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Respiratory Tract Diseases - Top 30 Publications

Genetic profiling of putative breast cancer stem cells from malignant pleural effusions.

A common symptom during late stage breast cancer disease is pleural effusion, which is related to poor prognosis. Malignant cells can be detected in pleural effusions indicating metastatic spread from the primary tumor site. Pleural effusions have been shown to be a useful source for studying metastasis and for isolating cells with putative cancer stem cell (CSC) properties. For the present study, pleural effusion aspirates from 17 metastatic breast cancer patients were processed to propagate CSCs in vitro. Patient-derived aspirates were cultured under sphere forming conditions and isolated primary cultures were further sorted for cancer stem cell subpopulations ALDH1+ and CD44+CD24-/low. Additionally, sphere forming efficiency of CSC and non-CSC subpopulations was determined. In order to genetically characterize the different tumor subpopulations, DNA was isolated from pleural effusions before and after cell sorting, and compared with corresponding DNA copy number profiles from primary tumors or bone metastasis using low-coverage whole genome sequencing (SCNA-seq). In general, unsorted cells had a higher potential to form spheres when compared to CSC subpopulations. In most cases, cell sorting did not yield sufficient cells for copy number analysis. A total of five from nine analyzed unsorted pleura samples (55%) showed aberrant copy number profiles similar to the respective primary tumor. However, most sorted subpopulations showed a balanced profile indicating an insufficient amount of tumor cells and low sensitivity of the sequencing method. Finally, we were able to establish a long term cell culture from one pleural effusion sample, which was characterized in detail. In conclusion, we confirm that pleural effusions are a suitable source for enrichment of putative CSC. However, sequencing based molecular characterization is impeded due to insufficient sensitivity along with a high number of normal contaminating cells, which are masking genetic alterations of rare cancer (stem) cells.

Comorbidities of rheumatoid arthritis: Results from the Korean National Health and Nutrition Examination Survey.

This study aimed to evaluate the prevalence of comorbidities in patients with rheumatoid arthritis (RA) compared with the non-RA population. The 2010-2012 Korea National Health and Nutrition Examination Survey (KNHANES), which assesses the general health status of populations in South Korea using interviews and basic health assessment, was analyzed retrospectively. Weighted prevalence and odds ratio (OR) of comorbidities were analyzed in patients with RA compared with the non-RA population. The overall weighted (n = 37,453,158) prevalence of RA was 1.5%. Patients with RA were older and more female predominant than subjects without RA. The prevalence of living in an urban area, college graduation, alcohol consumption and smoking was lower in patients with RA than non-RA. Patients with RA had more comorbidities including hypertension, dyslipidemia, myocardial infarction (MI) or angina, stoke, osteoarthritis, lung cancer, colon cancer, pulmonary tuberculosis, asthma, diabetes, depression, thyroid disease and chronic kidney disease. After adjusting socioeconomic and lifestyle characteristics, RA was associated with an increased prevalence of MI or angina (OR 1.86, 95% CI 1.17-2.96, p = 0.009), pulmonary TB (OR 1.95, 95% CI 1.24-3.09, p = 0.004), asthma (OR 1.97, 95% CI 1.05-3.71, p = 0.036), thyroid disease (OR 1.71, 95% CI 1.05-2.77), depression (OR 2.38, 95% CI 1.47-3.85, p < 0.001) and hepatitis B (OR 2.34, 95% CI 1.15-4.80, p = 0.020) compared with the non-RA population. Prevalence of solid cancer was not significantly associated with RA after adjustment.

Correlation of EGFR or KRAS mutation status with 18F-FDG uptake on PET-CT scan in lung adenocarcinoma.

18F-fluoro-2-deoxy-glucose (18F-FDG) positron emission tomography (PET) is a functional imaging modality based on glucose metabolism. The correlation between EGFR or KRAS mutation status and the standardized uptake value (SUV) of 18F-FDG PET scanning has not been fully elucidated.

Changes in Rates of Ventilator-Associated Pneumonia-Reply.

Radiofrequency versus microwave ablation for treatment of the lung tumours: LUMIRA (lung microwave radiofrequency) randomized trial.

The LUMIRA trial evaluated the effectiveness of radiofrequency (RFA) and microwave ablation (MWA) in lung tumours ablation and defining more precisely their fields of application. It is a controlled prospective multi-centre random trial with 1:1 randomization. Fifty-two patients in stage IV disease (15 females and 37 males, mean age 69 y.o., range 40-87) were included. We randomized the patients in two different subgroups: MWA group and RFA group. For each group, we evaluated the technical and clinical success, the overall survival and complication rate. Inter-group difference was compared using Chi-square test or Fisher's exact test for categorical variables and one-way ANOVA test for continuous variables. For RFA group, there was a significant reduction in tumour size only between 6 and 12 months (p value = 0.0014). For MWA group, there was a significant reduction in tumour size between 6 and 12 months (p value = 0.0003) and between pre-therapy and 12 months (p value = 0.0215). There were not significant differences between the two groups in terms of survival time (p value = 0.883), while the pain level in MWA group was significantly less than in RFA group (1.79 < 3.25, p value = 0.0043). In conclusion, our trial confirms RFA and MWA are both excellent choices in terms of efficacy and safety in lung tumour treatments. However, when compared to RFA therapy, MWA produced a less intraprocedural pain and a significant reduction in tumour mass.

DNA methylation profiling in peripheral lung tissues of smokers and patients with COPD.

Epigenetics changes have been shown to be affected by cigarette smoking. Cigarette smoke (CS)-mediated DNA methylation can potentially affect several cellular and pathophysiological processes, acute exacerbations, and comorbidity in the lungs of patients with chronic obstructive pulmonary disease (COPD). We sought to determine whether genome-wide lung DNA methylation profiles of smokers and patients with COPD were significantly different from non-smokers. We isolated DNA from parenchymal lung tissues of patients including eight lifelong non-smokers, eight current smokers, and eight patients with COPD and analyzed the samples using Illumina's Infinium HumanMethylation450 BeadChip.

Women Epidemiology Lung Cancer (WELCA) study: reproductive, hormonal, occupational risk factors and biobank.

Lung cancer aetiology and clinical aspects have been mainly studied in men, although specific risk factors probably exist in women. Here we present the rationale, design and organization of the WELCA study (Women Epidemiology Lung CAncer) that has been launched to investigate lung cancer in women, focusing particularly on hormonal and occupational factors.

The treatment of primary mediastinal large B-cell lymphoma: a two decades monocentric experience with 98 patients.

The purpose of this study is to investigate the most suitable first-line approach and the best combination treatment for primary mediastinal large B-cell lymphoma (PMLBCL) as they have been matter of debate for at least two decades.

Radiosensitizing effect of diosmetin on radioresistant lung cancer cells via Akt signaling pathway.

Radiotherapy is a powerful tool in the treatment of cancer that has the advantage of preserving normal tissues. However, tumor radioresistance currently remains a major impediment to effective RT. Thus, exploring effective radiation sensitizers is urgently needed. In this study, we have shown that diosmetin, the aglycone of the lavonoid glycoside from olive leaves, citrus fruits and some medicinal herbs, has a promising effect on radiotherapy sensitization. In our results, DIO could induce G1 phase arrest and thus enhance the radiosensitivity of radioresistant A549/IR lung cancer cells. Furthermore, DIO also restrains the IR-induced DNA damage repair by inhibiting the activated Akt signaling pathway. The combination of Akt inhibition (DIO, LY294002 or MK-2206) and radiation potently blocked A549/IR cancer cell proliferation. In summary, these observations suggest that the natural compound DIO could act as a potential drug for the treatment of radioresistant lung cancer cells.

Voice disorder in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic disease characterized by progressive tissue damage. In recent decades, novel treatments have greatly extended the life span of SLE patients. This creates a high demand for identifying the overarching symptoms associated with SLE and developing therapies that improve their life quality under chronic care. We hypothesized that SLE patients would present dysphonic symptoms. Given that voice disorders can reduce life quality, identifying a potential SLE-related dysphonia could be relevant for the appraisal and management of this disease. We measured objective vocal parameters and perceived vocal quality with the GRBAS (Grade, Roughness, Breathiness, Asthenia, Strain) scale in SLE patients and compared them to matched healthy controls. SLE patients also filled a questionnaire reporting perceived vocal deficits. SLE patients had significantly lower vocal intensity and harmonics to noise ratio, as well as increased jitter and shimmer. All subjective parameters of the GRBAS scale were significantly abnormal in SLE patients. Additionally, the vast majority of SLE patients (29/36) reported at least one perceived vocal deficit, with the most prevalent deficits being vocal fatigue (19/36) and hoarseness (17/36). Self-reported voice deficits were highly correlated with altered GRBAS scores. Additionally, tissue damage scores in different organ systems correlated with dysphonic symptoms, suggesting that some features of SLE-related dysphonia are due to tissue damage. Our results show that a large fraction of SLE patients suffers from perceivable dysphonia and may benefit from voice therapy in order to improve quality of life.

Transcriptional networks are associated with resistance to Mycobacterium tuberculosis infection.

Understanding mechanisms of resistance to M. tuberculosis (M.tb) infection in humans could identify novel therapeutic strategies as it has for other infectious diseases, such as HIV.

The ET-1-mediated carbonylation and degradation of ANXA1 induce inflammatory phenotype and proliferation of pulmonary artery smooth muscle cells in HPS.

Hepatopulmonary syndrome (HPS) is a serious complication of advanced liver disease, which markedly increases mortality. Pulmonary vascular remodelling (PVR) induced by circulating mediators plays an important role in the pathogenesis of HPS, while the underlying mechanism remains undefined. In the present study, we reported that endothelin-1 (ET-1) is up-regulated and annexin A1(ANXA1) is down-regulated in HPS rat, and ET-1 decreases the ANXA1 expression in a dose-dependent manner in rat pulmonary arterial smooth muscle cells (PASMCs). Then, we showed that ANXA1 can decrease nuclear p-ERK1/2 accumulation and decrease the cyclin D1 expression, thus resulting in the subsequent inhibition of PASMCs proliferation. As previously reported, we confirmed that ET-1 decreases the ANXA1 protein levels by the carbonylation and degradation of ANXA1. In conclusion, our research links the signaling cascade of ET1-ANXA1-cell proliferation to a potential therapeutic strategy for blocking IPS-associated PVR.

Advances in the Prevention and Treatment of High Altitude Illness.

High altitude illness encompasses a spectrum of clinical entities to include: acute mountain sickness, high altitude cerebral edema, and high altitude pulmonary edema. These illnesses occur as a result of a hypobaric hypoxic environment. Although a mild case of acute mountain sickness may be self-limited, high altitude cerebral edema and high altitude pulmonary edema represent critical emergencies that require timely intervention. This article reviews recent advances in the prevention and treatment of high altitude illness, including new pharmacologic strategies for prophylaxis and revised treatment guidelines.

Serum low-density lipoprotein and low-density lipoprotein expression level at diagnosis are favorable prognostic factors in patients with small-cell lung cancer (SCLC).

Patients with small-cell lung cancer (SCLC) patients demonstrate varied survival outcomes. Previous studies have reported that lipoproteins are associated with prognosis in various cancers; however, the role of low-density lipoprotein (LDL) and low-density lipoprotein- cholesterol (LDLR) in patients with SCLC has not been studied.

Genetic variant of miR-4293 rs12220909 is associated with susceptibility to non-small cell lung cancer in a Chinese Han population.

Non-small cell lung cancer is one of the most common cancers and the leading cause of cancer death worldwide. Genetic variants in regulatory regions of some miRNAs might be involved in non-small cell lung cancer susceptibility and survival. rs12220909 (G/C) genetic polymorphism in miR-4293 has been shown to be associated with decreased risk of esophageal squamous cell carcinoma. However, the influence of rs12220909 genetic variation on non-small cell lung cancer susceptibility has not been reported. In order to evaluate the potential association between miR-4293 rs12220909 and non-small cell lung cancer risk in a Chinese population, we performed a case-control study among 998 non-small cell lung cancer cases and 1471 controls. The data shows that miR-4293 rs12220909 was significantly associated with decreased susceptibility to non-small cell lung cancer (GC vs.GG: OR = 0.681, 95%CI = 0.555-0.835, P = 2.19E-4; GG vs. GC+CC: OR = 0.687, 95%CI = 0.564-0.837, P = 1.95E-4), which indicates that rs12220909 in miR-4293 may play a significant role in the development of non-small cell lung cancer.

Diabetes mellitus in patients with chronic obstructive pulmonary disease-The impact on mortality.

Chronic obstructive pulmonary disease (COPD) is the leading cause of morbidity and mortality worldwide. There is evidence to support a connection between COPD and diabetes mellitus (DM), another common medical disorder. However, additional research is required to improve our knowledge of these relationships and their possible implications. In this study, we investigated the impact of DM on patient outcomes through the clinical course of COPD.

Real-world treatment patterns for patients receiving second-line and third-line treatment for advanced non-small cell lung cancer: A systematic review of recently published studies.

Most patients with advanced non-small cell lung cancer (NSCLC) have a poor prognosis and receive limited benefit from conventional treatments, especially in later lines of therapy. In recent years, several novel therapies have been approved for second- and third-line treatment of advanced NSCLC. In light of these approvals, it is valuable to understand the uptake of these new treatments in routine clinical practice and their impact on patient care. A systematic literature search was conducted in multiple scientific databases to identify observational cohort studies published between January 2010 and March 2017 that described second- or third-line treatment patterns and clinical outcomes in patients with advanced NSCLC. A qualitative data synthesis was performed because a meta-analysis was not possible due to the heterogeneity of the study populations. A total of 12 different study cohorts in 15 articles were identified. In these cohorts, single-agent chemotherapy was the most commonly administered treatment in both the second- and third-line settings. In the 5 studies that described survival from the time of second-line treatment initiation, median overall survival ranged from 4.6 months (95% CI, 3.8-5.7) to 12.8 months (95% CI, 10.7-14.5). There was limited information on the use of biomarker-directed therapy in these patient populations. This systematic literature review offers insights into the adoption of novel therapies into routine clinical practice for second- and third-line treatment of patients with advanced NSCLC. This information provides a valuable real-world context for the impact of recently approved treatments for advanced NSCLC.

Evolution of the neuraminidase gene of seasonal influenza A and B viruses in Thailand between 2010 and 2015.

The neuraminidase inhibitors (NAIs) oseltamivir and zanamivir are commonly used for the treatment and control of influenza A and B virus infection. However, the emergence of new influenza virus strains with reduced susceptibility to NAIs may appear with the use of these antivirals or even naturally. We therefore screened the neuraminidase (NA) sequences of seasonal influenza virus A(H1N1), A(H1N1)pdm09, A(H3N2), and influenza B virus strains identified in Thailand for the presence of substitutions previously reported to reduce susceptibility to NAIs. We initially examined oseltamivir resistance (characterized by the H275Y mutation in the NA gene) in 485 A(H1N1)pdm09 strains circulating in Thailand and found that 0.82% (4/485) had this substitution. To further evaluate the evolution of the NA gene, we also randomly selected 98 A(H1N1)pdm09, 158 A(H3N2), and 69 influenza B virus strains for NA gene amplification and sequencing, which revealed various amino acid mutations in the active site of the NA protein previously shown to be associated with reduced susceptibility to NAIs. Phylogenetic analysis of the influenza virus strains from this study and elsewhere around the world, together with the estimations of nucleotide substitution rates and selection pressure, and the predictions of B-cell epitopes and N-linked glycosylation sites all provided evidence for the ongoing evolution of NA. The overall rates of NA evolution for influenza A viruses were higher than for influenza B virus at the nucleotide level, although influenza B virus possessed more genealogical diversity than that of influenza A viruses. The continual surveillance of the antigenic changes associated with the NA protein will not only contribute to the influenza virus database but may also provide a better understanding of selection pressure exerted by antiviral use.

Accessory gene regulator (Agr) functionality in Staphylococcus aureus derived from lower respiratory tract infections.

Characterization of Staphylococcus aureus clinical isolates derived from lower respiratory tract infections (LRTIs), and correlation between the functionality of the accessory gene regulator (Agr) and genotypic and phenotypic characteristics, clinical variables and clinical outcome.

Plasma from patients with anti-glomerular basement membrane disease could recognize microbial peptides.

Infection has long been suspected as a trigger of autoimmune diseases, and molecular mimicry mechanism was hypothesized in this study. Microbe originated peptides were searched from the Uniprot database based on a previous defined critical amino acid motif within α3129-150, isoleucine137, tryptophan140, glycine142, phenylalanine 143 and phenylalanine 145. 23826 microbial peptides were identified using our searching strategy, among which seven were related with human infections. Circulating IgG and IgM antibodies against the seven microbial peptides were detected using ELISA in 76 patients with anti-GBM disease. Four peptides were recognized by both IgG and IgM antibodies, and one peptide was recognized by IgG antibodies only. Peptides from Bacteroides, Saccharomyces cerevisiae, and Bifidobacterium thermophilum possessed the highest recognition frequency with the prevalence of 73.7%, 61.8% and 67.1% for IgG, 56.6%, 44.7% and 67.1% for IgM in anti-GBM patients. Patients with antibodies against these microbial peptides showed more severe kidney injury, including higher serum creatinine and higher percentage of crescent formation. In conclusion, antibodies against microbial peptides were identified in the circulation of anti-GBM patients, implying its etiological role in eliciting autoimmune response against α3(IV)NC1 through molecular mimicry.

Peritonsillar Abscess.

Peritonsillar abscess is the most common deep infection of the head and neck, occurring primarily in young adults. Diagnosis is usually made on the basis of clinical presentation and examination. Symptoms and findings generally include fever, sore throat, dysphagia, trismus, and a "hot potato" voice. Drainage of the abscess, antibiotic therapy, and supportive therapy for maintaining hydration and pain control are the cornerstones of treatment. Most patients can be managed in the outpatient setting. Peritonsillar abscesses are polymicrobial infections, and antibiotics effective against group A streptococcus and oral anaerobes should be first-line therapy. Corticosteroids may be helpful in reducing symptoms and speeding recovery. Promptly recognizing the infection and initiating therapy are important to avoid potentially serious complications, such as airway obstruction, aspiration, or extension of infection into deep neck tissues. Patients with peritonsillar abscess are usually first encountered in the primary care outpatient setting or in the emergency department. Family physicians with appropriate training and experience can diagnose and treat most patients with peritonsillar abscess.

Chronic Obstructive Pulmonary Disease: Diagnosis and Management.

The diagnosis of chronic obstructive pulmonary disease (COPD) should be suspected in patients with risk factors (primarily a history of smoking) who report dyspnea at rest or with exertion, chronic cough with or without sputum production, or a history of wheezing. COPD may be suspected based on findings from the history and physical examination, but must be confirmed by spirometry to detect airflow obstruction. Findings that are most helpful to rule in COPD include a smoking history of more than 40 pack-years, a self-reported history of COPD, maximal laryngeal height, and age older than 45 years. The combination of three clinical variables-peak flow rate less than 350 L per minute, diminished breath sounds, and a smoking history of 30 pack-years or more-is another good clinical predictor, whereas the absence of all three of these signs essentially rules out airflow obstruction. Pharmacotherapy and smoking cessation are the mainstays of treatment, and pulmonary rehabilitation, long-term oxygen therapy, and surgery may be considered in select patients. Current guidelines recommend starting monotherapy with an inhaled bronchodilator, stepping up to combination therapy as needed, and/or adding inhaled corticosteroids as symptom severity and airflow obstruction progress.

Aquaporin 1 controls the functional phenotype of pulmonary smooth muscle cells in hypoxia-induced pulmonary hypertension.

Vascular remodelling in hypoxia-induced pulmonary hypertension (PH) is driven by excessive proliferation and migration of endothelial and smooth muscle cells. The expression of aquaporin 1 (AQP1), an integral membrane water channel protein involved in the control of these processes, is tightly regulated by oxygen levels. The role of AQP1 in the pathogenesis of PH, however, has not been directly addressed so far. This study was designed to characterize expression and function of AQP1 in pulmonary vascular cells from human arteries and in the mouse model of hypoxia-induced PH. Exposure of human pulmonary vascular cells to hypoxia significantly induced the expression of AQP1. Similarly, levels of AQP1 were found to be upregulated in lungs of mice with hypoxia-induced PH. The functional role of AQP1 was further tested in human pulmonary artery smooth muscle cells demonstrating that depletion of AQP1 reduced proliferation, the migratory potential, and, conversely, increased apoptosis of these cells. This effect was associated with higher expression of the tumour suppressor gene p53. Using the mouse model of hypoxia-induced PH, application of GapmeR inhibitors targeting AQP1 abated the hypoxia-induced upregulation of AQP1 and, of note, reversed PH by decreasing both right ventricular pressure and hypertrophy back to the levels of control mice. Our data suggest an important functional role of AQP1 in the pathobiology of hypoxia-induced PH. These results offer novel insights in our pathogenetic understanding of the disease and propose AQP1 as potential therapeutic in vivo target.

Curcumin Analogue CA15 Exhibits Anticancer Effects on HEp-2 Cells via Targeting NF-κB.

Laryngeal carcinoma remains one of the most common malignancies, and curcumin has been proven to be effective against head and neck cancers in vitro. However, it has not yet been applied in clinical settings due to its low stability. In the current study, we synthesized 34 monocarbonyl analogues of curcumin with stable structures. CA15, which exhibited a stronger inhibited effect on laryngeal cancer cells HEp-2 but a lower toxicity on hepatic cells HL-7702 in MTT assay, was selected for further analysis. The effects of CA15 on cell viability, proliferation, migration, apoptosis, and NF-κB activation were measured using MTT, Transwell migration, flow cytometry, Western blot, and immunofluorescence assays in HEp-2 cells. An NF-κB inhibitor, BMS-345541, as well as curcumin was also tested. Results showed that CA15 induced decreased toxicity towards HL-7702 cells compared to curcumin and BMS-345541. However, similar to BMS-345541 and curcumin, CA15 not only significantly inhibited proliferation and migration and induced caspase-3-dependent apoptosis but also attenuated TNF-α-induced NF-κB activation in HEp-2 cells. These results demonstrated that curcumin analogue CA15 exhibited anticancer effects on laryngeal cancer cells via targeting of NF-κB.

Diagnosis of biofilm infections in cystic fibrosis patients.

Chronic Pseudomonas aeruginosa biofilm lung infection in cystic fibrosis patients is the best described biofilm infection in medicine. The initial focus can be the paranasal sinuses and then follows repeated colonization and infection of the lungs by aspiration. The matrix of the biofilms is dominated by alginate and the pathogenesis of tissue damage is immune complex-mediated chronic inflammation dominated by polymorphonuclear leukocytes and their products (DNA, oxygen radicals and proteases). The P. aeruginosa biofilm infection can be diagnosed by microscopy of lung tissue, sputum and mucus from the paranasal sinuses, where aggregates of the bacteria are found surrounded by the abundant alginate matrix. Specific PNA-FISH probes can be used to identify P. aeruginosa and other pathogens in situ in the biofilms. Growth of mucoid colonies from the locations mentioned above is also diagnostic for biofilm infection. Rise of specific anti-P. aeruginosa antibodies is likewise diagnostic, IgG in serum in case of lung infection, sIgA in saliva or nasal secretions in case of paranasal sinus infection. Similar approaches have been developed to diagnose chronic biofilm infections in cystic fibrosis caused by other pathogens e.g., Stenotrophomonas, Burkholderia multivorans, Achromobacter xylosoxidans and Mycobacterium abscessus complex.

Biofilms and host response - helpful or harmful.

Biofilm infections are one of the modern medical world's greatest challenges. Probably, all non-obligate intracellular bacteria and fungi can establish biofilms. In addition, there are numerous biofilm-related infections, both foreign body-related and non-foreign body-related. Although biofilm infections can present in numerous ways, one common feature is involvement of the host response with significant impact on the course. A special characteristic is the synergy of the innate and the acquired immune responses for the induced pathology. Here, we review the impact of the host response for the course of biofilm infections, with special focus on cystic fibrosis, chronic wounds and infective endocarditis.

Microenvironmental characteristics and physiology of biofilms in chronic infections of CF patients are strongly affected by the host immune response.

In vitro studies of Pseudomonas aeruginosa and other pathogenic bacteria in biofilm aggregates have yielded detailed insight into their potential growth modes and metabolic flexibility under exposure to gradients of substrate and electron acceptor. However, the growth pattern of P. aeruginosa in chronic lung infections of cystic fibrosis (CF) patients is very different from what is observed in vitro, for example, in biofilms grown in flow chambers. Dense in vitro biofilms of P. aeruginosa exhibit rapid O2 depletion within <50-100 μm due to their own aerobic metabolism. In contrast, in vivo investigations show that P. aeruginosa persists in the chronically infected CF lung as relatively small cell aggregates that are surrounded by numerous PMNs, where the activity of PMNs is the major cause of O2 depletion rendering the P. aeruginosa aggregates anoxic. High levels of nitrate and nitrite enable P. aeruginosa to persist fueled by denitrification in the PMN-surrounded biofilm aggregates. This configuration creates a potentially long-term stable ecological niche for P. aeruginosa in the CF lung, which is largely governed by slow growth and anaerobic metabolism and enables persistence and resilience of this pathogen even under the recurring aggressive antimicrobial treatments of CF patients. As similar slow growth of other CF pathogens has recently been observed in endobronchial secretions, there is now a clear need for better in vitro models that simulate such in vivo growth patterns and anoxic microenvironments in order to help unravel the efficiency of existing or new antimicrobials targeting anaerobic metabolism in P. aeruginosa and other CF pathogens. We also advocate that host immune responses such as PMN-driven O2 depletion play a central role in the formation of anoxic microniches governing bacterial persistence in other chronic infections such as chronic wounds.

Positional therapy in sleep apnoea - one fits all? What determines success in positional therapy in sleep apnoea syndrome.

Positional therapy is a simple means of therapy in sleep apnoea syndrome, but due to controversial or lacking evidence, it is not widely accepted as appropriate treatment. In this study, we analysed data to positional therapy with regard to successful reduction of AHI and predictors of success.

Cisplatin-enriching cancer stem cells confer multidrug resistance in non-small cell lung cancer via enhancing TRIB1/HDAC activity.

Chemotherapeutic agents are generally used as a frontline therapy for non-small cell lung cancer (NSCLC). However, resistance to chemotherapy arises rapidly in NSCLC, and the reasons for chemotherapy resistance have not been fully determined. Here, we found cisplatin, but not paclitaxel and doxorubicin, induced the enrichment of cancer stem cell (CSC) and conferred multidrug resistance in NSCLC cell lines. In vivo study confirmed drug-resistant tumors displayed the enhanced expressions of CSC transcription factors. Mechanistically, cisplatin treatment resulted in C/EBP-β-dependent increasing of TRIB1. The crucial role of TRIB1 in cisplatin-induced enrichment of CSC and drug resistance was verified by knockdown TRIB1. Interestingly, cisplatin treatment also contributed to the increasement of HDAC, the interaction of TRIB1 with HDAC, and inactivation of p53. Similarly, the silencing of HDAC led to reduction of cisplatin-induced CSC, and combined knockdown of HDAC and TRIB1 exhibited enhanced effect. Additionally, the combination of HDAC inhibitor and cisplatin showed a reinforced antitumor action in NSCLC cell lines with TRIB1-dependent manner and remarkably shrink tumors in xenograft models. Moreover, cisplatin-treated NSCLC patients with high levels of TRIB1 exhibited a significantly poorer prognosis. Our findings illustrate a novel perspective in the evolution of chemotherapy resistance and provide a promising approach for the treatment of patients with NSCLC.

WDR79 promotes the proliferation of non-small cell lung cancer cells via USP7-mediated regulation of the Mdm2-p53 pathway.

WD repeat protein 79 (WDR79) is a member of the WD-repeat protein family and functions as a scaffold protein during telomerase assembly, Cajal body formation and DNA double strand break repair. We have previously shown that WDR79 is frequently overexpressed in cell lines and tissues derived from non-small cell lung cancer (NSCLC) and it accelerates cell proliferation in NSCLC. However, the detailed mechanism underlying the role of WDR79 in the proliferation of NSCLC cells remains unclear. Here, we report the discovery of a molecular interaction between WDR79 and USP7 and show its functional significance in linking the Mdm2-p53 pathway to the proliferation of NSCLC cells. We found that WDR79 colocalized and interacted with USP7 in the nucleus of NSCLC cells. This event, in turn, reduced the ubiquitination of Mdm2 and p53, thereby increasing the stability and extending the half-life of the two proteins. We further found that the functional effects of WDR79 depended upon USP7, because the knockdown of USP7 resulted in their attenuation. Finally, we demonstrated that WDR79 promoted the proliferation of NSCLC cells via USP7. Taken together, our findings reveal a novel molecular function of WDR79 and may lead to broadly applicable and innovative therapeutic avenues for NSCLC.