A comparison of treatment response to biologics in asthma-COPD overlap and pure asthma: Findings from the PRISM study.

Background: Despite the increasing use of biologics in severe asthma, there is limited research on their use in asthma-chronic obstructive pulmonary disease overlap (ACO). We compared real-world treatment responses to biologics in ACO and asthma. Methods: We conducted a multicenter, retrospective, cohort study using data from the Precision Medicine Intervention in Severe Asthma (PRISM). ACO was defined as post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.7 and a smoking history of >10 pack-years. Physicians selected biologics (omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab) based on each United States Food & Drug Administration (FDA) approval criteria. Results: After six-month treatment with biologics, both patients with ACO (N = 13) and asthma (N = 81) showed positive responses in FEV1 (10.69 ± 17.17 vs. 11.25 ± 12.87 %, P = 0.652), Asthma Control Test score (3.33 ± 5.47 vs. 5.39 ± 5.42, P = 0.290), oral corticosteroid use (-117.50 ± 94.38 vs. -115.06 ± 456.85 mg, P = 0.688), fractional exhaled nitric oxide levels (-18.62 ± 24.68 vs. -14.66 ± 45.35 ppb, P = 0.415), sputum eosinophils (-3.40 ± 10.60 vs. -14.48 ± 24.01 %, P = 0.065), blood eosinophils (-36.47 ± 517.02 vs. -363.22 ± 1294.59, P = 0.013), and exacerbation frequency (-3.07 ± 4.42 vs. -3.19 ± 5.11, P = 0.943). The odds ratio for exacerbation and time-to-first exacerbation showed no significant difference after full adjustments, and subgroup analysis according to biologic type was also showed similar results. Conclusions: Biologics treatment response patterns in patients with ACO and asthma were comparable, suggesting that biologics should be actively considered for ACO patients as well.

KAAACI Allergic Rhinitis Guidelines: Part 2. Update in Non-pharmacological Management.

Allergic rhinitis is the most common chronic disease worldwide. Various upper airway symptoms lower quality of life, and due to the recurrent symptoms, multiple treatments are usually attempted rather than one definitive treatment. There are alternatives to medical (medication-based) and non-medical treatments. A guideline is needed to understand allergic rhinitis and develop an appropriate treatment plan. We have developed guidelines for medical treatment based on previous reports. The current guidelines herein are associated with the "KAAACI Evidence-Based Guidelines for Allergic Rhinitis in Korea, Part 1: Update in pharmacotherapy" in which we aimed to provide evidence-based recommendations for the medical treatment of allergic rhinitis. Part 2 focuses on non-pharmacological management, including allergen-specific immunotherapy, subcutaneous or sublingual immunotherapy, nasal saline irrigation, environmental management strategies, companion animal management, and nasal turbinate surgery. The evidence to support the treatment efficacy, safety, and selection has been systematically reviewed. However, larger controlled studies are needed to elevate the level of evidence to select rational non-medical therapeutic options for patients with allergic rhinitis.

Ni-Ion-Chelating Strategy for Mitigating the Deterioration of Li-Ion Batteries with Nickel-Rich Cathodes.

Ni-rich cathodes are the most promising candidates for realizing high-energy-density Li-ion batteries. However, the high-valence Ni4+ ions formed in highly delithiated states are prone to reduction to lower valence states, such as Ni3+ and Ni2+ , which may cause lattice oxygen loss, cation mixing, and Ni ion dissolution. Further, LiPF6 , a key salt in commercialized electrolytes, undergoes hydrolysis to produce acidic compounds, which accelerate Ni-ion dissolution and the interfacial deterioration of the Ni-rich cathode. Dissolved Ni ions migrate and deposit on the surface of the graphite anode, causing continuous electrolyte decomposition and threatening battery safety by forming Li dendrites on the anode. Herein, 1,2-bis(diphenylphosphino)ethane (DPPE) chelates Ni ions dissolved from the Ni-rich cathode using bidentate phosphine moieties and alleviates LiPF6 hydrolysis via complexation with PF5 . Further, DPPE reduces the generation of corrosive HF and HPO2 F2 substantially compared to the amounts observed using trimethyl phosphite and tris(trimethylsilyl) phosphite, which are HF-scavenging additives. Li-ion cells with Ni-rich cathodes and graphite anodes containing DPPE exhibit remarkable discharge capacity retentions of 83.4%, with high Coulombic efficiencies of >99.99% after 300 cycles at 45 °C. The results of this study will promote the development of electrolyte additives.

Clinical predictors of treatment response to tiotropium add-on therapy in adult asthmatic patients: From multicenter real-world cohort data in Korea.

Background: Tiotropium, a long-acting muscarinic antagonist, is recommended for add-on therapy to inhaled corticosteroids (ICS)-long-acting beta 2 agonists (LABA) for severe asthma. However, real-world studies on the predictors of response to tiotropium are limited. We investigated the real-world use of tiotropium in asthmatic adult patients in Korea and we identified predictors of positive response to tiotropium add-on. Methods: We performed a multicenter, retrospective, cohort study using data from the Cohort for Reality and Evolution of Adult Asthma in Korea (COREA). We enrolled asthmatic participants who took ICS-LABA with at least 2 consecutive lung function tests at 3-month intervals. We compared tiotropium users and non-users, as well as tiotropium responders and non-responders to predict positive responses to tiotropium, defined as 1) increase in forced expiratory volume in 1 s (FEV1) ≥ 10% or 100 mL; and 2) increase in asthma control test (ACT) score ≥3 after 3 months of treatment. Results: The study included 413 tiotropium users and 1756 tiotropium non-users. Tiotropium users had low baseline lung function and high exacerbation rate, suggesting more severe asthma. Clinical predictors for positive response to tiotropium add-on were 1) positive bronchodilator response (BDR) [odds ratio (OR) = 6.8, 95% confidence interval (CI): 1.6-47.4, P = 0.021] for FEV1 responders; 2) doctor-diagnosed asthma-chronic obstructive pulmonary disease overlap (ACO) [OR = 12.6, 95% CI: 1.8-161.5, P = 0.024], and 3) initial ACT score <20 [OR = 24.1, 95% CI: 5.45-158.8, P < 0.001] for ACT responders. FEV1 responders also showed a longer exacerbation-free period than those with no FEV1 increase (P = 0.014), yielding a hazard ratio for the first asthma exacerbation of 0.5 (95% CI: 0.3-0.9, P = 0.016). Conclusions: The results of this study suggest that tiotropium add-on for uncontrolled asthma with ICS-LABA would be more effective in patients with positive BDR or ACO. Additionally, an increase in FEV1 following tiotropium may predict a lower risk of asthma exacerbation.

Incidence and outcomes of adverse drug reactions to first-line anti-tuberculosis drugs and their effects on the quality of life: A multicenter prospective cohort study.

BACKGROUND: In tuberculosis (TB) treatment, adverse drug reactions (ADRs) can interrupt treatment and decrease the quality of life (QoL). We aimed to prospectively investigate the incidence of ADRs to first-line anti-TB drugs and related outcomes and QoL. METHODS: Adult patients with TB who had been treated with first-line anti-TB drugs in five Korean hospitals were enrolled. ADR questionnaire surveys and blood tests were performed four times serially, and QoL was assessed on the fourth TB treatment week (±2 weeks). RESULTS: Of 410 enrolled patients with TB (males, 62%; mean age, 52.1 ± 18.1 years [those aged ≥65 years, 26.6%]), 67.8% experienced any ADRs (≥ grade 2) to TB drugs. The most common ADR was fatigue (53.2%), followed by itching (42.7%) and anorexia (41.7%). Older adult patients experienced relatively more ADRs, including anorexia, dyspepsia, rash, dizziness, anemia, abnormal hepatic/renal function tests, and increased uric acid levels (p < 0.05). Treatment regimens changed for 9.5% of patients owing to ADRs to anti-TB drugs. Patients with any ADRs and older adult patients had significantly lower QoL than their counterparts (p < 0.05). Old age (odds ratio [OR], 1.02) and being male (OR 2.65) were independently associated with ADRs, whereas active smoking (OR 4.73) and a relatively long treatment phase (OR 5.13) were independently associated with hepatotoxicity. CONCLUSION: ADRs to first-line anti-TB drugs were common and related to relatively low QoL, especially among older adults. Although 9.5% of patients had ADR-related regimen changes, most patients with ADRs completed treatments successfully.

Jasmonate resistant 1 and ethylene responsive factor 11 are involved in chilling sensitivity in pepper fruit (Capsicum annuum L.).

Pepper fruit (Capsicum annuum L.) is sensitive to chilling stress with chilling injuries occurring below 7 °C; however, chilling injuries occur at different temperatures depending on the genotype. The present study aimed to identify the factors that affect chilling sensitivity in pepper fruits. A total of 112 F2 pepper fruits crossed between chilling-insensitive 'UZB-GJG-1999-51' and chilling-sensitive 'C00562' pepper were grouped according to the seed browning rate, which is a typical chilling symptom of pepper fruit under chilling conditions. Physiological traits, amino acids, fatty acids, as well as ethylene responsive factor (ERF) and jasmonate resistant 1 (JAR1) expression levels were analyzed, and their correlations with the seed browning rate were confirmed. The expression level of JAR1 showed a strong negative correlation with the seed browning rate (r = - 0.7996). The expression level of ERF11 and content of hydrogen peroxide showed strong positive correlation with the seed browning rate (r = 0.7622 and 0.6607, respectively). From these results, we inferred that JAR1 and ERF11 are important factors influencing the chilling sensitivity of pepper fruit.

Interactions of Nanoparticles with Macrophages and Feasibility of Drug Delivery for Asthma.

Understanding the interaction between nanoparticles and immune cells is essential for the evaluation of nanotoxicity and development of nanomedicines. However, to date, there is little data on the membrane microstructure and biochemical changes in nanoparticle-loaded immune cells. In this study, we observed the microstructure of nanoparticle-loaded macrophages and changes in lipid droplets using holotomography analysis. Quantitatively analyzing the refractive index distribution of nanoparticle-loaded macrophages, we identified the interactions between nanoparticles and macrophages. The results showed that, when nanoparticles were phagocytized by macrophages, the number of lipid droplets and cell volume increased. The volume and mass of the lipid droplets slightly increased, owing to the absorption of nanoparticles. Meanwhile, the number of lipid droplets increased more conspicuously than the other factors. Furthermore, alveolar macrophages are involved in the development and progression of asthma. Studies have shown that macrophages play an essential role in the maintenance of asthma-related inflammation and tissue damage, suggesting that macrophage cells may be applied to asthma target delivery strategies. Therefore, we investigated the target delivery efficiency of gold nanoparticle-loaded macrophages at the biodistribution level, using an ovalbumin-induced asthma mouse model. Normal and severe asthma models were selected to determine the difference in the level of inflammation in the lung. Consequently, macrophages had increased mobility in models of severe asthma, compared to those of normal asthma disease. In this regard, the detection of observable differences in nanoparticle-loaded macrophages may be of primary interest, as an essential endpoint analysis for investigating nanomedical applications and immunotheragnostic strategies.

Transcriptomic analysis of effects of 1-methylcyclopropene (1-MCP) and ethylene treatment on kiwifruit (Actinidia chinensis) ripening.

Ethylene (ET) is a gaseous phytohormone with a crucial role in the ripening of many fruits, including kiwifruit (Actinidia spp.). Meanwhile, treatment with 1-methylcyclopropene (1-MCP), an artificial ET inhibitor delays the ripening of kiwifruit. The objective of this study was to determine the effect of ET and 1-MCP application during time-course storage of kiwifruit. In addition, we aimed to elucidate the molecular details underlying ET-mediated ripening process in kiwifruit. For this purpose, we conducted a time-course transcriptomic analysis to determine target genes of the ET-mediated maturation process in kiwifruit during storage. Thousands of genes were identified to be dynamically changed during storage and clustered into 20 groups based on the similarity of their expression patterns. Gene ontology analysis using the list of differentially expressed genes (DEGs) in 1-MCP-treated kiwifruit revealed that the identified DEGs were significantly enriched in the processes of photosynthesis metabolism and cell wall composition throughout the ripening process. Meanwhile, ET treatment rapidly triggered secondary metabolisms related to the ripening process, phenylpropanoid (e.g. lignin) metabolism, and the biosynthesis of amino acids (e.g. Phe, Cys) in kiwifruit. It was demonstrated that ET biosynthesis and signaling genes were oppositely affected by ET and 1-MCP treatment during ripening. Furthermore, we identified a ET transcription factor, AcEIL (Acc32482) which is oppositely responsive by ET and 1-MCP treatment during early ripening, potentially one of key signaling factor of ET- or 1-MCP-mediated physiological changes. Therefore, this transcriptomic study unveiled the molecular targets of ET and its antagonist, 1-MCP, in kiwifruit during ripening. Our results provide a useful foundation for understanding the molecular details underlying the ripening process in kiwifruit.

Association between obesity and lung function changes by sex and age in adults with asthma.

OBJECTIVE: The lung function changes presenting before and after asthma treatment in obese people remain largely unknown. This study aimed to investigate the association between obesity and lung function changes before and after treatment in adults with asthma. METHODS: We enrolled 937 newly diagnosed asthma patients from Cohort for Reality and Evolution of Adult Asthma in Korea cohort in 2015-2017, who performed follow-up spirometry after three months of asthma treatment. The percentage changes (Δ) between the spirometry results before and after treatment were calculated. Patients were categorized into four body mass index (BMI) groups; underweight (<18.5), normal (18.5-22.9), overweight (23.0-24.9), and obese (≥25.0). Association between percent change of pulmonary function and BMI was analyzed according to sex and/or age (< 45 yrs, 45-65 yrs, ≥ 65 yrs), which were statistically corrected for age, sex, smoking status, and medication history. RESULTS: There was no consistent correlation between BMI and each lung function parameter. However, there were significant differences between BMI and ΔFEV1/FVC before and after 3 months of controller treatment. The obese asthmatics showed significantly lower ΔFEV1/FVC (6.0 ± 13.5%) than the underweight (12.6 ± 21.4%, P = 0.044) or normal weight (9.1 ± 14.6%, P = 0.031). Middle-aged women had higher BMI (24.11 ± 3.60 vs. 22.39 ± 3.52) and lower ΔFEV1/FVC (5.7 ± 11.9% vs. 8.9 ± 14.3%, P = 0.012) than young women. CONCLUSIONS: Obesity is negatively correlated with the ΔFEV1/FVC before and after controller treatment. Sex and age differentially contribute to lung function changes in response to asthma medications in adult asthmatics, showing a significant decrease in the ΔFEV1/FVC in middle-aged women.

Selective inhibition of prostaglandin D2 biosynthesis in human mast cells to overcome need for multiple receptor antagonists: Biochemical consequences.

BACKGROUND: The major mast cell prostanoid PGD2 is targeted for therapy of asthma and other diseases, because the biological actions include bronchoconstriction, vasodilation and regulation of immune cells mediated by three different receptors. It is not known if the alternative to selectively inhibit the biosynthesis of PGD2 affects release of other prostanoids in human mast cells. OBJECTIVES: To determine the biochemical consequences of inhibition of the hematopoietic prostaglandin D synthase (hPGDS) PGD2 in human mast cells. METHODS: Four human mast cell models, LAD2, cord blood derived mast cells (CBMC), peripheral blood derived mast cells (PBMC) and human lung mast cells (HLMC), were activated by anti-IgE or ionophore A23187. Prostanoids were measured by UPLC-MS/MS. RESULTS: All mast cells almost exclusively released PGD2 when activated by anti-IgE or A23187. The biosynthesis was in all four cell types entirely initiated by COX-1. When pharmacologic inhibition of hPGDS abolished formation of PGD2 , PGE2 was detected and release of TXA2 increased. Conversely, when the thromboxane synthase was inhibited, levels of PGD2 increased. Adding exogenous PGH2 confirmed predominant conversion to PGD2 under control conditions, and increased levels of TXB2 and PGE2 when hPGDS was inhibited. However, PGE2 was formed by non-enzymatic degradation. CONCLUSIONS: Inhibition of hPGDS effectively blocks mast cell dependent PGD2 formation. The inhibition was associated with redirected use of the intermediate PGH2 and shunting into biosynthesis of TXA2 . However, the levels of TXA2 did not reach those of PGD2 in naïve cells. It remains to determine if this diversion occurs in vivo and has clinical relevance.

A Nationwide Study of Severe Cutaneous Adverse Reactions Based on the Multicenter Registry in Korea.

BACKGROUND: Because severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) rarely occur, clinical data based on large-scale studies are still lacking. OBJECTIVE: To provide information on culprit drugs and clinical characteristics, including morbidity and mortality of SCARs based on a nationwide registry. METHODS: SCAR cases that occurred from 2010 to 2015 were recruited to the Korean SCAR registry from 34 tertiary referral hospitals. Demographics, causative drugs, causality, and clinical outcomes were collected by reviewing the medical record. RESULTS: A total of 745 SCAR cases (384 SJS/TEN cases and 361 DRESS cases) due to 149 drugs were registered. The main causative drugs were allopurinol (14.0%), carbamazepine (9.5%), vancomycin (4.7%), and antituberculous agents (6.3%). A strong preference for SJS/TEN was observed in carbonic anhydrase inhibitors (100%), nonsteroidal anti-inflammatory drugs (84%), and acetaminophen (83%), whereas dapsone (100%), antituberculous agents (81%), and glycopeptide antibacterials (78%) were more likely to cause DRESS. The mortality rate was 6.6% (SJS/TEN 8.9% and DRESS 4.2%). The median time to death was 19 days and 29 days in SJS/TEN and DRESS respectively, and 89.8% of deaths occurred within 60 days after the onset of the skin symptoms. CONCLUSION: Allopurinol, carbamazepine, vancomycin, and antituberculous agents were the leading causes of SCARs in Korea. Some drugs preferentially caused a specific phenotype. The mortality rate of SCARs was 6.6%, and most of the deaths occurred within 2 months.

A Randomized, Noninferiority Trial Comparing ICS + LABA with ICS + LABA + LAMA in Asthma-COPD Overlap (ACO) Treatment: The ACO Treatment with Optimal Medications (ATOMIC) Study.

BACKGROUND: Current guidelines for the treatment of asthma and chronic obstructive pulmonary disease overlap (ACO) recommend initial treatment using inhaled corticosteroids (ICSs) plus 1 or more bronchodilators. OBJECTIVE: To clarify which therapeutic effect is better between the ICS + long-acting ß2 agonist (LABA) and ICS + LABA + long-acting muscarinic antagonist (LAMA) treatment in patients with ACO. METHODS: We conducted a multicenter, 48-week, randomized, noninferiority trial. Patients with ACO were enrolled if they were treated with a moderate to high dose of ICS + LABA. In total, 303 patients were involved in the present trial, with 149 receiving ICS + LABA + LAMA. The primary end point was the time to first exacerbation. Secondary outcomes included changes in FEV1, forced vital capacity, FEV1/forced vital capacity ratio, asthma control, blood eosinophil count, and fractional exhaled nitric oxide. RESULTS: In the ICS + LABA treatment group, 29 of 154 patients (18.83%) experienced exacerbation, whereas 28 of 149 patients (18.79%) experienced exacerbation in the ICS + LABA + LAMA treatment group. The results of this noninferiority study were ultimately inconclusive (hazard ratio, 1.1; 95% CI, 0.66-1.84). However, the patients treated with the addition of LAMA showed significant improvements in FEV1 and forced vital capacity (P < .001). Asthma control did not improve in either group. CONCLUSIONS: Although this study was unable to conclude that ICS + LABA treatment is not inferior to ICS + LABA + LAMA in terms of exacerbation, it is obvious that the ICS + LABA + LAMA treatment group had improved lung function in ACO.

A Prospective Observation of Psychological Distress in Patients With Anaphylaxis.

PURPOSE: Anaphylaxis is an immediate allergic reaction characterized by potentially life-threatening, severe, systemic manifestations. While studies have evaluated links between serious illness and posttraumatic stress disorder (PTSD), few have investigated PTSD after anaphylaxis in adults. We sought to investigate the psychosocial burden of recent anaphylaxis in Korean adults. METHODS: A total of 203 (mean age of 44 years, 120 females) patients with anaphylaxis were recruited from 15 university hospitals in Korea. Questionnaires, including the Impact of Event Scale-Revised-Korean version (IES-R-K), the Korean version of the Beck Anxiety Inventory (K-BAI), and the Korean version of the Beck Depression Inventory (K-BDI), were administered. Demographic characteristics, causes and clinical features of anaphylaxis, and serum inflammatory markers, including tryptase, platelet-activating factor, interleukin-6, tumor necrosis factor-α, and C-reactive protein, were evaluated. RESULTS: PTSD (IES-R-K ≥ 25) was noted in 84 (41.4%) patients with anaphylaxis. Of them, 56.0% had severe PTSD (IES-R-K ≥ 40). Additionally, 23.2% and 28.1% of the patients had anxiety (K-BAI ≥ 22) and depression (K-BDI ≥ 17), respectively. IES-R-K was significantly correlated with both K-BAI (r = 0.609, p < 0.0001) and K-BDI (r = 0.550, p < 0.0001). Among the inflammatory mediators, tryptase levels were lower in patients exhibiting PTSD; meanwhile, platelet-activating factor levels were lower in patients exhibiting anxiety and depression while recovering from anaphylaxis. In multivariate analysis, K-BAI and K-BDI were identified as major predictive variables of PTSD in patients with anaphylaxis. CONCLUSIONS: In patients with anaphylaxis, we found a remarkably high prevalence of PTSD and associated psychological distresses, including anxiety and depression. Physicians ought to be aware of the potential for psychological distress in anaphylactic patients and to consider psychological evaluation.

Variation of clinical manifestations according to culprit drugs in DRESS syndrome.

PURPOSE: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but serious condition that systematically damages various internal organs through T-cell-mediated immunological drug reactions. We aimed to investigate whether clinical manifestations of DRESS syndrome differ according to culprit drugs. METHODS: We retrospectively analyzed data from 123 patients with probable/definite DRESS syndrome based on the RegiSCAR criteria (January 2011 to July 2016). The data were obtained from the Korean Severe Cutaneous Adverse Reaction Registry. Causality was assessed using the World Health Organization-Uppsala Monitoring Centre criteria. The culprit drugs were categorized as allopurinol, carbamazepine, anti-tuberculosis drug, vancomycin, cephalosporins, dapsone, and nonsteroidal anti-inflammatory drugs. RESULTS: Differences were observed among culprit drugs regarding the frequencies of hepatitis (P < 0.01), renal dysfunction (P < 0.0001), lymphadenopathy (P < 0.01), and atypical lymphocyte (P < 0.01). Latency period differed among culprit drugs (P < 0.0001), being shorter in vancomycin and cephalosporin. In terms of clinical severity, admission duration (P < 0.01) and treatment duration (P < 0.05) differed among culprit drugs, being longer in vancomycin and anti-tuberculosis drugs, respectively. CONCLUSIONS: Based on the findings, clinical manifestations, including latency period and clinical severity, may differ according to culprit drugs in DRESS syndrome.

Association of TG2 from mast cells and chronic spontaneous urticaria pathogenesis.

BACKGROUND: Mast cells and their mediators play important roles in chronic spontaneous urticaria (CSU) pathogenesis. Transglutaminase 2 (TG2) is expressed in activated mast cells and contributes to airway inflammation in allergic asthma. OBJECTIVE: To investigate the role of TG2 in CSU. METHODS: Patients with CSU (n = 72) and healthy controls (n = 51) were evaluated. Skin biopsy specimens were obtained from 5 patients with CSU and 2 healthy controls. Cord blood-derived human mast cells and peripheral blood-derived human mast cells were activated with IgE. TG2 activity and inflammatory mediators, such as histamine, leukotriene C4, and cytokines, were measured in serum or supernatant from cultured mast cells by enzyme-linked immunosorbent assay. Colocalization of mast cells and TG2 was determined in skin tissues by immunofluorescence. RESULTS: TG2 activity was significantly higher in serum samples from patients with CSU than in serum samples from healthy controls (P < .001). Colocalization of mast cell surface marker c-kit and TG2 was significantly increased in the lesional skin of patients with CSU compared with that in healthy controls. The levels of histamine, leukotriene C4, tumor necrosis factor α, transforming growth factor ß, and interleukins 4, 5, and 6 were significantly higher in patients with CSU than in healthy controls (P < .001). Serum TG2 levels had positive correlations with each inflammatory mediator (P < .001). TG2 activity was increased in cord blood-derived human mast cells (CBMCs) and peripheral blood-derived human mast cells activated with IgE compared with those without activation (P < .05). CONCLUSION: Our findings suggest that TG2 expressed in and released from mast cells plays an important role in CSU pathogenesis.

Urinary excretion of 9α,11ß-prostaglandin F2 and leukotriene E4 in patients with exercise-induced bronchoconstriction.

BACKGROUND: Increased levels of mast cell-derived eicosanoids, such as prostaglandin (PG) D2 and cysteinyl leukotrienes (CysLTs), have been reported in patients with exercise-induced bronchoconstriction (EIB), suggesting that mast cell activation is involved in the mechanism of EIB. However, it is still controversial since these results have not been reproduced in other studies. The aim of this study was to evaluate the role of PGD2 and LTE4 in adult asthma with EIB, as measuring urinary levels of their metabolites-9α,11ß-PGF2 and LTE4 before and after an exercise challenge test. METHODS: Eight patients with asthma and EIB and five normal controls without EIB were enrolled. Exercise challenge tests comprised of 6 min of treadmill exercise or free running were performed in all study subjects, and urine samples before and 1 h after the challenge were collected. Urinary levels of 9α,11ß-PGF2 and LTE4 were measured by enzyme immunoassay (EIA). RESULTS: No significant differences were observed in 9α,11ß-PGF2 and LTE4 levels before/after the exercise challenge between patients with EIB and normal controls. No significant increases in urinary levels of 9α,11ß-PGF2 or LTE4 were detected during the exercise challenge in patients with EIB and normal controls. No significant correlations were observed between the percent decrease in forced expiratory volume in 1 s (FEV1) or percent changes in 9α,11ß-PGF2 and LTE4 levels after the exercise challenge. CONCLUSIONS: Urinary 9α,11ß-PGF2 and LTE4 levels did not increase after an exercise challenge in patients with EIB, suggesting that urinary excretion of 9α,11ß-PGF2 and LTE4 may not be a good marker of mast cell activation in patients with EIB.

Prognostic role of p53 and Ki-67 immunohistochemical expression in patients with surgically resected lung adenocarcinoma: a retrospective study.

OBJECTIVE: p53 mutations and the Ki-67 protein are frequently observed in various types of human cancer; the abnormal expression of p53 and Ki-67 in the tumor is associated with poor survival of lung cancer patients. We aimed to assess the prognostic role of immunohistochemical (IHC) expression of p53 and Ki-67 in lung adenocarcinoma tissue. METHODS: Tumor samples from 136 patients who had undergone surgical resection for lung adenocarcinoma were retrospectively evaluated for p53 and Ki-67 expression by immunohistochemistry. Associations of clinical and pathologic variables with p53 and Ki-67 were determined using the χ(2) test. After excluding two patients (follow-up loss), 134 cases were evaluated for associations between p53, Ki-67, clinical and pathologic variables, and survival by using the Cox proportional hazards regression model and Kaplan-Meier method. RESULTS: In the 136 patients, p53 was positive in 71.0% (93/131), and Ki-67 showed high in 49.2% (61/124). Unlike p53, Ki-67 was associated with male sex, smoking, and poor tumor differentiation (P=0.004, P=0.001 and P=0.006). Of these, poor tumor differentiation strongly was correlated with high level of Ki-67 expression (P=0.008). Neither p53 nor Ki-67 was associated with increased risk of death (P=0.318, P=0.053); however, age ≥60 years and lymph node involvement were significant predictors of death (P=0.039 and P=0.042). The log-rank test revealed a significant association between Ki-67 and lower survival in all patients (χ(2)=5637; P=0.018); however, the risk was limited to stage III cases (χ(2)=5.939; P=0.015). Unlike p53, patients with high level of Ki-67 expression showed lower 3-year actuarial survival than those without (log-rank test, χ(2)=4.936; P=0.026). CONCLUSIONS: IHC expression of Ki-67 in lung adenocarcinoma tissue shows stronger association with poor tumor differentiation, and negatively affects patients' survival in advanced-stage lung cancer; however, the role of p53 on patient outcome needs further study.

Upper airways in aspirin-exacerbated respiratory disease.

PURPOSE OF REVIEW: This review updates the status of chronic rhinosinusitis with nasal polyps (CRSwNP) in aspirin-exacerbated respiratory disease (AERD) in the contexts of epidemiology, diagnosis, pathogenesis, and treatment. RECENT FINDINGS: Recent studies have shown that prostaglandin E2 (PGE2) deficiency induces an AERD phenotype in PGE2 synthase-1 knock-out mice and also PGE2 resistance in granulocytes of AERD patients. The numbers of platelet-adherent leukocytes increase in AERD patients, enhancing production of cysteinyl leukotrienes (CysLTs) via transcellular metabolism of arachidonate. INF-γ released from eosinophils of the sinus tissue of AERD patients promotes eosinophil maturation, increases leukotriene-associated gene expression, and releases CysLTs. The serum periostin level has been suggested to be a useful biomarker predicting the AERD/CRSwNP phenotype. Aspirin desensitization was reported to decrease the levels of CD4⁺ T cell-derived cytokines, including INF-γ and IL-10, in line with the newly defined role of INF-γ in AERD. SUMMARY: Recent findings further support the notion that arachidonic acid metabolism is dysregulated in AERD patients. This is reflected by resistance to PGE2, overproduction of CysLTs by enhanced numbers of platelet-adherent leukocytes, and cellular stimulation by INF-γ released from eosinophils. Aspirin desensitization may be a useful treatment option in AERD patients exhibiting recalcitrant CRSwNP.

An update on the pathogenesis of the upper airways in aspirin-exacerbated respiratory disease.

PURPOSE OF REVIEW: The key features of aspirin-exacerbated respiratory diseases (AERDs) include chronic, severe asthma and a high prevalence (60-80%) of chronic rhinosinusitis with nasal polyps, all of which are exacerbated by exposure to aspirin and other NSAIDs. Although the pathogenic mechanisms of AERD are not completely understood, repeated instances have shown intense eosinophilic infiltrations of upper and lower airway mucosa, and dysregulation of arachidonate metabolisms. Here, recent updates on the pathogenic mechanisms of chronic rhinosinusitis with nasal polyps in aspirin-exacerbated respiratory diseases are summarized. RECENT FINDINGS: Intense eosinophilic infiltration is closely related to the elevated production of cytokines and chemokines such as IL-5 and eotaxin. The response of local immunoglobulin E to staphylococcal enterotoxins contributes to eosinophilic inflammation in nasal polyp tissue. Other characteristics include the overproduction of cysteinyl leukotrienes and increased expression of cysteinyl leukotriene receptor-1, reduced production of prostaglandin E2, and the down-regulation of cyclooxygenase-2 and E-prostanoid receptor subtype-2. A recent gene expression profiling study has also suggested that periostin is the most up-regulated gene in the nasal polyp tissue of AERD patients. SUMMARY: Chronic rhinosinusitis with nasal polyps is a major comorbid condition of AERD patients that is closely associated with severe asthmatic symptoms. Significant pathologic findings in nasal polyp tissues include intense eosinophilic inflammation, which is caused by elevated production of eosinophil-related cytokines and chemokines, specific immunoglobulin E responses to staphylococcal enterotoxins, and altered arachidonic acid metabolism. This could affect the current treatments and methodologies that are used to control asthma, leading to a more severe and intractable AERD phenotype.

Methyl jasmonate and 1-methylcyclopropene treatment effects on quinone reductase inducing activity and post-harvest quality of broccoli.

Effect of pre-harvest methyl jasmonate (MeJA) and post-harvest 1-methylcyclopropene (1-MCP) treatments on broccoli floret glucosinolate (GS) concentrations and quinone reductase (QR, an in vitro anti-cancer biomarker) inducing activity were evaluated two days prior to harvest, at harvest and at 10, 20, and 30 days of post-harvest storage at 4 °C. MeJA treatments four days prior to harvest of broccoli heads was observed to significantly increase floret ethylene biosynthesis resulting in chlorophyll catabolism during post-harvest storage and reduced product quality. Post-harvest treatment with 1-methylcyclopropene (1-MCP), which competitively binds to protein ethylene receptors, maintained post-harvest floret chlorophyll concentrations and product visual quality in both control and MeJA-treated broccoli. Transcript abundance of BoPPH, a gene which is responsible for the synthesis of pheophytinase, the primary enzyme associated with chlorophyll catabolism in broccoli, was reduced by 1-MCP treatment and showed a significant, negative correlation with floret chlorophyll concentrations. The GS, glucobrassicin, neoglucobrassicin, and gluconasturtiin were significantly increased by MeJA treatments. The products of some of the GS from endogenous myrosinase hydrolysis [sulforaphane (SF), neoascorbigen (NeoASG), N-methoxyindole-3-carbinol (NI3C), and phenethyl isothiocyanate (PEITC)] were also quantified and found to be significantly correlated with QR. Sulforaphane, the isothiocyanate hydrolysis product of the GS glucoraphanin, was found to be the most potent QR induction agent. Increased sulforaphane formation from the hydrolysis of glucoraphanin was associated with up-regulated gene expression of myrosinase (BoMyo) and the myrosinase enzyme co-factor gene, epithiospecifier modifier1 (BoESM1). This study demonstrates the combined treatment of MeJA and 1-MCP increased QR activity without post-harvest quality loss.