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Background: Chronic obstructive pulmonary disease (COPD) is characterized, at least in part, by autoimmunity through amplified T helper 1 and 17 (Th1 and Th17) immune responses. The loss of immune tolerance controlled by programmed death-ligand 1 (PD-L1) may contribute to this. Objectives: We studied the tolerogenic role of PD-L1+ dendritic cells (DCs) and their subtypes in relation to specific T cell immunity and the clinical phenotypes of COPD. Methods: We used flow cytometry to analyze PD-L1 expression by the DCs and their subtypes in the peripheral blood mononuclear cells (PBMCs) from normal participants and those with COPD. T cell proliferation and the signature cytokines of T cell subtypes stimulated with elastin as autoantigens were measured using flow cytometry and enzyme-linked immunosorbent assays (ELISA), respectively. Measurement and main results: A total of 83 participants were enrolled (normal, n = 29; COPD, n = 54). A reduced PD-L1+ conventional dendritic cell 1 (cDC1) ratio in the PBMCs of the patients with COPD was shown (13.7 ± 13.7%, p = 0.03). The decrease in the PD-L1+ cDC1 ratio was associated with a rapid decline in COPD (p = 0.02) and correlated with the CD4+ T cells (r = −0.33, p = 0.02). This is supported by the NCBI GEO database accession number GSE56766, the researchers of which found that the gene expressions of PD-L1 and CD4, but not CD8 were negatively correlated from PBMC in COPD patients (r = −0.43, p = 0.002). Functionally, the PD-L1 blockade enhanced CD4+ T cell proliferation stimulated by CD3/elastin (31.2 ± 22.3%, p = 0.04) and interleukin (IL)-17A production stimulated by both CD3 (156.3 ± 54.7, p = 0.03) and CD3/elastin (148 ± 64.9, p = 0.03) from the normal PBMCs. The PD-L1 blockade failed to increase IL-17A production in the cDC1-depleted PBMCs. By contrast, there was no significant change in interferon (IFN)-γ, IL-4, or IL-10 after the PD-L1 blockade. Again, these findings were supported by the NCBI GEO database accession number GSE56766, the researchers of which found that only the expression of RORC, a master transcription factor driving the Th17 cells, was significantly negatively correlated to PD-L1 (r = −0.33, p = 0.02). Conclusions: Circulating PD-L1+ cDC1 was reduced in the patients with COPD, and the tolerogenic role was suppressed with susceptibility to self-antigens and linked to rapid decline caused by Th17-skewed chronic inflammation. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) with a low arousal threshold (low-ArTH) phenotype can cause minor respiratory events that exacerbate sleep fragmentation. Although anthropometric features may affect the risk of low-ArTH OSA, the associations and underlying mechanisms require further investigation. This study investigated the relationships of body fat and water distribution with polysomnography parameters by using data from a sleep center database. The derived data were classified as those for low-ArTH in accordance with criteria that considered oximetry and the frequency and type fraction of respiratory events and analyzed using mean comparison and regression approaches. The low-ArTH group members (n = 1850) were significantly older and had a higher visceral fat level, body fat percentage, trunk-to-limb fat ratio, and extracellular-to-intracellular (E–I) water ratio compared with the non-OSA group members (n = 368). Significant associations of body fat percentage (odds ratio [OR]: 1.58, 95% confident interval [CI]: 1.08 to 2.3, p < 0.05), trunk-to-limb fat ratio (OR: 1.22, 95% CI: 1.04 to 1.43, p < 0.05), and E–I water ratio (OR: 1.32, 95% CI: 1.08 to 1.62, p < 0.01) with the risk of low-ArTH OSA were noted after adjustments for sex, age, and body mass index. These observations suggest that increased truncal adiposity and extracellular water are associated with a higher risk of low-ArTH OSA. [ABSTRACT FROM AUTHOR]

Background: Long-term exposure to PM2.5 (particulate matter with an aerodynamic diameter of ≤ 2.5 μm) is associated with pulmonary injury and emphysema in patients with chronic obstructive pulmonary disease (COPD). We investigated mechanisms through which the long noncoding RNA lnc-IL7R contributes to cellular damage by inducing oxidative stress in COPD patients exposed to PM2.5. Methods: Associations of serum lnc-IL7R levels with lung function, emphysema, and previous PM2.5 exposure in COPD patients were analyzed. Reactive oxygen species and lnc-IL7R levels were measured in PM2.5-treated cells. The levels of lnc-IL7R and cellular senescence–associated genes, namely p16INK4a and p21CIP1/WAF1, were determined through lung tissue section staining. The effects of p16INK4a or p21CIP1/WAF1 regulation were examined by performing lnc-IL7R overexpression and knockdown assays. The functions of lnc-IL7R-mediated cell proliferation, cell cycle, senescence, colony formation, and apoptosis were examined in cells treated with PM2.5. Chromatin immunoprecipitation assays were conducted to investigate the epigenetic regulation of p21CIP1/WAF1. Results: Lnc-IL7R levels decreased in COPD patients and were negatively correlated with emphysema or PM2.5 exposure. Lnc-IL7R levels were upregulated in normal lung epithelial cells but not in COPD cells exposed to PM2.5. Lower lnc-IL7R expression in PM2.5-treated cells induced p16INK4a and p21CIP1/WAF1 expression by increasing oxidative stress. Higher lnc-IL7R expression protected against cellular senescence and apoptosis, whereas lower lnc-IL7R expression augmented injury in PM2.5-treated cells. Lnc-IL7R and the enhancer of zeste homolog 2 (EZH2) synergistically suppressed p21CIP1/WAF1 expression through epigenetic modulation. Conclusion: Lnc-IL7R attenuates PM2.5-mediated p21CIP1/WAF1 expression through EZH2 recruitment, and its dysfunction may augment cellular injury in COPD. [ABSTRACT FROM AUTHOR]

Immunotherapy is one of the most promising forms of cancer treatment. In particular, immune checkpoint blockers (ICBs) represent some of the leading candidates which many drug developers have heavily invested in. During pre-clinical development and prior to human clinical trials, animal tests are a critical component for determining the safety and efficacy of newly developed ICBs for cancer treatment. In this study, we strive to demonstrate the feasibility of using hollow fiber assay microtube array membrane (MTAM-HFA) in the screening of anti-cancer ICBs. The MTAM-HFA process was carried out by encapsulating peripheral blood mononuclear cells (PBMCs) and the target cancer cells (cell lines or primary cells) and subcutaneously implanting them into Balb/C mice. At predetermined time points combination regimens of PD-1/PD-L1+ were administered accordingly and at a predetermined time point, the MTAMs were retrieved, and cell viability assays were carried out. The outcomes of the MTAM-HFA were compared against the clinical outcome of patients. Clinical comparison demonstrated excellent correlation between the screening outcome of MTAM-HFA of PD-1/PD-L1+ combination therapy and the clinical outcome of the lung cancer patients. Basic cell studies revealed that the utilization of MTAM-HFA in PD-1/PD-L1+ combination therapy revealed enhanced T-cell activity upon the administration of the PD-1/PD-L1 drug; thereby resulting in the reduction of tumor cell viability by up to 70%, and the cytotoxic effects by 82%. The outcome was echoed in the in vivo cell studies. This suggested that the MTAM-HFA system is suitable for use in PD-1/PD-L1+ screening and the accuracy, rapidity and cost effectiveness made it extremely suitable for application as a companion diagnostic system in both personalized medicine for cancer treatment and could potentially be applied to screen for candidate compounds in the development of next generation PD-1/PD-L1+ combination therapies. [ABSTRACT FROM AUTHOR]

Despite rapidly evolving pathobiological mechanistic demystification, coupled with advances in diagnostic and therapeutic modalities, chronic obstructive pulmonary disease (COPD) remains a major healthcare and clinical challenge, globally. Further compounded by the dearth of available curative anti-COPD therapy, it is posited that this challenge may not be dissociated from the current lack of actionable COPD pathognomonic molecular biomarkers. There is accruing evidence of the involvement of protracted 'smoldering' inflammation, repeated lung injury, and accelerated lung aging in enhanced predisposition to or progression of COPD. The relatively novel uncharacterized human long noncoding RNA lnc-IL7R (otherwise called LOC100506406) is increasingly designated a negative modulator of inflammation and regulator of cellular stress responses; however, its role in pulmonary physiology and COPD pathogenesis remains largely unclear and underexplored. Our previous work suggested that upregulated lnc-IL7R expression attenuates inflammation following the activation of the toll-like receptor (TLR)-dependent innate immune system, and that the upregulated lnc-IL7R is anti-correlated with concomitant high PM2.5, PM10, and SO2 levels, which is pathognomonic for exacerbated/aggravated COPD in Taiwan. In the present study, our quantitative analysis of lnc-IL7R expression in our COPD cohort (n = 125) showed that the lnc-IL7R level was significantly correlated with physiological pulmonary function and exhibited COPD-based stratification implications (area under the curve, AUC = 0.86, p < 0.001). We found that the lnc-IL7R level correctly identified patients with COPD (sensitivity = 0.83, specificity = 0.83), precisely discriminated those without emphysematous phenotype (sensitivity = 0.48, specificity = 0.89), and its differential expression reflected disease course based on its correlation with the COPD GOLD stage (r = −0.59, p < 0.001), %LAA-950insp (r = −0.30, p = 0.002), total LAA (r = −0.35, p < 0.001), FEV1(%) (r = 0.52, p < 0.001), FVC (%) (r = 0.45, p < 0.001), and post-bronchodilator FEV1/FVC (r = 0.41, p < 0.001). Consistent with other data, our bioinformatics-aided dose–response plot showed that the probability of COPD decreased as lnc-IL7R expression increased, thus, corroborating our posited anti-COPD therapeutic potential of lnc-IL7R. In conclusion, reduced lnc-IL7R expression not only is associated with inflammation in the airway epithelial cells but is indicative of impaired pulmonary function, pathognomonic of COPD, and predictive of an exacerbated/ aggravated COPD phenotype. These data provide new mechanistic insights into the ailing lung and COPD progression, as well as suggest a novel actionable molecular factor that may be exploited as an efficacious therapeutic strategy in patients with COPD. [ABSTRACT FROM AUTHOR]

Tumor antigen-specific T cell function is limited by immune tolerance in the tumor microenvironment. In the tumor microenvironment, tumor cells upregulate PD-L1 expression to promote T cell exhaustion by PD-1/PD-L1 interactions and undergo mutations to avoid being targeted by tumor antigen-specific T cells. Thus, tumor cells escape the immune surveillance by causing immune tolerance. We reason that a chimeric molecule made of a PD-L1-specific antibody linked to a cleavable antigenic peptide can target the antigenic peptide to the tumor microenvironment, resulting in the blockade of the PD-1/PD-L1 pathway and killing tumor cells through the coating of antigenic peptide. Here, we have generated a therapeutic chimeric protein containing the PD-L1 single-chain variable fragment (scFv) linked to a cleavable model cytotoxic T lymphocyte (CTL) epitope: E7 CTL peptide. Our study demonstrated that our chimeric protein (named PDL1-scFv-Fc-RE7) can target PD-L1-expressing tumor cells and enable E7 presentation by releasing cleavable E7 CTL peptide to coat tumor cells, resulting in tumor clearance by E7-specific CD8+ T cells. The presentation of the E7 peptide by cancer cells can then render tumor cells susceptible to the killing of preexisting E7-specific CD8+ T cells and contribute to tumor clearance. Our finding suggests a synergistic approach to not only enhance antigen-specific tumor clearance but also bypass immune tolerance. [ABSTRACT FROM AUTHOR]

Epidemiological studies identified the relationship between air pollution and pulmonary tuberculosis. Effects of lung-deposited dose of particulate matter (PM) on culture-positive pulmonary tuberculosis remain unclear. This study investigates the association between lung-deposited dose of PM and pulmonary tuberculosis pleurisy. A case-control study of subjects undergoing pleural effusion drainage of pulmonary tuberculosis (case) and chronic heart failure (control) was conducted. Metals and biomarkers were quantified in the pleural effusion. The air pollution exposure was measured and PM deposition in the head, tracheobronchial, alveolar region, and total lung region was estimated by Multiple-path Particle Dosimetry (MPPD) Model. We performed multiple logistic regression to examine the associations of these factors with the risk of tuberculosis. We observed that 1-μg/m3 increase in PM10 was associated with 1.226-fold increased crude odds ratio (OR) of tuberculosis (95% confidence interval (CI): 1.023–1.469, p<0.05), 1-μg/m3 increase in PM2.5-10 was associated with 1.482-fold increased crude OR of tuberculosis (95% CI: 1.048–2.097, p < 0.05), 1-ppb increase in NO2 was associated with 1.218-fold increased crude OR of tuberculosis (95% CI: 1.025–1.447, p < 0.05), and 1-ppb increase in O3 was associated with 0.735-fold decreased crude OR of tuberculosis (95% CI: 0.542 0.995). We observed 1-μg/m3 increase in PM deposition in head and nasal region was associated with 1.699-fold increased crude OR of tuberculosis (95% CI: 1.065–2.711, p < 0.05), 1-μg/m3 increase in PM deposition in tracheobronchial region was associated with 1.592-fold increased crude OR of tuberculosis (95% CI: 1.095–2.313, p < 0.05), 1-μg/m3 increase in PM deposition in alveolar region was associated with 3.981-fold increased crude OR of tuberculosis (95% CI: 1.280–12.386, p < 0.05), and 1-μg/m3 increase in PM deposition in total lung was associated with 1.511-fold increased crude OR of tuberculosis (95% CI: 1.050–2.173, p < 0.05). The results indicate that particle deposition in alveolar region could cause higher risk of pulmonary tuberculosis pleurisy than deposition in other lung regions. [ABSTRACT FROM AUTHOR]

Patients with chronic obstructive pulmonary disease (COPD) are susceptible to bacterial infections, which worsen lung inflammation and contribute to lung function decline and acute exacerbation. Long noncoding (lnc) RNAs are emerging regulators of inflammation with unknown clinical relevance. Herein, we report that levels of the Toll‐like receptor (TLR)‐related lnc interleukin (IL) 7 receptor (IL7R) were significantly reduced in peripheral blood mononuclear cells from patients with COPD compared with those from normal controls, and the levels were correlated with pulmonary function. Moreover lnc‐IL7R levels were reduced in lavaged alveolar macrophages and primary human small airway epithelial cells (HSAEpCs) from patients with COPD. Lnc‐IL7R knockdown in primary human macrophages, HSAEpCs, and human pulmonary microvascular endothelial cells (HPMECs) significantly augmented the induction of proinflammatory mediators after TLR2/4 activation. By contrast, lnc‐IL7R overexpression attenuated inflammation after TLR2/4 activation. Similar results with lnc‐IL7R‐mediated inflammation were observed in COPD HSAEpCs. Mechanistically, lnc‐IL7R mediated a repressive chromatin state of the proinflammatory gene promoter as a result of decreased acetylation (H3K9ac) and increased methylation (H3K9me3 and H3K27me3). Plasma lnc‐IL7R levels were reduced in patients with COPD who experienced more acute exacerbation in the previous year. Notably, patients with lower lnc‐IL7R levels in the subsequent year had increased exacerbation risk. Low lnc‐IL7R expression in COPD may augment TLR2/4‐mediated inflammation and be associated with acute exacerbation. [ABSTRACT FROM AUTHOR]

Purpose: Bronchoscopy is useful in lung cancer detection, but cannot be used to differentiate cancer types. A computer‐aided diagnosis (CAD) system was proposed to distinguish malignant cancer types to achieve objective diagnoses. Methods: Bronchoscopic images of 12 adenocarcinoma and 10 squamous cell carcinoma patients were collected. The images were transformed from a red–blue–green (RGB) to a hue–saturation–value (HSV) color space to obtain more meaningful color textures. By combining significant textural features (P < 0.05) in a machine learning classifier, a prediction model of malignant types was established. Results: The performance of the CAD system achieved an accuracy of 86% (19/22), a sensitivity of 90% (9/10), a specificity of 83% (10/12), a positive predictive value of 82% (9/11), and a negative predictive value of 91% (10/11) in distinguishing lung cancer types. The area under the receiver operating characteristic curve was 0.82. Conclusions: On the basis of extracted HSV textures of bronchoscopic images, the CAD system can provide recommendations for clinical diagnoses of lung cancer types. [ABSTRACT FROM AUTHOR]

Background: VEGF plays a key role in tumor angiogenesis and immunosuppression. VEGF‐blocking has proven beneficial for EGFR mutant and wild‐type nonsquamous non‐small cell lung cancer (nonsq‐NSCLC); however, the number of cycles and treatment line yielding the optimal benefit are unknown. Methods: We retrospectively analyzed the data of 115 patients with advanced/metastatic nonsq‐NSCLC administered at least one cycle of bevacizumab. The number of bevacizumab cycles was treated as a time‐dependent covariate. Predictors of overall survival (OS) were investigated. Results: Bevacizumab was used as first‐line treatment in 47 (40.9%) patients, with a median of five cycles (range: 1–31). Eastern Cooperative Oncology Group performance status ≥ 2 (hazard ratio [HR] 4.78, 95% confidence interval [CI] 2.68–8.51; P < 0.001), wild‐type EGFR (HR 2.61, 95% CI 1.45–4.70; P = 0.001), and bleeding during bevacizumab treatment (HR 3.63, 95% CI 1.77–7.45; P < 0.001) were predictive of poor OS; the number of bevacizumab cycles and first‐line administration were not. In the wild‐type EGFR subgroup, the number of bevacizumab cycles (≥ 5 vs. 1–4) was associated with a significant OS benefit (HR 0.28, 95% CI 0.08–0.98; P = 0.044); first‐line administration also showed an OS benefit (HR 0.48, 95% CI 0.20–1.17; P = 0.105). A significant association between the number of cycles and EGFR status was identified (P = 0.046). Conclusion: OS benefit is negatively affected by bleeding events in bevacizumab‐treated patients. Prolonged and early introduction of bevacizumab may provide an OS benefit for patients with wild‐type EGFR nonsq‐NSCLC. [ABSTRACT FROM AUTHOR]

Potential adverse effects of human exposure to carbon black (CB) have been reported, but limited knowledge regarding CB-regulated metabolism is currently available. To evaluate how physical parameters of CB influence metabolism, we investigated CB and diesel exhaust particles (DEPs) and attempted to relate various physical parameters, including the hydrodynamic diameter, zeta potential, and particle number concentrations, to lung energy metabolism in female BALB/c mice. A body weight increase was arrested by 3 months of exposure to CB of smaller-size fractions, which was negatively correlated with pyruvate in plasma. There were no significant differences in cytotoxic lactate dehydrogenase (LDH) or total protein in bronchoalveolar lavage fluid (BALF) after 3 months of CB exposure. However, we observed alterations in acetyl CoA and the NADP/NADPH ratio in lung tissues with CB exposure. Additionally, the NADP/NADPH ratio was associated with the zeta potential of CB. Mild peribronchiovascular and interstitial inflammation and multinucleated giant cells (macrophages) with a transparent and rhomboid appearance and containing foreign bodies were observed in lung sections. We suggest that physical characteristics of CB, such as the zeta potential, may disrupt metabolism after pulmonary exposure. These results, therefore, provide the first evidence of a link between pulmonary exposure to CB and metabolism. [ABSTRACT FROM AUTHOR]

NEK2 (NIMA-related expressed kinase 2) is a serine/threonine centrosomal kinase that acts as a critical regulator of centrosome structure and function. Aberrant NEK2 activities lead to failure in regulating centrosome duplication. NEK2 overexpression promotes tumorigenesis and is associated with poor prognosis in several cancers. Increased NEK2 expression during the late pathological stage has been detected in the Oncomine liver dataset and hepatocellular carcinoma (HCC) specimens. Elevated NEK2 protein is associated with poor overall survival in patients with HCC. However, the precise roles and mechanisms of NEK2 in liver cancer progression remain largely unknown. An earlier functional study revealed that NEK2 mediates drug resistance (cisplatin or lipo-doxorubicin) via expression of an ABCC10 transporter. Active angiogenesis and metastasis underlie the rapid recurrence and poor survival of HCC. Results from the current study showed that NEK2 mediates tumor growth, metastasis and angiogenesis in vivo. NEK2-mediated drug resistance was blocked by a specific PI3K or AKT inhibitor. Moreover, NEK2 mediated liver cancer cell migration via pAKT/NF-κB signaling and matrix metalloproteinase (MMP) activation. Angiogenesis was induced via the same signaling pathway and IL-8 stimulation. Our findings collectively indicate that NEK2 modulates hepatoma cell functions, including growth, drug resistance, metastasis and angiogenesis via downstream genes activation. [ABSTRACT FROM AUTHOR]

Emerging risk factors for tuberculosis (TB) infection, such as air pollution, play a significant role at both the individual and population levels. However, the association between air pollution and TB remains unclear. The objective of this study was to examine the association between outdoor air pollution and sputum culture conversion in TB patients. In the present study, 389 subjects were recruited from a hospital in Taiwan from 2010 to 2012: 144 controls with non-TB-related pulmonary diseases with negative sputum cultures and 245 culture-positive TB subjects. We observed that a 1 μg/m(3) increase in particulate matter of ≤10 μm in aerodynamic diameter (PM10) resulted in 4% higher odds of TB (odds ratio =1.04, 95% confidence interval =1.01-1.08, P<0.05). The chest X-ray grading of TB subjects was correlated to 1 year levels of PM10 (R (2)=0.94, P<0.05). However, there were no associations of pulmonary cavitation or treatment success rate with PM10. In subjects with TB-positive cultures, annual exposure to ≥50 μg/m(3) PM10 was associated with an increase in the time required for sputum culture conversion (hazard ratio =1.28, 95% confidence interval: 1.07-1.84, P<0.05). In conclusion, chronic exposure to ≥50 μg/m(3) PM10 may prolong the sputum culture conversion of TB patients with sputum-positive cultures. [ABSTRACT FROM AUTHOR]

Objective: Smoking has been associated with tuberculosis (TB); however, the effects of smoking on the effectiveness of TB treatment remain unclear.Materials and Methods: Data were retrieved from case notes and interviews of subjects registered in the TB-reporting system from 2010 to 2012. Study cases were defined as subjects with TB-positive sputum cultures, whereas the controls were defined as subjects with non-TB-related pulmonary diseases. Statistical analyses included logistic regression and multivariate Cox proportional hazard regression models.Results: A total of 245 cases with cultures positive for TB and 114 controls with non-TB-related pulmonary diseases and negative sputum cultures were recruited. Current smokers had the highest failure rate (33%) for TB treatment, and they had the most severe pulmonary lesions based on chest X-ray grading. Current smokers had a 1.36-fold (95% confidence interval 1.03-2.36, P<0.05) higher odds ratio for cultures positive for TB compared with nonsmokers. In subjects with TB-positive cultures, current smoking was associated with an increase in treatment days required for cultures to convert from positive to negative (hazard ratio 1.12, 95% confidence interval 1.03-1.39; P<0.05).Conclusion: Longer periods of treatment may be required for TB patients who are current smokers. [ABSTRACT FROM AUTHOR]

Background Protein oxidation is considered to be one of the main causes of cell death, and methionine is one of the primary targets of reactive oxygen species (ROS). However, the mechanisms by which nickel nanoparticles (NiNPs) cause oxidative damage to proteins remain unclear. Objectives The objective of this study is to investigate the effects of NiNPs on the methionine sulfoxide reductases (MSR) protein repairing system. Methods Two physically similar nickel-based nanoparticles, NiNPs and carbon-coated NiNP (C-NiNPs; control particles), were exposed to human epithelial A549 cells. Cell viability, benzo(a)pyrene diolepoxide (BPDE) protein adducts, methionine oxidation, MSRA and B3, microtubule-associated protein 1A/1B-light chain 3 (LC3) and extracellular signal-regulated kinase (ERK) phosphorylation were investigated. Results Exposure to NiNPs led to a dose-dependent reduction in cell viability and increased BPDE protein adduct production and methionine oxidation. The methionine repairing enzymatic MSRA and MSRB3 production were suppressed in response to NiNP exposure, suggesting the oxidation of methionine to MetO by NiNP was not reversed back to methionine. Additionally, LC3, an autophagy marker, was down-regulated by NiNPs. Both NiNP and C-NiNP caused ERK phosphorylation. LC3 was positively correlated with MSRA ( r = 0.929, p < 0.05) and MSRB3 ( r = 0.893, p < 0.05). Conclusions MSR was made aberrant by NiNP, which could lead to the dysfunction of autophagy and ERK phosphorylation. The toxicological consequences may be dependent on the chemical characteristics of the nanoparticles. [ABSTRACT FROM AUTHOR]

Background: Endobronchial ultrasound-guided transbronchial aspiration (EBUS-TBNA) has the potential to improve nodal diagnosis and staging in non-small cell lung cancer (NSCLC). This study was performed to explore the roles of EBUS-TBNA in NSCLC. Methods: From 2007 to 2009, 164 NSCLC patients were examined by EBUS-TBNA. The patients were divided into a diagnosis group (n = 64) and a staging group (n = 100). Results: For all patients, the diagnostic sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 92.3%, 100%, 100%, 88.2%, and 95.1%, respectively. In the diagnosis group, the diagnostic sensitivity, specificity, PPV, NPV, and accuracy were 89.7%, 100%, 100%, 86.2%, and 94.4%, respectively. Thirty five patients (54.7%) positive for malignancy as determined by EBUS-TBNA avoided surgery. In the staging group, the diagnostic sensitivity, specificity, PPV, NPV, accuracy, and surgery avoidance rate were 93.8%, 100%, 100%, 89.7%, 96%, and 61%, respectively. Conclusions: EBUS-TBNA is a feasible and effective tool for NSCLC diagnosis and staging that also reduces surgery rates. Patients with NSCLC should initially undergo the less invasive EBUS-TBNA procedure for diagnosis and staging of NSCLC. However, negative findings must be confirmed by surgery. [ABSTRACT FROM AUTHOR]

Objectives: Docetaxel and pemetrexed have been validated as therapeutics for previously treated advanced non-small-cell lung cancer (NSCLC), but tolerability is a concern for standard treatment with docetaxel administered once every 3 weeks (tri-weekly 75-mg/m2 schedule). We conducted this retrospective study to compare the efficacy and toxicity of weekly low-dose docetaxel versus tri-weekly pemetrexed for previously treated advanced NSCLC. Methods: Consecutive patients who received low-dose single docetaxel (30 mg/m2 on days 1 and 8 every 3 weeks) or pemetrexed (500 mg/m2 every 3 weeks) at a single university-affiliated hospital following failure of previous treatment were retrospectively reviewed. Their outcomes and toxicity profiles were determined. Results: 179 patients were included between 2005 and 2008 (docetaxel, n = 79; pemetrexed, n = 100). Both groups had similar hematologic (16.5 vs. 15.0%; p = 0.84) and non-hematologic (20.3 vs. 24%; p = 0.55) toxicities. After controlling for confounding factors, docetaxel remained superior to pemetrexed for progression-free survival (median 4.0 vs. 2.4 months; hazard ratio 0.64; 95% CI 0.47-0.87; p = 0.005) and overall survival (median 15.0 vs.8.5 months; hazard ratio 0.54; 95% CI 0.38-0.77; p <0.001). Conclusion: Although this study showed that weekly low doses of docetaxel were as tolerable as pemetrexed for previously treated advanced NSCLC, a prospective design is needed to confirm this finding. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aberrant activation of the epidermal growth factor receptor (EGFR/ERBB1) by erythroblastic leukemia viral oncogene homolog (ERBB) ligands contributes to various tumor malignancies, including lung cancer and colorectal cancer (CRC). Epiregulin (EREG) is one of the EGFR ligands and is low expressed in most normal tissues. Elevated EREG in various cancers mainly activates EGFR signaling pathways and promotes cancer progression. Notably, a higher EREG expression level in CRC with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) is related to better efficacy of therapeutic treatment. By contrast, the resistance of anti-EGFR therapy in CRC was driven by low EREG expression, aberrant genetic mutation and signal pathway alterations. Additionally, EREG overexpression in non-small cell lung cancer (NSCLC) is anticipated to be a therapeutic target for EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, recent findings indicate that EREG derived from macrophages promotes NSCLC cell resistance to EGFR-TKI treatment. The emerging events of EREG-mediated tumor promotion signals are generated by autocrine and paracrine loops that arise from tumor epithelial cells, fibroblasts, and macrophages in the tumor microenvironment (TME). The TME is a crucial element for the development of various cancer types and drug resistance. The regulation of EREG/EGFR pathways depends on distinct oncogenic driver mutations and cell contexts that allows specific pharmacological targeting alone or combinational treatment for tailored therapy. Novel strategies targeting EREG/EGFR, tumor-associated macrophages, and alternative activation oncoproteins are under development or undergoing clinical trials. In this review, we summarize the clinical outcomes of EREG expression and the interaction of this ligand in the TME. The EREG/EGFR pathway may be a potential target and may be combined with other driver mutation targets to combat specific cancers. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) continues to pose a therapeutic challenge. This may be connected with its nosological heterogeneity, broad symptomatology spectrum, varying disease course, and therapy response. The last three decades has been characterized by increased understanding of the pathobiology of COPD, with associated advances in diagnostic and therapeutic modalities; however, the identification of pathognomonic biomarkers that determine disease severity, affect disease course, predict clinical outcome, and inform therapeutic strategy remains a work in progress. Objectives: Hypothesizing that a multi-variable model rather than single variable model may be more pathognomonic of COPD emphysema (COPD-E), the present study explored for disease-associated determinants of disease severity, and treatment success in Taiwanese patients with COPD-E. Methods: The present single-center, prospective, non-randomized study enrolled 125 patients with COPD and 43 healthy subjects between March 2015 and February 2021. Adopting a multimodal approach, including bioinformatics-aided analyses and geospatial modeling, we performed an integrated analysis of selected epigenetic, clinicopathological, geospatial, and air pollutant variables, coupled with correlative analyses of time-phased changes in pulmonary function indices and COPD-E severity. Results: Our COPD cohort consisted of 10 non-, 57 current-, and 58 ex-smokers (median age = 69 ± 7.76 years). Based on the percentages of low attenuation area below − 950 Hounsfield units (%LAA-950insp), 36 had mild or no emphysema (%LAA-950insp < 6), 22 were moderate emphysema cases (6 ≤ %LAA-950insp < 14), and 9 presented with severe emphysema (%LAA-950insp ≥ 14). We found that BMI, lnc-IL7R, PM2.5, PM10, and SO2 were differentially associated with disease severity, and are highly-specific predictors of COPD progression. Per geospatial levels, areas with high BMI and lnc-IL7R but low PM2.5, PM10, and SO2 were associated with fewer and ameliorated COPD cases, while high PM2.5, PM10, and SO2 but low BMI and lnc-IL7R characterized places with more COPD cases and indicated exacerbation. The prediction pentad effectively differentiates patients with mild/no COPD from moderate/severe COPD cases, (mean AUC = 0.714) and exhibited very high stratification precision (mean AUC = 0.939). Conclusion: Combined BMI, lnc-IL7R, PM2.5, PM10, and SO2 levels are optimal classifiers for accurate patient stratification and management triage for COPD in Taiwan. Low BMI, and lnc-IL7R, with concomitant high PM2.5, PM10, and SO2 levels is pathognomonic of exacerbated/aggravated COPD in Taiwan. [ABSTRACT FROM AUTHOR]