GRIK5 stimulates colon cancer growth and metastasis through cAMP/PKA/CADM3 signaling.

Glutamate receptor, ionotropic, kainate 5 (GRIK5) is a member of glutamate receptors participating, and the kainate receptor family has been proved to regulate cell proliferation and transformation. Our study aimed at exploring the role of GRIK5 in colon tumor progression. Three hundred and ninety eight colon cancer patients in The Cancer Genome Atlas Program (TCGA) data set and 26 clinical colon cancer patients were included for GRIK5 expression and prognosis analysis. GRIK5 overexpressed HCT116 and CT26 cell lines were established for cell proliferation and Transwell assay. Western blot analysis and immunostaining assay was conducted to evaluate the activation of activation of cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cell adhesion molecular 3 (CADM3) signaling in cell lines and tumor tissues. Subcutaneous CT26-bearing mice model was established to examine GRIK5-induced tumor growth and metastasis in vivo. Our study identified GRIK5 to be upregulated in patients with colon cancer, and higher GRIK5 levels correlated with the poor overall survival in patients. In vitro, GRIK5 overexpression markedly enhanced the proliferative properties and aggressive behaviors of colon cancer cells. Mechanistically, GRIK5 induced the activation of cAMP/PKA signaling, proceeded with augmented CADM3 expression, eventually resulting in sustained tumor growth. GRIK5 was a crucial scaffold in enabling colon cancer growth and metastasis, which offered a promising target for therapeutic manipulation of colon cancer.

A label-free G-quadruplex aptamer fluorescent aptasensor for visual and real-time kanamycin detection in lake and human samples.

Antibiotic abuse is considered a serious problem affecting human health, necessitating that great attention be paid to explore robust, simple and sensitive methods for rapid evaluation. In this paper, we developed a fluorescent aptasensor for visual and real-time kanamycin detection by taking advantage of the label-free strategy based on H-aggregate disassembly of a chiral cyanine dye induced by a G-quadruplex aptamer. The good sensitivity and selectivity enabled this aptasensor to have a detection limit as low as 43 nM and have high specificity for kanamycin recognition. Furthermore, this assay was successfully applied for the detection of kanamycin in lake water and urine with excellent recoveries.

Associations between comorbidities and annual incidence plus frequency of asthma exacerbation hospitalisation during the past year: data from CARN study.

PURPOSE: While asthma comorbidities are associated with higher health care utilisation, lower quality of life and poorer asthma control, the impact of asthma comorbidities on hospitalisation for asthma exacerbation (H-AX) remains less recognised. We aim to analyse the impact of asthma comorbidities on H-AX. METHODS: Based on a national survey on asthma control and disease perception (CARN 2015 study), we analysed the impact of comorbidities on annual incidence and frequency of H-AX in China. Information on demographic characteristics, asthma comorbidities and annual incidence and frequency of H-AX were presented in this study. RESULTS: Among 3875 ambulatory asthma patients, 75.9% (2941/3875) had comorbidities, and 26.4% (1017/3858) experienced H-AX during past year. After adjusting for confounding factors such as demographic data, smoking status and asthma control, COPD [OR = 2.189, 95% CI (1.673, 2.863)] and coronary heart disease [OR = 1.387, 95% CI (1.032, 1.864)] were associated with higher annual incidence, while allergic rhinitis [OR = 0.692, 95% CI (0.588, 0.815)] was associated with lower annual incidence, of H-AX. In terms of frequency, allergic rhinitis [OR = 1.630, 95% CI (1.214, 2.187)], COPD [OR = 1.472, 95% CI (1.021, 2.122)] and anxiety [OR = 2.609, 95% CI (1.051, 6.477)] showed statistically significant correlation with frequent H-AX. CONCLUSIONS: COPD and coronary heart disease were associated with higher annual incidence, while allergic rhinitis was associated with lower annual incidence of H-AX. Allergic rhinitis, COPD and anxiety were associated with frequent H-AX. Comorbidities may have an important role in the risk and frequency of annual hospitalisations due to asthma exacerbation. The goal of asthma control should rely on a multi-disciplinary treatment protocol.

Tiotropium in Early-Stage Chronic Obstructive Pulmonary Disease.

BACKGROUND: Patients with mild or moderate chronic obstructive pulmonary disease (COPD) rarely receive medications, because they have few symptoms. We hypothesized that long-term use of tiotropium would improve lung function and ameliorate the decline in lung function in patients with mild or moderate COPD. METHODS: In a multicenter, randomized, double-blind, placebo-controlled trial that was conducted in China, we randomly assigned 841 patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (mild) or 2 (moderate) severity to receive a once-daily inhaled dose (18 µg) of tiotropium (419 patients) or matching placebo (422) for 2 years. The primary end point was the between-group difference in the change from baseline to 24 months in the forced expiratory volume in 1 second (FEV1) before bronchodilator use. Secondary end points included the between-group difference in the change from baseline to 24 months in the FEV1 after bronchodilator use and the between-group difference in the annual decline in the FEV1 before and after bronchodilator use from day 30 to month 24. RESULTS: Of 841 patients who underwent randomization, 388 patients in the tiotropium group and 383 in the placebo group were included in the full analysis set. The FEV1 in patients who received tiotropium was higher than in those who received placebo throughout the trial (ranges of mean differences, 127 to 169 ml before bronchodilator use and 71 to 133 ml after bronchodilator use; P<0.001 for all comparisons). There was no significant amelioration of the mean (±SE) annual decline in the FEV1 before bronchodilator use: the decline was 38±6 ml per year in the tiotropium group and 53±6 ml per year in the placebo group (difference, 15 ml per year; 95% confidence interval [CI], -1 to 31; P=0.06). In contrast, the annual decline in the FEV1 after bronchodilator use was significantly less in the tiotropium group than in the placebo group (29±5 ml per year vs. 51±6 ml per year; difference, 22 ml per year [95% CI, 6 to 37]; P=0.006). The incidence of adverse events was generally similar in the two groups. CONCLUSIONS: Tiotropium resulted in a higher FEV1 than placebo at 24 months and ameliorated the annual decline in the FEV1 after bronchodilator use in patients with COPD of GOLD stage 1 or 2. (Funded by Boehringer Ingelheim and others; Tie-COPD ClinicalTrials.gov number, NCT01455129 .).

Polymorphisms of NF-κB pathway genes influence adverse drug reactions of gefitinib in NSCLC patients.

Gefitinib is a widely used targeted therapeutic drug in East Asian non-small cell lung cancer (NSCLC) patients. This research retrospectively investigated the relationship between the polymorphisms of genes involved in NF-κB pathways and gefitinib-related Adverse Drug Reactions (ADRs). From 2011 to 2016, 109 NSCLC patients were enrolled in this study. Thirty-two SNPs of 15 genes were genotyped with a Sequenom MassARRAY system. We collected 34 paired RNA samples before and after gefitinib administration for the detection of whole blood RNA expression of genes in NF-κB pathways (NFKBIA, NFKB1, NFKB2, RELA, RELB, and TNFAIP3). IKBKB rs2272733 (CC vs non-CC: OR = 0.256, 95% CI 0.087-0.753, P = 0.013) and IKBKE rs12142086 (CC vs non-CC: OR = 3.640, 95% CI 1.320-10.039, P = 0.013) were significantly associated with gefitinib-induced skin toxicity. IKBKE rs2151222 was associated with diarrhea with the odds ratio of non-TT vs TT as 0.162 (non-TT vs TT: 95% CI 0.034-0.775, P = 0.023). Furthermore, RELA rs11227247 was a predictor for hepatic toxicity (GG vs non-GG: OR = 0.212, 95% CI 0.062-0.726, P = 0.013). None of the gene expression levels after drug administration were determined to be significant predictors for adverse drug reactions by a logistics regression analysis. Polymorphisms of IKBKB, IKBKE, and RELA are potential biomarkers for predicting gefitinib-related ADRs. Further studies are needed to understand the underlying mechanisms for diagnostic and prophylactic therapy applications.

Repeated Exposure to Streptococcus pneumoniae Exacerbates Chronic Obstructive Pulmonary Disease.

Streptococcus pneumoniae is commonly found in patients with chronic obstructive pulmonary disease (COPD) and is linked to acute exacerbation of COPD. However, current clinical therapy neglects asymptomatic insidious S. pneumoniae colonization. We studied the roles of repeated exposure to S. pneumoniae in COPD progression using a mouse model. C57BL/6J mice were intranasally inoculated with S. pneumoniae ST262 every 4 weeks with or without cigarette smoke (CS) exposure up to 20 weeks to maintain persistent S. pneumoniae presence in the lower airways. Streptococcus pneumoniae enhanced CS-induced inflammatory cell infiltration at 12 to 20 weeks of exposure. Streptococcus pneumoniae also increased CS-induced release of inflammatory cytokines, including IL-1ß, tumor necrosis factor-α, IL-12 (p70), and IL-5 at 20 weeks of exposure. Moreover, a combination of CS and S. pneumoniae caused alveolar epithelial injury, a decline in lung function, and an increased expression of platelet-activating factor receptor and bacterial load. Our results suggest that repeated exposure to S. pneumoniae in lower airways exacerbates CS-induced COPD.

Early risk factors of the exacerbation of coronavirus disease 2019 pneumonia.

The purpose of this study was to investigate the early risk factors for the exacerbation of coronavirus disease 2019 (COVID-19) pneumonia. Restrospective analysis of clinical data of 85 patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including gender, age, comorbidities, symptoms, blood routine, clotting profile, biochemical examination, albumin, myocardial enzyme profile, inflammatory markers, and chest computed tomography (CT). All laboratory examinations were measured within first 24 hours after admission, and chest CT was performed before admission. A total of 56 (65.9%) patients had a history of exposure to the Huanan seafood market in Wuhan. Fever and dry cough accounted for the highest percentage of all symptoms. Male COVID-2019 patients were more likely to develop severe pneumonia. Patients with severe and critical conditions are older and have higher rates of hypertension (P = .003) and coronary heart disease (P = .017). All severe and critical patients infected with SARS-CoV-2 showed bilateral lung involvement and have more multiple lobes involvement than common patients (P < .001). Severe and critical patients showed higher white blood cell count (P = .006), neutrophil (NEU) count (P = .001), NEU% (P = .002), procalcitonin (P = .011), C-reactive protein (P = .003), prothrombin time (P = .035), D-dimer (P = .025), aspartate aminotransferase (P = .006), and lower lymphocyte (LYM) count (P = .019), LYM% (P = .001), albumin (P < .001). Logistic regression analysis showed that NEU count is an independent risk factor for deterioration, with the threshold of 6.5 × 109 ·L-1 . We concluded that the laboratory independent risk factor for the progression of COVID-19 pneumonia is NEU count. In addition, COVID-19 patients with bilateral lung involvement or multiple lobes involvement should be taken seriously and actively treated to prevent deterioration of the disease.

A multicenter RCT of noninvasive ventilation in pneumonia-induced early mild acute respiratory distress syndrome.

RATIONALE: Our pilot study suggested that noninvasive ventilation (NIV) reduced the need for intubation compared with conventional administration of oxygen on patients with "early" stage of mild acute respiratory distress syndrome (ARDS, PaO2/FIO2 between 200 and 300). OBJECTIVES: To evaluate whether early NIV can reduce the need for invasive ventilation in patients with pneumonia-induced early mild ARDS. METHODS: Prospective, multicenter, randomized controlled trial (RCT) of NIV compared with conventional administration of oxygen through a Venturi mask. Primary outcome included the numbers of patients who met the intubation criteria. RESULTS: Two hundred subjects were randomized to NIV (n = 102) or control (n = 98) groups from 21 centers. Baseline characteristics were similar in the two groups. In the NIV group, PaO2/FIO2 became significantly higher than in the control group at 2 h after randomization and remained stable for the first 72 h. NIV did not decrease the proportion of patients requiring intubation than in the control group (11/102 vs. 9/98, 10.8% vs. 9.2%, p = 0.706). The ICU mortality was similar in the two groups (7/102 vs. 7/98, 4.9% vs. 3.1%, p = 0.721). Multivariate analysis showed minute ventilation greater than 11 L/min at 48 h was the independent risk factor for NIV failure (OR, 1.176 [95% CI, 1.005-1.379], p = 0.043). CONCLUSIONS: Treatment with NIV did not reduce the need for intubation among patients with pneumonia-induced early mild ARDS, despite the improved PaO2/FIO2 observed with NIV compared with standard oxygen therapy. High minute ventilation may predict NIV failure. TRIAL REGISTRATION: NCT01581229 . Registered 19 April 2012.

Feasibility of Biological Applications for Zirconium Nitride Powders Synthesized by Gas-Solid Elemental Combination Method.

ZrN powders were successfully synthesized via a facile, economical and efficient gas-solid elemental combination method. The feasibility of biological applications for the ZrN powders were further studied. Firstly, the physical properties including hardness, density and surface roughness were characterized. These results indicated remarkable physical property of ZrN with the harness, density and surface roughness of 551.6 gf · mm-2, 6.47 g cm-3 and 0.11 µm, respectively. Then the in vitro cytotoxicity was evaluated and the hemolysis activity was also performed in red blood cells (RBCs) of mice to investigate the biocompatibility of ZrN powders. Meanwhile, the potentiodynamic polarization test was carried out in PBS to explore its corrosion resistance. The ZrN powders with remarkable physical property and good biocompatibility were demonstrated to have potential application in the field of bone tissue engineering especially in implants protective coatings.

Specific risk factors contributing to early and late recurrences of intrahepatic cholangiocarcinoma after curative resection.

BACKGROUND: Most intrahepatic cholangiocarcinoma (ICC) patients experienced tumor recurrences even after curative resection, but the optimal cut-off time point and the specific risk factors for early and late recurrences of ICC have not been clearly defined. The objective of the current study was to define specific risk factors for early and late recurrences of ICC after radical hepatectomy. METHODS: Included in this study were 259 ICC patients who underwent curative surgery at our hospital between January 2005 and December 2009. Recurrences in these patients were followed-up prospectively. Piecewise regression model and the minimum P value approach were used to estimate the optimal cut-off time point for early and late recurrences. Then, Cox's proportional hazards regression model was used to identify specific independent risk factors for early and late recurrences. RESULTS: Early and late recurrences occurred in 130 and 74 patients, respectively, and the 12th month was confirmed as the optimal cut-off time point for early and late recurrences. Cox's proportional hazards regression model showed that microvascular invasion (HR = 2.084, 95% CI 1.115-3.897, P = 0.021), multiple tumors (HR = 2.071, 95% CI 1.185-3.616, P = 0.010), abnormal elevation of serum CA19-9 (HR = 1.619, 95% CI 1.076-2.437, P = 0.021), and the negative hepatitis B status (HR = 1.650, 95% CI 1.123-2.427, P = 0.011) were independent risk factors for early recurrence, and HBV-DNA level > 106 IU/mL (HR = 1.785, 95% CI 1.015-3.141, P = 0.044) and a hepatolithiasis history (HR = 2.538, 95% CI 1.165-5.533, P = 0.010) contributed to late recurrence independently. CONCLUSION: Specific risk factors and mechanisms may relate to early and late recurrences of ICC after curative resection.

Molecular Subtyping and Prognostic Assessment Based on Tumor Mutation Burden in Patients with Lung Adenocarcinomas.

The distinct molecular subtypes of lung cancer are defined by monogenic biomarkers, such as EGFR, KRAS, and ALK rearrangement. Tumor mutation burden (TMB) is a potential biomarker for response to immunotherapy, which is one of the measures for genomic instability. The molecular subtyping based on TMB has not been well characterized in lung adenocarcinomas in the Chinese population. Here we performed molecular subtyping based on TMB with the published whole exome sequencing data of 101 lung adenocarcinomas and compared the different features of the classified subtypes, including clinical features, somatic driver genes, and mutational signatures. We found that patients with lower TMB have a longer disease-free survival, and higher TMB is associated with smoking and aging. Analysis of somatic driver genes and mutational signatures demonstrates a significant association between somatic RYR2 mutations and the subtype with higher TMB. Molecular subtyping based on TMB is a potential prognostic marker for lung adenocarcinoma. Signature 4 and the mutation of RYR2 are highlighted in the TMB-High group. The mutation of RYR2 is a significant biomarker associated with high TMB in lung adenocarcinoma.

The Efficacy and Safety of Once-daily Fluticasone Furoate/Umeclidinium/Vilanterol Versus Twice-daily Budesonide/Formoterol in a Subgroup of Patients from China with Symptomatic COPD at Risk of Exacerbations (FULFIL Trial).

The FULFIL study evaluated once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100 µg/62.5 µg/25 µg versus twice-daily budesonide/formoterol (BUD/FOR) 400 µg/12 µg in patients with symptomatic COPD at risk of exacerbations. FULFIL demonstrated clinically meaningful and statistically significant improvements at Week 24 in trough forced expiratory volume in 1 second (FEV1), St George's Respiratory Questionnaire (SGRQ) Total scores and reduced exacerbation frequency. Predefined analyses were performed to evaluate treatment effects in a subgroup of patients recruited in China (China subgroup; FF/UMEC/VI, n = 32; BUD/FOR, n = 29). Analyses included treatment by region (China versus non-China) to allow estimated treatment effects in patients from China to be compared with those of the non-China subgroup and the overall FULFIL intent-to-treat (ITT) population. In the China subgroup at Week 24: the mean change from baseline in trough FEV1 was 125 mL (95% confidence interval [CI] 36, 214) for FF/UMEC/VI and -70 mL (95% CI -163, 23) BUD/FOR (between-treatment difference: 195 mL [95% CI 67, 323]; p = 0.003) and in SGRQ Total score was -5.6 units (95% CI -10.5, -0.7) and -0.3 units (95% CI -5.4, 4.7), respectively (between-treatment difference: -5.3 [95% CI -12.3, 1.7]; p = 0.140). Fewer moderate/severe exacerbations occurred with FF/UMEC/VI than BUD/FOR (16% and 28%, respectively). The overall incidence of adverse events was similar between arms (FF/UMEC/VI: 38%; BUD/FOR: 31%). This prespecified subgroup analysis of patients recruited in China to FULFIL demonstrated comparable efficacy and safety to that observed in the non-China and in the overall ITT populations, for FF/UMEC/VI versus BUD/FOR.

Lipopolysaccharides promote a shift from Th2-derived airway eosinophilic inflammation to Th17-derived neutrophilic inflammation in an ovalbumin-sensitized murine asthma model.

INTRODUCTION: The currently available treatments for severe asthma are insufficient. Infiltration of neutrophils rather than eosinophils into the airways is an important inflammatory characteristic of severe asthma. However, the mechanism of the phenotypic change from eosinophilic to neutrophilic inflammation has not yet been fully elucidated. METHODS: In the current study, we examined the effect of lipopolysaccharides (LPS) on eosinophilic asthmatic mice sensitized with ovalbumin (OVA), as well as the roles of interleukin (IL)-17A/T helper (Th) 17 cells on the change in the airway inflammatory phenotype from eosinophilic to neutrophilic inflammation in asthmatic lungs of IL-17A-deficient mice. RESULTS: Following exposure of OVA-induced asthmatic mice to LPS, neutrophil-predominant airway inflammation rather than eosinophil-predominant inflammation was observed, with increases in airway hyperresponsiveness (AHR), the IL-17A level in bronchoalveolar lavage fluid (BALF) and Th17 cells in the spleen and in the pulmonary hilar lymph nodes. Moreover, the neutrophilic asthmatic mice showed decreased mucus production and Th2 cytokine levels (IL-4 and IL-5). In contrast, IL-17A knockout (KO) mice exhibited eosinophil-predominant lung inflammation, decreased AHR, mucus overproduction and increased Th2 cytokine levels and Th2 cells. CONCLUSION: These findings suggest that the eosinophilic inflammatory phenotype of asthmatic lungs switches to the neutrophilic phenotype following exposure to LPS. The change in the inflammatory phenotype is strongly correlated with the increases in IL-17A and Th17 cells.

MicroRNA-190b confers radio-sensitivity through negative regulation of Bcl-2 in gastric cancer cells.

OBJECTIVES: To determine the role of miR-190b in radio-sensitivity of gastric cancer (GC). RESULTS: In radio-resistant GC cells, down-regulation of miR-190b and up-regulation of Bcl-2 were observed. The protein expression of Bcl-2 was negatively regulated by miR-190b. Overexpression of miR-190b significantly decreased cell viability and enhanced radio-sensitivity of GC cells. Of note, these effects of miR-190b on GC cells radio-sensitivity were abolished by Bcl-2. CONCLUSION: miR-190b confers radio-sensitivity of GC cells, possibly via negative regulation of Bcl-2.

ADRB2 signaling promotes HCC progression and sorafenib resistance by inhibiting autophagic degradation of HIF1α.

BACKGROUND & AIMS: Considerable evidence suggests that adrenergic signaling played an essential role in tumor progression. However, its role in hepatocellular carcinoma (HCC) and the underlying mechanisms remain unknown. METHODS: The effect of adrenaline in hepatocarcinogenesis was observed in a classical diethylnitrosamine-induced HCC mouse model. Effects of ADRB2 signaling inhibition in HCC cell lines were analyzed in proliferation, apoptosis, colony formation assays. Autophagy regulation by ADRB2 was assessed in immunoblotting, immunofluorescence and immunoprecipitation assays. In vivo tumorigenic properties and anticancer effects of sorafenib were examined in nude mice. Expression levels of ADRB2 and hypoxia-inducible factor-1α (HIF1α) in 150 human HCC samples were evaluated by immunohistochemistry. RESULTS: We uncovered that adrenaline promoted DEN-induced hepatocarcinogenesis, which was reversed by the ADRB2 antagonist ICI118,551. ADRB2 signaling also played an essential role in sustaining HCC cell proliferation and survival. Notably, ADRB2 signaling negatively regulated autophagy by disrupting Beclin1/VPS34/Atg14 complex in an Akt-dependent manner, leading to HIF1α stabilization, reprogramming of HCC cells glucose metabolism, and the acquisition of resistance to sorafenib. Conversely, inhibition of ADRB2 signaling by ICI118,551, or knockdown ADRB2 expression, led to enhanced autophagy, HIF1α destabilization, tumor growth suppression, and improved anti-tumor activity of sorafenib. Consistently, ADRB2 expression correlated positively with HIF1α in HCC specimens and was associated with HCC outcomes. CONCLUSIONS: Our results uncover an important role of ADRB2 signaling in regulating HCC progression. Given the efficacy of ADRB2 modulation on HCC inhibition and sorafenib resistance, adrenoceptor antagonist appears to be a putative novel treatment for HCC and chemoresistance. LAY SUMMARY: ADRB2 signaling played an essential role in sustaining hepatocellular carcinoma cell proliferation and survival. ADRB2 signaling negatively regulated autophagy, leading to hypoxia-inducible factor-1α stabilization, reprogramming of hepatocellular carcinoma cells glucose metabolism, and the acquisition of resistance to sorafenib. Adrenoceptor antagonist appears to be a putative novel treatment for hepatocellular carcinoma and chemoresistance.

Does IL-17 Respond to the Disordered Lung Microbiome and Contribute to the Neutrophilic Phenotype in Asthma?

Th17/IL-17 plays an important role in host defense and hyperimmune responses against pathogenic bacteria accompanied by the recruitment of neutrophils. Th17-associated immune response is also involved in the pathogenesis of asthma, which is known as a noninfectious allergic airway disease and has been shown to be heterogeneous. Th17-associated inflammation usually contributes to the neutrophilic phenotype, which is often characterized by greater severity, airflow obstruction, and steroid resistance. Concurrently, advanced culture-independent molecular techniques have increased our understanding of the lung microbiome and demonstrated that disorders of the lung microbiome, including changes of the total burden, diversity, and community composition, may contribute to severe, treatment-resistant neutrophilic asthma, although the precise mechanism is still unclear. Because Th17/IL-17 plays a role in bacteria-mediated immune responses and is involved in neutrophilic asthma, there may be a link between them. We review the effects of Th17/IL-17 on bacteria and asthma, showing the possibility that Th17/IL-17 may be a key player in neutrophilic asthma which may be characterized as severe or treatment-resistant by responding to the disordered lung microbiome.

Efficacy and Safety of Indacaterol/Glycopyrronium (IND/GLY) Versus Salmeterol/Fluticasone in Chinese Patients with Moderate-to-Severe Chronic Obstructive Pulmonary Disease: The Chinese Cohort from the LANTERN Study.

Inhaled indacaterol/glycopyrronium fixed-dose combination (IND/GLY) is approved in over 80 countries, including the EU, Japan, Australia and Switzerland and the US. The LANTERN study evaluated the efficacy of IND/GLY compared with inhaled long-acting ß2-agonist (LABA)/inhaled corticosteroid (ICS) or salmeterol/fluticasone (SFC) in patients with moderate-to-severe COPD with a history of ≤1 exacerbation in the previous year. Here we present the efficacy and safety of IND/GLY versus SFC in the Chinese cohort from the LANTERN study. LANTERN was a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group study conducted in patients with moderate-to-severe COPD with a history of ≤1 exacerbation in the previous year. The patients were randomized (1:1) to once-daily IND/GLY (110/50 µg) or twice-daily SFC (50/500 µg). The primary endpoint was non-inferiority of IND/GLY versus SFC in terms of trough FEV1. Of the total 744 patients randomized in the LANTERN study, 598 (80.4%) were from Mainland China and randomized to IND/GLY (n = 298) or SFC (n = 300), and 553 (92.5%) completed the study. IND/GLY showed superiority over SFC with a statistically significant and clinically meaningful improvement in trough FEV1, FEV1 AUC0-4h, peak FEV1 and trough forced vital capacity (FVC) change from the baseline. Annualized rate of moderate or severe COPD exacerbations was significantly lower (43%) with IND/GLY compared with SFC (rate ratio: 0.57, p = 0.015). Overall, adverse events were lower for IND/GLY (34.6%) versus SFC (43.1%). IND/GLY was superior in achieving bronchodilation versus SFC in a Chinese subgroup of patients from this study. Clinicaltrials.gov identifier: NCT01709903.

Dll4 in the DCs isolated from OVA-sensitized mice is involved in Th17 differentiation inhibition by 1,25-dihydroxyvitamin D3 in vitro.

INTRODUCTION: T helper 17 cell (Th17) cells play an important role in neutrophilic asthma, and 1,25(OH)2D3 has been reported to modulate the proliferation and differentiation of T cells. In this study, we examined the effects of 1,25(OH)2D3 on the dendritic cell (DC)-mediated regulation of Th17differentiation from OVA-sensitized mice. METHODS: DCs were isolated from ovalbumin-sensitized mouse spleens. Lipopolysaccharide (LPS) was administered to stimulate the DCs for 24 h, and dexamethasone or 1,25(OH)2D3 was applied simultaneously. The expression of Notch ligand delta-like ligand 4 (Dll4) in the DCs was detected in each group. All the groups of treated DCs were co-cultured with T cells, and Dll4 was inhibited in these groups. After 24 h, Th17 and Treg cell differentiation and the IL-17A levels were measured. RESULTS: Dll4 expression was increased in LPS-treated DCs compared with the control group (p = 0.05), resulting in increased Th17 cell differentiation (p = 0.002). Treatment with 1,25(OH)2D3 inhibited the Dll4 expression(p = 0.04) and decreased Th17 cell differentiation (p = 0.001) in DCs that was induced by LPS. Directly inhibiting Dll4 reduced Th17 cell differentiation, and Th17 cell differentiation was not further inhibited by 1,25(OH)2D3 once Dll4 was blocked. CONCLUSIONS: These result suggest that Dll4 in the DCs isolated from OVA-sensitized mice is involved in Th17 differentiation inhibition by 1,25(OH)2D3.

Local coordination geometry perturbed ß-diketone dysprosium single-ion magnets.

A series of three ß-diketone mononuclear dysprosium complexes, namely, Dy(TFI)3(H2O)2 (1), Dy(TFI)3(bpy) (2), and [Dy(TFI)3(Phen)]·0.02CHCl3 (3) (TFI = 2-(2,2,2-trifluoroethyl)-1-indone, bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline) have been designed and synthesized. Crystal structure analysis reveals that complexes 1-3 have haveisomorphic structures in which the central Dy(III) ion is eight-coordinated by six oxygen atoms from three TFI ligands and two O/N atoms from auxiliary ligands, forming a distorted bicapped trigonal prismatic geometry for 1, a distorted dodecahedral geometry for 2, and a distorted square antiprismatic geometry for 3, respectively. Magnetic studies indicate that complex 2 with D(2d) symmetry and 3 with D(4d) symmetry exhibit slow magnetic relaxation with barrier heights (U(eff)/k(B)) of 48.8 K for 2 and 57.9 K for 3. Strikingly, the relaxation time (τ) of 0.0258 s for 3 is about 20 times that for 2, which is presumably associated with larger rotation of the SAP surroundings for 3. Further, complexes 2 and 3 exhibit essential magnetic hysteresis loops at 1.8 K. These extend the recent reports of the single-ion magnets (SIMs) of ß-diketone mononuclear dysprosium complexes.

NAT2 slow acetylation genotypes contribute to asthma risk among Caucasians: evidence from 946 cases and 1,091 controls.

NAT2 plays a critical role in external chemical detoxification. Thus, polymorphism of NAT2 has been suggested to associate with several disorders. A number of studies have been devoted to the relationship between NAT2 polymorphism and asthma risk. However, the results were inconclusive. In this study we aimed to derive a more precise estimation of the association. A literature search in the common databases was conducted and then meta-analyses evaluating the association of NAT2 polymorphism and asthma risk were performed. Eligible studies were identified for the period up to May 2013. A total of five case-control studies containing 946 cases and 1,091 controls were lastly included for analysis. The overall data showed that slow acetylators of NAT2 might have an association with increased asthma risk (OR 2.20; 95% CI 1.31-3.72). The pooled data suggest that slow acetylators of NAT2 might contribute to asthma risk among Caucasians. Future studies are needed to confirm this conclusion.