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IntroductionThe COPD bacteriome associates with disease severity, exacerbations, and mortality. While COPD patients are susceptible to fungal sensitisation, the role of the fungal mycobiome remains uncertain.MethodsWe report the largest multicenter evaluation of the COPD airway mycobiome to date including participants from Asia (Singapore and Malaysia) and the United Kingdom (Scotland) when stable (n=337) and during exacerbations (n=66) as well as non-diseased controls (n=47). Longitudinal mycobiome analyses performed during and following COPD exacerbations (n=34) were examined in terms of exacerbation frequency, two-year mortality, and the occurrence of serum specific-IgE against selected fungi.ResultsA distinct mycobiome profile is observed in COPD compared to controls evidenced by increased alpha diversity (Shannon-index) (p<0.001). Significant airway mycobiome differences including greater inter-fungal interaction (by co-occurrence) characterise very frequent COPD exacerbators (≥3 exacerbations per year) (PERMANOVA, adjusted p<0.001). Longitudinal analyses during exacerbations and following treatment with antibiotics and corticosteroids did not reveal any significant change in airway mycobiome profile. Unsupervised clustering resulted in two clinically distinct COPD groups, (1) with increased symptoms (CAT score) and Saccharomyces dominance and (2) with very frequent exacerbations and higher mortality characterised by Aspergillus, Penicillium and Curvularia with a concomitant increase in serum specific IgE levels against the same fungi. During acute exacerbations of COPD, lower fungal diversity associates with higher two-year mortality.ConclusionThe airway mycobiome in COPD is characterised by specific fungal genera associated with exacerbations and increased mortality.

IntroductionAllergic sensitisation to fungi such as Aspergillus are associated to poor clinical outcomes in asthma, bronchiectasis and cystic fibrosis, however, clinical relevance in COPD remains unclear.MethodsPatients with stable COPD (n=446) and non-diseased controls (n=51) were prospectively recruited across three countries (Singapore, Malaysia and Hong Kong) and screened against a comprehensive allergen panel including house dust mites, pollens, cockroach and fungi. For the first time, using a metagenomics approach, we assess outdoor and indoor environmental allergen exposure in COPD. We identify key fungi in outdoor air and develop specific-IgE assays against the top culturable fungi, linking sensitisation responses to COPD outcomes. Indoor air and surface allergens were prospectively evaluated by metagenomics in the homes of n=11 COPD patients and linked to clinical outcome.ResultsHigh frequencies of sensitisation to a broad range of allergens occurs in COPD. Fungal sensitisation associates with frequent exacerbations, and, unsupervised clustering reveals a “highly sensitised fungal predominant” sub-group demonstrating significant symptomatology, frequent exacerbations and poor lung function. Outdoor and indoor environments serve as important reservoirs of fungal allergen exposure in COPD, and, promote a sensitisation response to outdoor air fungi. Indoor (home) environments with high fungal allergens associate with greater COPD symptoms and poorer lung function illustrating the importance of environmental exposures on clinical outcomes in COPD.ConclusionFungal sensitisation is prevalent in COPD and associates with frequent exacerbations representing a potential treatable trait. Outdoor and indoor (home) environments represent a key source of fungal allergen exposure, amenable to intervention, in “sensitised” COPD.

We report the first case of epithelial-to-mesenchymal transition (EMT) as the cause of acquired resistance to the second-generation -tyrosine kinase inhibitor (TKI), afatinib in a patient with advanced non-small cell lung cancer (NSCLC) harboring a sensitizing mutation. Patients with -mutant NSCLC inevitably develop acquired resistance while on-TKI treatment. EMT which renders cancer cells more invasive and migratory is one of the mechanisms of acquired resistance to -TKIs and correlates with a poor prognosis. Possible therapeutic strategies in patients with EMT include blocking M2 muscarinic receptor signalling, targeting EMT with histone deacetylase inhibitors such as entinostat and MEK-inhibitors such as selumetinib, inhibition of microRNAs, immunotherapy and inhibiting fibroblast growth factor receptor-1.

Background: Chemotherapy is one of the primary treatments for both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), however, chemoresistance develops over time and is a bottleneck to effective chemotherapy worldwide. Therefore, the development of new potent therapeutic agents to overcome chemoresistance is of utmost importance. Triptolide is a natural component extracted from Tripterygium Wilfordii, a Chinese plant; our study aimed to evaluate its anti-tumor effects in taxol-resistant human lung adenocarcinoma and investigate its molecular mechanisms of chemoresistance.Methods: Triptolide's inhibition of cell viability was detected by sulforhodamine B (SRB) assay. Cell cycle was measured by flow cytometry and cell apoptosis was assessed by flow cytometry and western blot.Expression of β-catenin was analyzed by western blot and immunofluorescence (IF). The anti-tumor effects of triptolide were determined using a subcutaneous in-vivo model. Cell proliferation and apoptosis were evaluated by immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, respectively. The expression level of p-p70S6K and p-GSK-3α/β was evaluated by western blot and IHC.Results: Triptolide inhibited cell proliferation, induced S-phase cell cycle arrest and apoptosis in taxolresistant A549 (A549/TaxR) cells. Moreover, intraperitoneal injection of triptolide resulted in a significant delay of tumor growth without obvious systemic toxicity in mice. Additionally, triptolide reversed epithelialmesenchymal transition (EMT) through repression of the p70S6K/GSK3/β-catenin signaling pathway. Conclusions:Our study provides evidence that triptolide can reverse EMT in taxol-resistant lung adenocarcinoma cells and impairs tumor growth by inhibiting the p70S6K/GSK3/β-catenin pathway, indicating that triptolide has potential to be used as a new therapeutic agent for taxol-resistant lung adenocarcinoma.

Background Available data on influenza burden across Southeast Asia are largely limited to pediatric populations, with inconsistent findings. Methods We conducted a multicenter, hospital-based active surveillance study of adults in Malaysia with community-acquired pneumonia (CAP), acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and acute exacerbation of asthma (AEBA), who had influenza-like illness ≤10 days before hospitalization. We estimated the rate of laboratory-confirmed influenza and associated complications over 13 months (July 2018–August 2019) and described the distribution of causative influenza strains. We evaluated predictors of laboratory-confirmed influenza and severe clinical outcomes using multivariate analysis. Results Of 1106 included patients, 114 (10.3%) were influenza-positive; most were influenza A (85.1%), with A/H1N1pdm09 being the predominant circulating strain during the study following a shift from A/H3N2 from January–February 2019 onwards. In multivariate analyses, an absence of comorbidities (none versus any comorbidity [OR (95%CI), 0.565 (0.329–0.970)], p = 0.038) and of dyspnea (0.544 (0.341–0.868)], p = 0.011) were associated with increased risk of influenza positivity. Overall, 184/1106 (16.6%) patients were admitted to intensive care or high-dependency units (ICU/HDU) (13.2% were influenza positive) and 26/1106 (2.4%) died (2.6% were influenza positive). Males were more likely to have a severe outcome (ICU/HDU admission or death). Conclusions Influenza was a significant contributor to hospitalizations associated with CAP, AECOPD and AEBA. However, it was not associated with ICU/HDU admission in this population. Study registration, NMRR ID: NMRR-17-889-35,174.

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