and cause of absence. Those with asthma (9.7% of students) were absent (mean = 9.2 days) approximately 1.5 more days compared to those without asthma (mean = 7.9 days) (p = .006). In the analysis comparing asthma severity and absenteeism, after adjusting for demographic variables and enrollment time, mean days absent increased with increasing asthma severity level: mild intermittent (mean = 8.5 days), mild persistent (mean = 11.3 days), moderate persistent (mean = 10.3 days), and severe persistent (mean = 11.6 days) (p = .001). Out of 1537 tracked absences that resulted from illness, 478 (31%) were due specifically to asthma-related symptoms. Children with asthma are absent from school more often compared to their healthy peers and this appears to be driven by the underlying severity of symptoms. (J Sch Health. 2006;76(1):18-24).

Absenteeism↗
PubMed2006

Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals.

Epithelial hyperplasia and metaplasia are common features of inflammatory and neoplastic disease, but the basis for the altered epithelial phenotype is often uncertain. Here we show that long-term ciliated cell hyperplasia coincides with mucous (goblet) cell metaplasia after respiratory viral clearance in mouse airways. This chronic switch in epithelial behavior exhibits genetic susceptibility and depends on persistent activation of EGFR signaling to PI3K that prevents apoptosis of ciliated cells and on IL-13 signaling that promotes transdifferentiation of ciliated to goblet cells. Thus, EGFR blockade (using an irreversible EGFR kinase inhibitor designated EKB-569) prevents virus-induced increases in ciliated and goblet cells whereas IL-13 blockade (using s-IL-13Ralpha2-Fc) exacerbates ciliated cell hyperplasia but still inhibits goblet cell metaplasia. The distinct effects of EGFR and IL-13 inhibitors after viral reprogramming suggest that these combined therapeutic strategies may also correct epithelial architecture in the setting of airway inflammatory disorders characterized by a similar pattern of chronic EGFR activation, IL-13 expression, and ciliated-to-goblet cell metaplasia.

Animals↗
PubMed2006

Influenza vaccine in patients with asthma.

Influenza virus continues to be a major cause of respiratory infection and is an important contributor to morbidity and mortality in at-risk populations, including those with underlying pulmonary conditions such as asthma. Vaccination with inactivated influenza vaccine remains the most popular method in controlling influenza through prevention. Current guidelines recommend the administration of the influenza vaccine to all patients with asthma. However, a third or fewer of those patients with asthma are currently receiving this vaccine. In this review, the risk-versus-benefit of influenza vaccination in children and adults with asthma is evaluated, based on the current evidence.

Asthma↗
PubMed2005

Tumor growth instability and the onset of invasion.

Motivated by experimental observations, we develop a mathematical model of chemotactically directed tumor growth. We present an analytical study of the model as well as a numerical one. The mathematical analysis shows that: (i) tumor cell proliferation by itself cannot generate the invasive branching behavior observed experimentally, (ii) heterotype chemotaxis provides an instability mechanism that leads to the onset of tumor invasion, and (iii) homotype chemotaxis does not provide such an instability mechanism but enhances the mean speed of the tumor surface. The numerical results not only support the assumptions needed to perform the mathematical analysis but they also provide evidence of (i), (ii), and (iii). Finally, both the analytical study and the numerical work agree with the experimental phenomena.

Animals↗
PubMed2005

Investigative bronchoprovocation and bronchoscopy in airway diseases.

RATIONALE: Basic and clinical research strategies used for many lung diseases have depended on volunteer subjects undergoing bronchoscopy to establish access to the airways to collect biological specimens and tissue, perhaps with added bronchoprovocation in asthma syndromes. These procedures have yielded a wealth of important scientific information. Since the last critical review more than a decade ago, some of the techniques and applications have changed, and untoward events have occurred, raising safety concerns and increasing institutional review scrutiny. OBJECTIVES AND METHODS: To reappraise these investigational methods in the context of current knowledge, the National Heart, Lung, and Blood Institute and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health convened a working group to review these procedures used for airway disease research, emphasizing asthma and chronic obstructive pulmonary disease. MAIN RESULTS: The group reaffirmed the scientific importance of investigative bronchoscopy and bronchoprovocation, even as less invasive technologies evolve. The group also considered the safety of bronchoscopy and bronchoprovocation with methacholine and antigen to be acceptable for volunteer subjects and patients, but stressed the need to monitor this closely and to emphasize proper training of participating medical research personnel. Issues were raised about vulnerable volunteers, especially children who need surrogates for informed consent. CONCLUSION: This review of investigative bronchoscopy and bronchoprovocation could serve as the basis for future guidelines for the use of these procedures in the United States.

Asthma↗
PubMed2005

Scaling of local slopes, conservation laws, and anomalous roughening in surface growth.

We argue that symmetries and conservation laws greatly restrict the form of the terms entering the long wavelength description of growth models exhibiting anomalous roughening. This is exploited to show by dynamic renormalization group arguments that intrinsic anomalous roughening cannot occur in local growth models. However, some conserved dynamics may display superroughening if a given type of term is present.

Journal Article↗