Intravesicular Solute Delivery and Surface Area Regulation in Giant Unilamellar Vesicles Driven by Cycles of Osmotic Stresses.

Phospholipid bilayers are dynamic cellular components that undergo constant changes in their topology, facilitating a broad diversity of physiological functions including endo- and exocytosis, cell division, and intracellular trafficking. These shape transformations consume energy, supplied invariably by the activity of proteins. Here, we show that cycles of oppositely directed osmotic stresses─unassisted by any protein activity─can induce well-defined remodeling of giant unilamellar vesicles, minimally recapitulating the phenomenologies of surface area homeostasis and macropinocytosis. We find that a stress cycle consisting of deflationary hypertonic stress followed by an inflationary hypotonic one prompts an elaborate sequence of membrane shape changes ultimately transporting molecular cargo from the outside into the intravesicular milieu. The initial osmotic deflation produces microscopic spherical invaginations. During the subsequent inflation, the first subpopulation contributes area to the swelling membrane, thereby providing a means for surface area regulation and tensional homeostasis. The second subpopulation vesiculates into the lumens of the mother vesicles, producing pinocytic vesicles. Remarkably, the gradients of solute concentrations between the GUV and the daughter pinocytic vesicles create cascades of water current, inducing pulsatory transient poration that enable solute exchange between the buds and the GUV interior. This results in an efficient water-flux-mediated delivery of molecular cargo across the membrane boundary. Our findings suggest a primitive physical mechanism for communication and transport across protocellular compartments driven only by osmotic stresses. They also suggest plausible physical routes for intravesicular, and possibly intracellular, delivery of ions, solutes, and molecular cargo stimulated simply by cycles of osmotic currents of water.

Hospitalized acute exacerbation in chronic obstructive pulmonary disease - impact on long-term renal outcomes.

INTRODUCTION: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a common and preventable event in patients with chronic obstructive pulmonary disease (COPD). Data regarding the impact of AECOPD on short- and long-term renal outcomes are lacking. METHODS: We included all COPD patients who were followed at Queen Mary Hospital (QMH) in year 2015 and reviewed their clinical/renal outcomes in subsequent five years. Relationships between AECOPD and adverse renal outcomes were evaluated. RESULTS: 371 COPD patients were included. 169 patients had hospitalized AECOPD in past one year (HAE group) while 202 patients did not (non-HAE group). 285 patients (76.8%) had renal progression/death and 102 (27.5%) patients developed acute kidney injury (AKI). HAE group showed a more rapid eGFR decline than non-HAE group (-4.64 mL/min/1.73m2/year vs. -2.40 mL/min/1.73m2/year, p = 0.025). HAE group had significantly higher risk for renal progression/death at 5 years [adjusted OR (aOR) 2.380 (95% CI = 1.144-4.954), p = 0.020]. The frequency of hospitalized AECOPD in past 3 years, any AECOPD in past 3 years, hospitalized AECOPD in past 3 years were also predictive of renal progression/death at 5 years [aOR were 1.176 (95% CI = 1.038- 1.331), 2.998 (95% CI = 1.438-6.250) and 2.887 (95% CI = 1.409-5.917) respectively; p = 0.011, 0.003 and 0.004]. HAE group also showed significantly higher risk of AKI [adjusted HR (aHR) 2.430; 95% CI = 1.306-4.519, p = 0.005]. CONCLUSIONS: AECOPD, in particular HAE, was associated with increased risk of renal progression/death and AKI. Prevention of AECOPD, especially HAE, may potentially improve short- and long-term renal outcomes in COPD patients.

Increased exacerbations of bronchiectasis following recovery from mild COVID-19 in patients with non-cystic fibrosis bronchiectasis.

BACKGROUND AND OBJECTIVE: Respiratory viral infection is a common trigger of bronchiectasis exacerbation. Knowledge of the intermediate to long-term effect of COVID-19 on bronchiectasis is poor. METHODS: A retrospective cohort study of patient records was conducted to assess the frequency of bronchiectasis exacerbation following recovery from mild-to-moderate COVID-19. The exacerbation frequency at baseline, using 2019 and 2019-2021 data, was compared with that during the 1 year following recovery. RESULTS: A total of 234 adult patient records who had a confirmed diagnosis of bronchiectasis were identified, of whom 52 (22.2%) were classified as the COVID-19 group. Patients with COVID-19 had significantly more frequent annual exacerbations of bronchiectasis (total exacerbations and hospitalizations). Compared with 2019-2021 data, the total exacerbation frequency decreased by 0.1 ± 0.51 per year among non-COVID-19 patients but increased by 0.68 ± 1.09 per year among the COVID-19 group (p < 0.001). Compared with 2019 only data, exacerbation frequency decreased by 0.14 ± 0.79 per year among non-COVID-19 patients but increased by 0.76 ± 1.17 per year in the COVID-19 group, p < 0.001. The annual frequency of hospitalization for bronchiectasis increased by 0.01 ± 0.32 per year among non-COVID-19 patients and increased by 0.39 ± 1.06 per year in the COVID-19 group (p < 0.001) compared with 2019 to 2021 data. When compared with only 2019 data, it remained unchanged at 0 ± 0.43 per year among non-COVID-19 patients but increased to 0.38 ± 1.12 per year among COVID-19 patients (p < 0.001). CONCLUSION: Mild-to-moderate COVID-19 was associated with an increase in frequency of bronchiectasis exacerbation and frequency of hospitalizations following recovery.

High-sensitivity C-reactive protein level in stable-state bronchiectasis predicts exacerbation risk.

BACKGROUND: Elevation of systemic inflammatory markers were found to correlate with increased disease extent, reduced lung function and higher risk of future severe exacerbations in patients with bronchiectasis. Although a significant correlation of circulating hs-CRP levels with HRCT scores and resting oxygen saturation in patients with stable-state non-cystic fibrosis (CF) bronchiectasis was suggested, there is little data on the relationship between hs-CRP and the prognosis of bronchiectasis and a lack of data on the role of hs-CRP in predicting bronchiectasis exacerbation. METHODS: A prospective study was conducted on Chinese patients with non- CF bronchiectasis from 1st October to 31st December 2021. Baseline serum hs-CRP were obtained at stable-state. The follow-up period lasted for one year. Co-primary endpoints were the development of any bronchiectasis exacerbation and hospitalized bronchiectasis exacerbation. RESULTS: Totally 123 patients were included. Higher hs-CRP was associated with increased risk to develop any bronchiectasis exacerbation, adjusted odds ratio (aOR) of 2.254 (95% CI = 1.040-4.885, p = 0.039), and borderline significantly increased hospitalized bronchiectasis exacerbation with aOR of 1.985 (95% CI = 0.922-4.277, p = 0.080). CONCLUSION: Baseline serum hs-CRP level at stable-state can predict risk of bronchiectasis exacerbation, which is reflecting chronic low-grade inflammation in bronchiectasis.

Worsening of asthma control after recovery from mild to moderate COVID-19 in patients from Hong Kong.

BACKGROUND: While there are postulations that asthma is potentially associated with severe coronavirus disease 2019 (COVID-19), there has been conflicting results from studies on the impact mild-to-moderate COVID-19 on asthma control after recovery. METHODS: A case control study on the association between mild-to-moderate COVID-19 and asthma control post infection was conducted. The primary outcome was a reduction in Asthma Control Test (ACT) score by ≥ 3 points post-COVID infection. The secondary outcomes included the change in ACT score, the proportion of patient with ACT score who dropped to ≤ 15 on enrolment visit and the need for escalation of asthma maintenance therapy. RESULTS: Out of the total of 221 adult patients with asthma recruited, 111 had mild-to-moderate COVID-19 within 30 to 270 days prior to study enrolment. The adjusted odds ratio (aOR) for a reduction in ACT score by ≥ 3 points after COVID-19 was 3.105 (95% CI = 1.385-6.959, p = 0.006). The odds of escalation of asthma maintenance therapy by at least 1 Global Initiative for Asthma (GINA) step was 4.733 (95% CI = 1.151-19.467, p = 0.031) and asthma patient are more likely to become uncontrolled after COVID-19 [aOR = 5.509 (95% CI = 1.061-28.600, p = 0.042)]. CONCLUSION: Mild-to-moderate COVID-19 among asthma patients, upon recovery, was associated with worsening of asthma symptom, lower ACT score, a higher need for escalation of asthma maintenance therapy and more uncontrolled asthma.

An Evaluation of Gene-Diet Interaction Statistical Methods and Discovery of rs7175421-Whole Grain Interaction in Lung Cancer.

Dietary factors show different effects on genetically diverse populations. Scientific research uses gene-environment interaction models to study the effects of dietary factors on genetically diverse populations for lung cancer risk. However, previous study designs have not investigated the degree of type I error inflation and, in some instances, have not corrected for multiple testing. Using a motivating investigation of diet-gene interaction and lung cancer risk, we propose a training and testing strategy and perform real-world simulations to select the appropriate statistical methods to reduce false-positive discoveries. The simulation results show that the unconstrained maximum likelihood (UML) method controls the type I error better than the constrained maximum likelihood (CML). The empirical Bayesian (EB) method can compete with the UML method in achieving statistical power and controlling type I error. We observed a significant interaction between SNP rs7175421 with dietary whole grain in lung cancer prevention, with an effect size (standard error) of -0.312 (0.112) for EB estimate. SNP rs7175421 may interact with dietary whole grains in modulating lung cancer risk. Evaluating statistical methods for gene-diet interaction analysis can help balance the statistical power and type I error.

Prediction model on disease recurrence for low risk resected stage I lung adenocarcinoma.

BACKGROUND AND OBJECTIVE: Although stage I non-small cell lung carcinoma (NSCLC) typically carries a good prognosis following complete resection, early disease recurrence can occur. An accurate survival prediction model would help refine a follow-up strategy and personalize future adjuvant therapy. We developed a post-operative prediction model based on readily available clinical information for patients with stage I adenocarcinoma. METHODS: We retrospectively studied the disease-free survival (DFS) of 408 patients with pathologically confirmed low-risk stage I adenocarcinoma of lung who underwent curative resection from 2013 to 2017. A tree-based method was employed to partition the cohort into subgroups with distinct DFS outcome and stepwise risk ratio. These covariates were included in multivariate analysis to build a scoring system to predict disease recurrence. The model was subsequently validated using a 2011-2012 cohort. RESULTS: Non-smoker status, stage IA disease, epidermal-growth factor receptor mutants and female gender were associated with better DFS. Multivariate analysis identified smoking status, disease stage and gender as factors necessary for the scoring system and yielded 3 distinct risk groups for DFS [99.4 (95% CI 78.3-125.3), 62.9 (95% CI 48.2-82.0), 33.7 (95% CI 24.6-46.1) months, p < 0.005]. External validation yielded an area under the curve by receiver operating characteristic analysis of 0.863 (95% CI 0.755-0.972). CONCLUSION: The model could categorize post-operative patients using readily available clinical information, and may help personalize a follow-up strategy and future adjuvant therapy.

Does the clopidogrel CYP2C19 genotype assay predict postprocedure stenosis in cerebral aneurysms treated with a flow diverter?

OBJECTIVE: Flow diverters have emerged as a popular modality for treating cerebral aneurysms but require dual antiplatelet therapy (DAPT) after placement. Clopidogrel is a common choice but is a prodrug that some patients may not convert into an active metabolite. The CYP2C19 genotype assay is used to predict activation speed; however, limited data exist showcasing whether this genotype accurately predicts postprocedure complications after flow diversion treatment of cerebral aneurysms. Therefore, the authors sought to characterize whether CYP2C19 genotype correlated with the development of postprocedure intimal hyperplasia (stenosis) after flow diverter placement. METHODS: Medical records were reviewed for patients who underwent flow diverter treatment of cerebral aneurysm at a single academic institution between January 1, 2012, and May 31, 2020. Patient demographics and comorbidities were reviewed alongside CYP2C19 genotype assay, DAPT regimen, and postprocedure angiogram data. Stenosis was defined based on review of angiogram data by two independent physicians. RESULTS: In this review of 120 unique cerebral aneurysms, 102 received DAPT with clopidogrel and 18 received DAPT with an alternative agent. Stenosis was present on 3-month follow-up angiogram for 35/102 (34.3%) aneurysms receiving DAPT with clopidogrel and in 11/18 (61.1%) aneurysms receiving an alternative DAPT regimen (p = 0.031). The CYP2C19 genotype did not correlate with postprocedure stenosis (p = 0.35). CONCLUSIONS: Clopidogrel was a significantly more effective DAPT agent for preventing stenosis when compared to nonclopidogrel DAPT regimens. The clopidogrel CYP2C19 genotype did not predict postprocedure stenosis in this cohort of 120 cerebral aneurysms treated with a flow diverter.

Surfactant-Mediated Solubilization of Myelin Figures: A Multistep Morphological Cascade.

Lamellar mesophases of insoluble lipids are readily solubilized by the micellar mesophases of soluble surfactants. This simple process underscores a broad array of biochemical methodologies, including purification, reconstitution, and crystallization of membrane proteins, as well as the isolation of detergent-resistant membrane fractions. Although much is now known about the thermodynamic driving forces of membrane solubilization, the kinetic pathways by which the surfactant alters vesicular mesophases are only beginning to be appreciated. Little is known about how these interactions affect the solubilization of more complex, multilamellar mesophases. Here, we investigate how a common zwitterionic detergent affects the solubilization of a smectic, multilamellar, cylindrical mesophase of lipids, called the myelin figure. Our results reveal that myelin solubilization occurs in a multistep manner, producing a well-defined sequence of morphologically distinct intermediates en route to complete solubilization. The kinetic processes producing these intermediates include (1) coiling, which encompasses the formation, propagation, and tightening of extended helices; (2) thinning, which reflects the unbinding of lamellae in the smectic stacks; and (3) detachment or retraction, which either dissociates the myelinic protrusion from the source lipid mass or returns the myelinic protrusion to the source lipid mass─all in transit toward complete solubilization. These occasionally overlapping steps are most pronounced in single-lipid component myelins, while compositionally graded multicomponent myelins inhibit the coiling step and detach more frequently. Taken together, the appearance of these intermediates during the solubilization of myelins suggests a complex free-energy landscape characterizing myelin solubilization populated by metastable, morphological intermediates correlated with locally minimized changes in energy dependent upon the mesophase's composition. This then predicts the accessibility of structurally distinct, kinetic intermediates─such as loose and tight coiled helices, peeled myelins, retracted tubes, and detached protrusions─before reaching the stable ground state corresponding to a dissolved suspension of mixed surfactant-lipid micelles.

Nonequilibrium Self-Organization of Lipids into Hierarchically Ordered and Compositionally Graded Cylindrical Smectics.

When a dry mass of certain amphiphiles encounters water, a spectacular interfacial instability ensues: It gives rise to the formation of ensembles of fingerlike tubular protrusions called myelin figures─tens of micrometers wide and tens to hundreds of micrometers long─representing a novel class of nonequilibrium higher-order self-organization. Here, we report that when phase-separating mixtures of unsaturated lipid, cholesterol, and sphingomyelin are hydrated, the resulting myelins break symmetry and couple their compositional degrees of freedom with the extended myelinic morphology: They produce complementary, interlamellar radial gradients of concentrations of cholesterol (and sphingomyelin) and unsaturated lipid, which stands in stark contrast to interlamellar, lateral phase separation in equilibrated morphologies. Furthermore, the corresponding gradients of molecule-specific chemistries (i.e., cholesterol extraction by methyl-ß-cyclodextrin and GM1 binding by cholera toxin) produce unusual morphologies comprising compositionally graded vesicles and buckled tubes. We propose that kinetic differences in the information processing of hydration characteristics of individual molecules while expending energy dictate this novel behavior of lipid mixtures undergoing hydration.

Association of genetic polymorphisms of CYP3A4 and CYP2D6 with gefitinib-induced toxicities.

Dermatological, gastrointestinal and hepatic toxicities are the most common adverse events associated with gefitinib use. Gefitinib is metabolized by cytochrome P450. Inconsistent associations of single nucleotide genetic polymorphisms of CYP450 and gefitinib-induced adverse effects were reported. We aim to investigate the association between CYP450 genetic polymorphism and the development of gefitinib-associated adverse events. A retrospective cohort study of Chinese patients with metastatic nonsmall cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations who received first-line gefitinib treatment was conducted. Single nucleotide polymorphisms (SNPs) of CYP2D6, CYP3A4 and CYP3A5 were assayed using a multiplex SNP microarray. Risks of development of gefitinib-induced toxicities associated with different SNPs were determined. Among the 152 patients treated with gefitinib, 52 (34.2%) had gefitinib-induced hepatotoxicity, 113 (74.3%) had cutaneous reactions and 53 (34.9%) had gastrointestinal adverse effects. CYP2D6*41 CT, CYP2D6*10 AA and CYP3A4*1/*1G TT genotypes were significantly associated with hepatic, cutaneous and gastrointestinal adverse effects [odds ratio (OR) 3.773; (95% confidence interval {CI},1.046-13.610; P = 0.043), 3.368 (95% CI, 1.000-11.345; P = 0.050) and 20.000 (95% CI, 2.381-167.965; P = 0.006), respectively]. CYP2D6*41 CT, CYP2D6*10 AA and CYP3A4*1/*1G TT genotypes may be associated with increased risks of gefitinib-induced toxicities in the liver, skin and gastrointestinal tract.

A multicenter retrospective cohort study on predicting the risk for amiodarone pulmonary toxicity.

BACKGROUND: Amiodarone is one of the most commonly used anti-arrhythmic agents. Amiodarone pulmonary toxicity is a potentially fatal adverse effect associated with amiodarone use. Previous studies on the epidemiology and risk factors for amiodarone pulmonary toxicity showed diverse results. METHODS: A multicenter retrospective cohort study was conducted to identify clinic-epidemiologic markers associated with amiodarone pulmonary toxicity for development of a prediction rule. Patients taking amiodarone who were managed in 3 centres in Hong Kong from 2005 to 2015 were included in this study. Penalized logistic regression was used to model the outcome as it is rare. RESULTS: A total of 34 cases with amiodarone pulmonary toxicity were identified among 1786 patients taking amiodarone for at least 90 days from 2005 to 2015. The incidence of amiodarone pulmonary toxicity was estimated to be 1.9%. The risk factors for amiodarone pulmonary toxicity included advanced age (OR 1.047, 95% CI 1.010-1.085, p = 0.013), ventricular arrhythmia (OR 2.703, 95% CI 1.053-6.935, p = 0.039), underlying lung disease (OR 2.511, 95% CI 1.146-5.501, p = 0.021) and cumulative dose of amiodarone (OR 4.762, 95% CI 1.310-17.309 p = 0.018). CONCLUSIONS: The incidence of amiodarone pulmonary toxicity in Chinese patients in Hong Kong is estimated to be 1.9% in this study. Age, underlying lung disease, ventricular arrhythmia and cumulative dose of amiodarone are associated with the development of amiodarone pulmonary toxicity. A prediction rule was developed to inform the risk of developing amiodarone pulmonary toxicity.

Isolated, Nonsyndromic Mucocutaneous Plexiform Neurofibromas: A Systematic Review of the Clinicopathologic Features.

ABSTRACT: Plexiform neurofibromas are benign neural tumors observed in association with neurofibromatosis. Isolated lesions exist. We conducted a systematic review of the published literature indexed in the PubMed/Medline database using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Thirty-five studies describing isolated plexiform neurofibromas were included detailing 41 tumors. Isolated lesions occur in all age groups, in both sexes and in all races. Cutaneous and mucosal lesions were reported. Asymptomatic, slowly enlarging masses were the most common clinical presentation, but lesions could be painful. Trauma-associated lesions were uncommon, but reported. Histopathologic features were similar to syndromic counterparts, but well-circumscribed/encapsulated lesions, rare association with diffuse neurofibroma, lack of reported malignant degeneration, and rare named-nerve origin were observed. Excision was curative in many cases, but recurrence could occur. Plexiform neurofibromas occur without neurofibromatosis in a subset of patients with isolated tumors.

Peptide-Oleate Complexes Create Novel Membrane-Bound Compartments.

A challenging question in evolutionary theory is the origin of cell division and plausible molecular mechanisms involved. Here, we made the surprising observation that complexes formed by short alpha-helical peptides and oleic acid can create multiple membrane-enclosed spaces from a single lipid vesicle. The findings suggest that such complexes may contain the molecular information necessary to initiate and sustain this process. Based on these observations, we propose a new molecular model to understand protocell division.

Risk factors for Pseudomonas aeruginosa colonization in non-cystic fibrosis bronchiectasis and clinical implications.

BACKGROUND: Pseudomonas aeruginosa is one of the commonest bacteria colonizing the airway in patients with non-cystic fibrosis bronchiectasis. Pseudomonas aeruginosa colonization is associated with poor outcomes in patients with bronchiectasis, including rapid decline in lung function, exacerbation frequency and hospitalization. METHODS: A cross-sectional study in Queen Mary Hospital, Hong Kong that included 350 Chinese patients with non-cystic fibrosis bronchiectasis to investigate the risk factors for Pseudomonas aeruginosa colonization and clinical implications on disease outcomes. DISCUSSIONS: Pseudomonas aeruginosa colonization was more commonly found in patients with longer duration of bronchiectasis and those on proton pump inhibitors (PPIs) with adjusted ORs of 1.066 (95% CI = 1.036-1.096, p < 0.001) and 2.815 (95% CI = 1.307-6.064, p = 0.008) respectively. Patients with Pseudomonas aeruginosa colonization have more extensive lung involvement and higher risks of exacerbation requiring hospitalization with adjusted ORs of 2.445 (95% CI = 1.283-4.657, p = 0.007) and 2.745 (95% CI = 1.012-7.449, p = 0.047) respectively. Pseudomonas aeruginosa colonization is more common among patients with longer duration of bronchiectasis and those on PPI. Pseudomonas aeruginosa colonization is associated with more extensive lung involvement and higher risks of exacerbation requiring hospitalization.

Tuberculosis infection and lung adenocarcinoma: Mendelian randomization and pathway analysis of genome-wide association study data from never-smoking Asian women.

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.

Role of early definitive management for newly diagnosed malignant pleural effusion related to lung cancer.

BACKGROUND AND OBJECTIVE: The advent of effective anti-cancer therapy has brought about uncertainty on the benefit of early definitive measures for newly diagnosed MPE from lung cancer. This study aims to investigate the outcomes of MPE in this setting. METHODS: Lung cancer patients with MPE at first presentation to a tertiary care hospital were followed up till death or censored from 2011 to 2018. Early MPE control measures included chemical pleurodesis or IPC before or shortly after oncological treatment. Predictors of time to MPE re-intervention were identified with Cox proportional hazard analyses. RESULTS: Of the 509 records screened, 233 subjects were eligible. One hundred and twenty-seven subjects received oral targeted therapy as first-line treatment and 34 (26.8%) underwent early definitive MPE control measures. Early MPE control measures in addition to targeted therapy, as compared to targeted therapy alone, significantly reduced the subsequent need of MPE re-intervention (23.5% vs 53.8%, P = 0.002). Similar benefits from MPE control measures were found in groups receiving systemic anti-cancer therapy or best supportive care (0% vs 52%, P = 0.003; 18% vs 56.7%, P = 0.024, respectively). In the group with targetable mutations, both early MPE control measures (HR: 0.25, 95% CI: 0.12-0.53, P < 0.001) and the use of targeted therapy (HR: 0.22, 95% CI: 0.10-0.46, P < 0.001) were independently associated with longer time to MPE re-interventions. CONCLUSION: Early MPE control measures in lung cancer has additional benefits on reducing the need and prolonging the time to MPE re-intervention, independent of anti-cancer therapies.

Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations.

To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance (P < 5 × 10-8), namely, rs7216064 (17q24.3, BPTF), for overall lung adenocarcinoma risk, and rs3817963 (6p21.3, BTNL2) which is specific to cases with EGFR mutations. In further sub-analyses by EGFR status, rs9387478 (ROS1/DCBLD1) and rs2179920 (HLA-DPB1) showed stronger estimated associations in EGFR-positive compared to EGFR-negative cases. Comparison of the overall associations with published results in Western populations revealed that the majority of these findings were distinct, underscoring the importance of distinct contributing factors for smoking and non-smoking lung cancer. Our results extend the catalogue of regions associated with lung adenocarcinoma in non-smoking Asian women and highlight the importance of how the germline could inform risk for specific tumour mutation patterns, which could have important translational implications.

Efficacy of gefitinib at reduced dose in EGFR mutant non-small cell lung carcinoma.

As a first-generation epidermal growth factor receptor-tyrosine kinase inhibitor, gefitinib was approved by the US Food and Drug Administration for treatment of advanced non-small cell carcinoma with sensitizing EGFR mutations. Gefitinib is known to have adverse effects, which may necessitate dose reduction or even change to alternative preparation of epidermal growth factor receptor-tyrosine kinase inhibitor. There has been concern on dose reduction resulting in reduced dose gefitinib, especially on its efficacy. This was a retrospective single-center cohort study conducted in Queen Mary Hospital in Hong Kong that included 159 Chinese patients with advanced adenocarcinoma of lung that carried sensitizing EGFR mutations and had received gefitinib as first-line treatment. Patients who had reduced dose at 250 mg alternate day were compared with those who were able to maintain on standard dose of gefitinib at 250 mg daily. The primary end-point was progression-free survival. Among the 159 patients, 17 (10.7 %) of them were on reduced dose gefitinib, 14 among the 17 patients (82.4%) because of hepatotoxicity, and 3 (17.6%) because of cutaneous side effects. Patients on reduced dose and standard dose of gefitinib have comparable median progression-free survival. Hazard ratio was 1.121 (95% confidence interval = 0. 655-1.917, P-value = 0.678) for the reduced dose group and 3.385 for the standard dose group (95% confidence interval = 2.181-5.255) respectively (P-value < 0.001). Dose reduction in gefitinib to 250 mg alternate day in response to adverse effects was not associated with inferior outcome for patients on first-line gefitinib for advanced non-small cell carcinoma. Dose reduction is a feasible option for patients who have significant adverse effects with gefitinib.

Minimal Reconstitution of Membranous Web Induced by a Vesicle-Peptide Sol-Gel Transition.

Positive strand RNA viruses replicate in specialized niches called membranous web within the cytoplasm of host cells. These virus replication organelles sequester viral proteins, RNA, and a variety of host factors within a fluid, amorphous matrix of clusters of endoplasmic reticulum (ER) derived vesicles. They are thought to form by the actions of a nonstructural viral protein NS4B, which remodels the ER and produces dense lipid-protein condensates. Here, we used in vitro reconstitution to identify the minimal components and elucidate physical mechanisms driving the web formation. We found that the N-terminal amphipathic domain of NS4B (peptide 4BAH2) and phospholipid vesicles (∼100-200 nm in diameter) were sufficient to produce a gel-like, viscoelastic condensate. This condensate coexists with the surrounding aqueous phase and affords rapid exchange of molecules. Together, it recapitulates the essential properties of the virus-induced membranous web. Our data support a novel phase separation mechanism in which phospholipid vesicles provide a supramolecular template spatially organizing multiple self-associating peptides thereby generating programmable multivalency de novo and inducing macroscopic phase separation.