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1.
J Allergy Clin Immunol Pract ; 11(12): 3662-3669.e2, 2023 12.
Article in English | MEDLINE | ID: mdl-37541619

ABSTRACT

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) has a triad of symptoms: nasal polyposis, asthma, and NSAID hypersensitivity. Little is known about symptom timing and disease progression. OBJECTIVE: The aim of this study is to characterize disease progression in N-ERD. METHODS: Patients with N-ERD were prospectively interviewed and classified into 4 groups based on their first symptom at initial N-ERD onset (asthma, nasal polyps, NSAID hypersensitivity, or all concurrently). Associations of patient characteristics with the 4 groups were examined, along with associations within the "asthma first" group. RESULTS: Patients (N = 240) were mostly female (68%) and self-identified as non-White (77%). Half (N = 119) reported asthma as the earliest symptom in the N-ERD triad. Compared with other groups, "asthma first" was associated with younger age of onset (25 years, standard error ±1.3, P < .001) and higher body mass index (BMI) (odds ratio [OR] = 1.3, 95% confidence interval [CI]: 1.06-1.7, P = .02). In this group, age of onset <20 years was associated with female sex, Latino ethnicity, and higher BMI (all P < .05). The "NSAID sensitivity first" group was significantly associated with male sex (OR = 3.3, 95% CI: 1.5-7.4, P = .004) and pollution exposure (OR = 4.4, 95% CI: 1.6-11.9, P = .003). At the initial presentation, 27% of patients were unaware of their N-ERD diagnosis. Black and Latino patients were more likely to be unaware of their N-ERD diagnosis compared with White (P = .003). The median diagnostic delay was 3 years (interquartile range: 0-5 years). CONCLUSIONS: In this cohort, N-ERD is highly variable in onset and progression, with sex, BMI, race and ethnicity, and environmental exposures significantly associated with disease patterns and diagnostic delay.


Subject(s)
Asthma, Aspirin-Induced , Asthma , Nasal Polyps , Respiration Disorders , Humans , Male , Female , Adult , Young Adult , Body Mass Index , Asthma, Aspirin-Induced/diagnosis , Asthma, Aspirin-Induced/epidemiology , Asthma, Aspirin-Induced/complications , Ethnicity , Delayed Diagnosis , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Asthma/diagnosis , Asthma/epidemiology , Asthma/complications , Nasal Polyps/complications , Environmental Exposure/adverse effects , Disease Progression
4.
Nat Commun ; 6: 7845, 2015 Aug 12.
Article in English | MEDLINE | ID: mdl-26263880

ABSTRACT

Gamma-ray 'glows' are long duration (seconds to tens of minutes) X-ray and gamma-ray emission coming from thunderclouds. Measurements suggest the presence of relativistic runaway electron avalanches (RREA), the same process underlying terrestrial gamma-ray flashes. Here we demonstrate that glows are relatively a common phenomena near the tops of thunderstorms, when compared with events such as terrestrial gamma-ray flashes. Examining the strongest glow measured by the airborne detector for energetic emissions, we show that this glow is measured near the end of a downward RREA, consistent with occurring between the upper positive charge layer and the negative screening layer above it. The glow discharges the upper positive layer by ≥9.6 mA, strong enough to be an important charging mechanism of the storm. For this glow, the gamma-ray flux observed is close to the value at which relativistic feedback processes become important, with an avalanche multiplication factor of 4,500.

5.
Pharmgenomics Pers Med ; 6: 25-36, 2013.
Article in English | MEDLINE | ID: mdl-23690695

ABSTRACT

Targeted therapies for cancer bring the hope of specific treatment, providing high efficacy and in some cases lower toxicity than conventional treatment. Although targeted therapeutics have helped immensely in the treatment of several cancers, like chronic myelogenous leukemia, colon cancer, and breast cancer, the benefit of these agents in the treatment of lung cancer remains limited, in part due to the development of drug resistance. In this review, we discuss the mechanisms of drug resistance and the current strategies used to treat lung cancer. A better understanding of these drug-resistance mechanisms could potentially benefit from the development of a more robust personalized medicine approach for the treatment of lung cancer.

6.
Sci Rep ; 2: 805, 2012.
Article in English | MEDLINE | ID: mdl-23150776

ABSTRACT

Dishevelled, a phosphoprotein scaffold, is a central component in all the Wnt-sensitive signaling pathways. In the present study, we report that Dishevelled is post-translationally modified, both in vitro and in vivo, via arginine methylation. We also show protein arginine methyl transferases 1 and 7 as the key enzymes catalyzing Dishevelled methylation. Interestingly, Wnt3a stimulation of F9 teratocarcinoma cells results in reduced Dishevelled methylation. Similarly, the methylation-deficient mutant of Dishevelled, R271K, displayed spontaneous membrane localization and robust activation of Wnt signaling; suggesting that differential methylation of Dishevelled plays an important role in Wnt signaling. Thus arginine methylation is shown to be an important switch in regulation of Dishevelled function and Wnt signaling.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Phosphoproteins/metabolism , Protein-Arginine N-Methyltransferases/metabolism , Adaptor Proteins, Signal Transducing/chemistry , Adaptor Proteins, Signal Transducing/genetics , Amino Acid Sequence , Animals , Arginine/metabolism , Cell Line , Cell Membrane/metabolism , Dishevelled Proteins , Drosophila , Drosophila Proteins , HEK293 Cells , Humans , Methylation , Mice , Molecular Sequence Data , Mutation , Phosphoproteins/chemistry , Phosphoproteins/genetics , Repressor Proteins/metabolism , Sequence Alignment , Signal Transduction , Substrate Specificity , Wnt Proteins/metabolism , Xenopus , Zebrafish
7.
PLoS One ; 7(3): e32921, 2012.
Article in English | MEDLINE | ID: mdl-22403725

ABSTRACT

Wnt7a is known to be a tumor suppressor that is lost in NSCLC, but no mechanism of loss has been established. Methylation of promoter regions has been established as a common mechanism of loss of tumor suppressor expression in NSCLC. We previously demonstrated that loss of Wnt7a in non-transformed lung epithelial cell lines led to increased cell growth, altered 3-D culture growth, and increased migration. The Wnt7a promoter has a higher percentage of methylation in NSCLC tumor tissue compared to matched normal lung tissue and methylation of the promoter region leads to decreased activity. We treated H157 and H1299 NSCLC cell lines with 5-Aza-2'-deoxycytidine and detected loss of Wnt7a promoter methylation, increased Wnt7a expression, and increased activity of the Wnt7a lung signaling pathway. When DNMT1 expression was knocked down by shRNA, expression of Wnt7a increased and methylation decreased. Together these data suggest that in NSCLC, Wnt7a is lost by methylation in a subset of tumors and that this methylation is maintained by DNMT1. Restoration of Wnt7a expression through demethylation could be an important therapeutic approach in the treatment of NSCLC.


Subject(s)
Carcinoma, Non-Small-Cell Lung/pathology , DNA (Cytosine-5-)-Methyltransferases/metabolism , DNA Methylation/drug effects , Lung Neoplasms/pathology , Smoke/adverse effects , Smoking/adverse effects , Wnt Proteins/genetics , Azacitidine/analogs & derivatives , Azacitidine/pharmacology , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , DNA (Cytosine-5-)-Methyltransferase 1 , Decitabine , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Epithelial Cells/pathology , Lung/pathology , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Phenotype , Promoter Regions, Genetic/drug effects , Promoter Regions, Genetic/genetics
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