Publications by authors named "Kang-Yun Lee"

115 Publications

Profiling of T Cell Repertoire in SARS-CoV-2-Infected COVID-19 Patients Between Mild Disease and Pneumonia.

J Clin Immunol 2021 May 5. Epub 2021 May 5.

Master Program in Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a public health emergency. The most common symptoms of COVID-19 are fever, cough, and fatigue. While most patients with COVID-19 present with mild illness, some patients develop pneumonia, an important risk factor for mortality, at early stage of viral infection, putting these patients at increased risk of death. So far, little has been known about differences in the T cell repertoires between COVID-19 patients with and without pneumonia during SARS-CoV-2 infection. Herein, we aimed to investigate T cell receptor (TCR) repertoire profiles and patient-specific SARS-CoV-2-associated TCR clusters between COVID-19 patients with mild disease (no sign of pneumonia) and pneumonia. The TCR sequencing was conducted to characterize the peripheral TCR repertoire profile and diversity. The TCR clustering and CDR3 annotation were exploited to further discover groups of patient-specific TCR clonotypes with potential SARS-CoV-2 antigen specificities. Our study indicated a slight decrease in the TCR repertoire diversity and a skewed CDR3 length usage in patients with pneumonia compared to those with mild disease. The SARS-CoV-2-associated TCR clusters enriched in patients with mild disease exhibited significantly higher TCR generation probabilities and most of which were highly shared among patients, compared with those from pneumonia patients. Importantly, using similarity network-based clustering followed by the sequence conservation analysis, we found different patterns of CDR3 sequence motifs between mild disease- and pneumonia-specific SARS-CoV-2-associated public TCR clusters. Our results showed that characteristics of overall TCR repertoire and SARS-CoV-2-associated TCR clusters/clonotypes were divergent between COVID-19 patients with mild disease and patients with pneumonia. These findings provide important insights into the correlation between the TCR repertoire and disease severity in COVID-19 patients.
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http://dx.doi.org/10.1007/s10875-021-01045-zDOI Listing
May 2021

Combination therapies with thiazolidinediones are associated with a lower risk of acute exacerbations in new-onset COPD patients with advanced diabetic mellitus: a cohort-based case-control study.

BMC Pulm Med 2021 Apr 29;21(1):141. Epub 2021 Apr 29.

Office of Data, Taipei Medical University, No. 250 Wuxing St., Taipei, 11031, Taiwan.

Background: The effects of oral antihyperglycaemic drugs (OADs) for type 2 diabetes mellitus (T2DM) on the outcomes of co-existing chronic obstructive pulmonary disease (COPD) patients are not well studied. We examined the association of combinational OADs and the risk of acute exacerbations of COPD (AECOPD) in T2DM patients with co-existing COPD.

Methods: A cohort-based case-control study was conducted using data from the National Health Insurance Research Database of Taiwan. Among new-onset COPD-T2DM patients, 65,370 were prescribed metformin and 2nd-line OADs before the date of COPD onset. Each AECOPD case was matched to 4 randomly selected controls according to the propensity score estimated by the patient's baseline characteristics. Conditional logistic regression analysis was performed to estimate the association between AECOPD risk and OAD use.

Results: Among COPD-T2DM patients, 3355 AECOPD cases and 13,420 matched controls were selected. Of the patients treated with a double combination of oral OADs (n = 12,916), those treated with sulfonylurea (SU) and thiazolidinediones (TZD) had a lower AECOPD risk than the patients who received metformin (MET) and SU, with an adjusted odds ratio (OR) of 0.69 (95% confidence interval [CI] 0.51-0.94, P = 0.02). Of the patients with a triple combination of oral OADs (n = 3859), we found that those treated with MET, SU and TZD had a lower risk of AECOPD (adjusted OR 0.81 (0.68-0.96, P = 0.01) than a combination of MET, SU and α-glucosidase inhibitors (AGIs) regardless of the level of COPD complexity.

Conclusion: Combination therapies with TZD were associated with a reduced risk of AECOPD in advanced T2DM patients with co-existing COPD.
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http://dx.doi.org/10.1186/s12890-021-01505-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086317PMC
April 2021

Novel App-Based Portable Spirometer for the Early Detection of COPD.

Diagnostics (Basel) 2021 Apr 27;11(5). Epub 2021 Apr 27.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.

Chronic obstructive pulmonary disease (COPD) is preventable and treatable. However, many patients remain undiagnosed and untreated due to the underutilization or unavailability of spirometers. Accordingly, we used Spirobank Smart, an app-based spirometer, for facilitating the early detection of COPD in outpatient clinics. This prospective study recruited individuals who were at risk of COPD (i.e., with age of ≥40 years, ≥10 pack-years of smoking, and at least one respiratory symptoms) but had no previous COPD diagnosis. Eligible participants were examined with Spirobank Smart and then underwent confirmatory spirometry (performed using a diagnostic spirometer), regardless of their Spirobank Smart test results. COPD was defined and confirmed using the postbronchodilator forced expiratory volume in 1 s/forced vital capacity values of <0.70 as measured by confirmatory spirometry. A total of 767 participants were enrolled and examined using Spirobank Smart; 370 participants (94.3% men, mean age of 60.9 years and mean 42.6 pack-years of smoking) underwent confirmatory spirometry. Confirmatory spirometry identified COPD in 103 participants (27.8%). At the optimal cutoff point of 0.74 that was determined using Spirobank Smart for COPD diagnosis, the area under the receiver operating characteristic was 0.903 (95% confidence interval (CI) = 0.860-0.947). Multivariate logistic regression revealed that participants who have an FEV/FVC ratio of <74% that was determined using Spirobank Smart (odds ratio (OR) = 58.58, 95% CI = 27.29-125.75) and old age (OR = 3.23, 95% CI = 1.04-10.07 for 60 ≤ age < 65; OR = 5.82, 95% CI = 2.22-15.27 for age ≥ 65) had a higher risk of COPD. The Spirobank Smart is a simple and adequate tool for early COPD detection in outpatient clinics. Early diagnosis and appropriate therapy based on GOLD guidelines can positively influence respiratory symptoms and quality of life.
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http://dx.doi.org/10.3390/diagnostics11050785DOI Listing
April 2021

Evaluation of the diagnostic accuracy of bronchial brushing cytology in lung cancer: A meta-analysis.

Cancer Cytopathol 2021 Apr 22. Epub 2021 Apr 22.

Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.

Background: Flexible bronchoscopy is commonly used to examine patients suspected to have lung cancer. Bronchial brushing is one of the cytological technologies for lung specimens obtained through a bronchoscope. However, the accuracy of bronchial brushing cytology (BBC) for lung cancer diagnosis is still inconclusive. The aim of this study was to evaluate the diagnostic accuracy of BBC.

Methods: A literature search was conducted with PubMed, Embase, the Cochrane Library, Web of Science, Biomed Central, Clinical Key, and ClinicalTrials.gov. Studies that assessed the efficacy of BBC in detecting lung cancer were included. Articles that estimated the accuracy on a per-patient basis were included. Review articles, case reports, and research that provided insufficient data to construct a 2 × 2 table were excluded. Both prospective trials and retrospective studies were included. English language studies were reviewed. Data synthesis was performed with a random-effects model.

Results: Seventeen studies with 2538 patients were included in the study. The meta-analysis for BBC generated a pooled sensitivity of 0.67 (95% confidence interval [CI], 0.65-0.70) and a pooled specificity of 0.91 (95% CI, 0.89-0.93). The pooled diagnostic odds ratio for BBC was 24.55 (95% CI, 12.39-48.66). The subgroup analysis for studies using liquid-based cytology (LBC) generated a pooled sensitivity of 0.68 and a pooled specificity of 0.92. The pooled diagnostic odds ratio of studies using LBC was 114.18.

Conclusions: These findings indicate that BBC is a discriminative diagnostic approach with moderate sensitivity and high specificity for diagnosing peripheral pulmonary lesions. BBC using LBC has higher diagnostic performance.
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http://dx.doi.org/10.1002/cncy.22436DOI Listing
April 2021

Alveolar epithelial inter-alpha-trypsin inhibitor heavy chain 4 deficiency associated with senescence-regulated apoptosis by air pollution.

Environ Pollut 2021 Jun 9;278:116863. Epub 2021 Mar 9.

School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address:

Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is a type II acute-phase protein; however, the role of pulmonary ITIH4 after exposure to air pollution remains unclear. In this study, we investigated the role of ITIH4 in the lungs in response to air pollution. ITIH4 expression in bronchoalveolar lavage fluid (BAL) of 47 healthy human subjects and of Sprague-Dawley rats whole-body exposed to air pollution was determined, and the underlying antiapoptotic and matrix-stabilizing pathways in alveolar epithelial A549 cells induced by diesel exhaust particles (DEPs) as well as ITIH4-knockdown were investigated. We found that an interquartile range (IQR) increase in PM was associated with a decrease of 2.673 ng/mL in ITIH4, an increase of 1.104 pg/mL of 8-isoprostane, and an increase of 6.918 pg/mL of interleukin (IL)-6 in human BAL. In rats, increases in 8-isoprostane, IL-6, and p53 and a decrease in sirtuin-1 (Sirt1) in the lungs and decreases in ITIH4 in the BAL, lungs, and serum were observed after PM and gaseous exposure. ITIH4 levels in lung lysates were correlated with levels in BAL samples (r = 0.377, p < 0.01), whereas ITIH4 levels in BAL were correlated with IL-6 levels (r = -0.420, p < 0.01). ITIH4 expression was significantly reduced in alveolar epithelial A549 cells by DEP in a dose-dependent manner. A decrease in Sirt1 and increases in phosphorylated extracellular signal-regulated kinase (p-ERK) and caspase-3 were observed after DEP exposure and ITIH4-knockdown. In conclusion, air pollution decreased ITIH4 expression in the lungs, which was associated with alveolar epithelial cell senescence and apoptosis. ITIH4 could be a vital protein in regulating alveolar cell destruction and its inhibition after exposure to air pollution.
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http://dx.doi.org/10.1016/j.envpol.2021.116863DOI Listing
June 2021

Transcriptome network analyses in human coronavirus infections suggest a rational use of immunomodulatory drugs for COVID-19 therapy.

Genomics 2021 03 20;113(2):564-575. Epub 2021 Jan 20.

Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan; Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan; Integrative Research Center for Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Division of Nephrology, Department of Internal Medicine, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan. Electronic address:

The recent outbreak of coronavirus disease 2019 (COVID-19) by SARS-CoV-2 has led to uptodate 24.3 M cases and 0.8 M deaths. It is thus in urgent need to rationalize potential therapeutic targets against the progression of diseases. An effective, feasible way is to use the pre-existing ΔORF6 mutant of SARS-CoV as a surrogate for SARS-CoV-2, since both lack the moiety responsible for interferon antagonistic effects. By analyzing temporal profiles of upregulated genes in ΔORF6-infected Calu-3 cells, we prioritized 55 genes and 238 ligands to reposition currently available medications for COVID-19 therapy. Eight of them are already in clinical trials, including dexamethasone, ritonavir, baricitinib, tofacitinib, naproxen, budesonide, ciclesonide and formoterol. We also pinpointed 16 drug groups from the Anatomical Therapeutic Chemical classification system, with the potential to mitigate symptoms of SARS-CoV-2 infection and thus to be repositioned for COVID-19 therapy.
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http://dx.doi.org/10.1016/j.ygeno.2020.12.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817445PMC
March 2021

Subjective sleep quality and association with depression syndrome, chronic diseases and health-related physical fitness in the middle-aged and elderly.

BMC Public Health 2021 01 19;21(1):164. Epub 2021 Jan 19.

Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.

Background: As a complex phenomenon, sleep quality is difficult to objectively define and measure, and multiple factors related to sleep quality, such as age, lifestyle, physical activity, and physical fitness, feature prominently in older adult populations. The aim of the present study was to evaluate subjective sleep quality using the Pittsburgh Sleep Quality Index (PSQI) and to associate sleep quality with health-related physical fitness factors, depressive symptoms, and the number of chronic diseases in the middle-aged and elderly.

Methods: We enrolled a total of 283 middle-aged and elderly participants from a rehabilitation clinic or health examination department. The PSQI was used to evaluate sleep quality. The health-related fitness assessment included anthropometric and physical fitness parameters. Depressive symptoms were measured with the Center for Epidemiologic Studies Depression Scale (CES-D) short form. Data were analyzed with SPSS 18.0, and descriptive statistics and logistic regression analysis were used for the analyses.

Results: Overall, 27.9% of participants in this study demonstrated bad sleepers (with a PSQI score of > 5), 10.2% of study participants frequently used sleep medication to help them fall asleep, and 6.0% reported having significant depressive symptoms (with a CES-D score of ≥10). There are two major findings: (1) depression symptoms, the number of chronic diseases, self-rated health, and arthritis were significantly associated with a poor sleep quality, and (2) the 2-min step test was associated with longer sleep latency. These results confirmed that the 2-min step was associated with a longer sleep latency among the health-related physical fitness items.

Conclusions: Our study found that depressive syndrome, chronic disease numbers, a poor self-rated health status, and arthritis were the main risk factors that influenced subjective sleep quality.
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http://dx.doi.org/10.1186/s12889-021-10206-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816352PMC
January 2021

Exposure to PM is associated with malignant pleural effusion in lung cancer patients.

Ecotoxicol Environ Saf 2021 Jan 10;208:111618. Epub 2020 Nov 10.

School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address:

Air pollution has been recognized to be a risk factor for lung cancer. The objective of this study was to investigate the effects of air pollution on heavy metal alterations in the pleural effusion of lung cancer patients. Pleural effusion was collected from patients with lung cancer and congestive heart failure (CHF). One-year average levels of particulate matter with an aerodynamic diameter of < 10 µm (PM), PM, NO, and SO were linked to the exposure of these subjects. Traffic-related metals, included Al, Fe, Cu, Zn, and Pb, were determined in the pleural effusion. Logistic regression models were used to examine their associations. There were 63 lung cancer patients and 31 CHF patients enrolled in the current study. We found that PM, PM, and NO were negatively correlated with Al in the pleural effusion, whereas PM was positively correlated with Zn in the pleural effusion. Increases in 1 μg/m of PM and 1 ng/mL of Zn were associated with lung cancer (adjusted OR=2.394, 95% CI= 1.446-3.964 for PM; adjusted OR=1.003, 95% CI=1.000-1.005 for Zn). Increases in PM and Zn in the pleural effusion increased the risk of malignant pleural effusion in lung cancer patients (adjusted OR=1.517; 95% CI=1.082-2.127 for PM; adjusted OR=1.002, 95% CI=1.000-1.005 for Zn). Furthermore, we observed that adenocarcinomas increased in association with a 1-μg/m increase in PM (crude OR=1.683; 95% CI=1.006-2.817) in lung cancer patients. In conclusion, PM exposure and the possible resultant Zn in the pleural effusion associated with the development of malignant pleural effusion in lung cancer.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111618DOI Listing
January 2021

Upregulation of CD109 Promotes the Epithelial-to-Mesenchymal Transition and Stemness Properties of Lung Adenocarcinomas via Activation of the Hippo-YAP Signaling.

Cells 2020 Dec 25;10(1). Epub 2020 Dec 25.

Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Xing Street, Taipei 11031, Taiwan.

Metastasis is the leading cause of death in lung adenocarcinomas. Identifying potential prognostic biomarkers and exploiting regulatory mechanisms could improve the diagnosis and treatment of lung cancer patients. We previously found that cluster of differentiation 109 (CD109) was upregulated in lung tumor tissues, and CD109 overexpression was correlated with the invasive and metastatic capacities of lung adenocarcinoma cells. However, the contribution of CD109 to lung tumorigenesis remains to be elucidated. In the present study, we identified that CD109 was upregulated in metastatic lung adenocarcinoma cells, and elevation of CD109 was correlated with epithelial-to-mesenchymal transition (EMT) traits in patients with lung adenocarcinoma. Functionally, CD109 expression was crucial for EMT gene expressions, tumor invasiveness, and cancer stemness properties. Moreover, elevation of CD109 was accompanied by upregulation of the yes-associated protein (YAP) signature in metastatic lung cancer cells and lung cancer patients, and activation of YAP was demonstrated to participate in CD109-elicited EMT gene expressions and tumor invasiveness. Our study reveals the molecular mechanism underlying CD109 in lung tumor aggressiveness, and CD109 could be a potential diagnostic and therapeutic target for lung cancer patients.
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http://dx.doi.org/10.3390/cells10010028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823273PMC
December 2020

Corrigendum to "The association of annual air pollution exposure with blood pressure among patients with sleep-disordered breathing", Sci. Total Environ., 543, Part A, 1 February 2016, 61-66.

Sci Total Environ 2021 Mar 20;759:143518. Epub 2020 Nov 20.

Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/j.scitotenv.2020.143518DOI Listing
March 2021

Novel PD-L1 mAb HC16 reveals upregulation of PD-L1 in BAC subtype.

Histol Histopathol 2021 Jan 28;36(1):77-89. Epub 2020 Oct 28.

Marine Research Station, Institute of Cellular and Organismic Biology, Academia Sinica, Jiaushi, Ilan, Taiwan.

Programmed death-ligand 1 (PD-L1) is an inhibitory transmembrane protein that can prevent autoimmune response. Upregulated PD-L1 serves as a predictive biomarker for patients who may respond well to immune checkpoint therapies. However, variable associations of PD-L1 level with prognoses have been reported. In this study, a short peptide sequence corresponding to PD-L1 amino acids 172-187 (from the extracellular Ig-like C-type domain, and with high predicted antigenicity and hydrophilicity) was used to generate a monoclonal antibody (mAb). The resultant PD-L1 mAb, clone HC16, was examined for binding specificity and reactivity in cancer cell-lines, as assessed by immunocytochemical, immunoblotting, and co-immunoprecipitation. The potential diagnostic and clinical applicability of clone HC16 was further tested using malignant tissue arrays derived from various cancer types analyzed with an automated immunohistochemical (IHC) staining platform. Additionally, tumor samples from patients diagnosed with non-small cell lung cancer (NSCLC) were analyzed by western blotting. Clone HC16 showed obvious staining activity in lung and breast cancer tissues. Interestingly, we observed that PD-L1 level was negatively associated with clinical stage in NSCLC. Strong PD-L1 expression tended to be found in patients diagnosed with bronchioloalveolar carcinoma (BAC). These results demonstrate that clone HC16 harbors good target specificity and is suitable for further development in diagnostic tools to assess PD-L1 expression in human tissues. In addition, our findings also suggest a role for PD-L1 in a non-invasive subtype of lung cancer.
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http://dx.doi.org/10.14670/HH-18-272DOI Listing
January 2021

Alteration in angiotensin-converting enzyme 2 by PM during the development of emphysema in rats.

ERJ Open Res 2020 Oct 5;6(4). Epub 2020 Oct 5.

Division of Pulmonary Medicine, Dept of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.

Introduction: Angiotensin-converting enzyme 2 (ACE2) provides an adhesion site for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients with COPD could have severe outcomes after SARS-CoV-2 infection. The objective of this study was to investigate ACE2 regulation by air pollution during the development of COPD.

Methods: Sprague Dawley rats were exposed to unconcentrated traffic-related air pollution for 3 and 6 months. We examined lung injury markers, oxidative stress, inflammation, emphysema, ACE2 and angiotensin II receptor type 1 (AT1) and 2 (AT2) in the lungs after exposure.

Results: Lung injury occurred due to an increase in permeability and lactate dehydrogenase cytotoxicity was observed after 6 months of exposure to fine particulate matter of <1 μm in aerodynamic diameter (PM). An α-antitrypsin deficiency and neutrophil elastase production with emphysema development were observed after 6 months of PM exposure. 8-isoprostane and interleukin-6 were increased after 3 and 6 months of PM exposure. Caspase-3 was increased after exposure to PM for 6 months. Upregulation of ACE2 was found after 3 months of PM exposure; however, ACE2 had decreased by 6 months of PM exposure. AT1 and AT2 had significantly decreased after exposure to PM for 6 months. Furthermore, smooth muscle hypertrophy had occurred after 6 months of PM exposure.

Conclusions: In conclusion, short-term exposure to PM increased the ACE2 overexpression in lungs. Long-term exposure to PM decreased the ACE2 overexpression in emphysema. Air pollution may be a risk for SARS-CoV-2 adhesion during the development of COPD.
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http://dx.doi.org/10.1183/23120541.00174-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533376PMC
October 2020

Survey of the management of patients with bronchiectasis: a pilot investigation in Asian populations.

Korean J Intern Med 2020 Sep 15. Epub 2020 Sep 15.

Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background/aims: Although international guidelines for bronchiectasis management have been published in Western countries, there is a lack of data about their application in Asian populations including patients with different phenotypes. We aimed to investigate the current status of bronchiectasis management in Asian populations.

Methods: A nationwide questionnaire survey was performed of Asian respiratory specialists from South Korea, Japan, Taiwan, Singapore, Vietnam, and Sri Lanka. Participants were invited by e-mail to answer a questionnaire comprising 25 questions based on international guidelines for the management of bronchiectasis.

Results: A total of 221 physicians participated in the survey. About half of them were Korean (50.2%), with the next most common nationalities being Japanese (23.1%), Taiwanese (13.6%), and Singaporean (7.7%). Only 18 (8.1%) responders had local guidelines for bronchiectasis. While 85 (38.5%) responders checked sputum acid-fast bacillus smear/culture about 1-3 times per year, only a small proportion of responders routinely performed a serum immunoglobulin test (36/221, 16.3%) or evaluated for allergic bronchopulmonary aspergillosis (41/221, 18.6%). Less than half (43.4%) of responders performed eradication treatment in patients with drug-sensitive Pseudomonas aeruginosa infection, mainly due to the limited availability of inhaled antibiotics (34.8%). In addition, 58.6% of responders considered physiotherapy such as airway clearance and pulmonary rehabilitation.

Conclusions: Discrepancies might exist between guideline recommendations and practice for bronchiectasis management in Asian populations, partly due to the limited availability of treatment in each country. The development of local guidelines that consider the phenotypes and situation will help to standardize and improve the management of bronchiectasis.
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http://dx.doi.org/10.3904/kjim.2020.223DOI Listing
September 2020

Impaired lnc-IL7R modulatory mechanism of Toll-like receptors is associated with an exacerbator phenotype of chronic obstructive pulmonary disease.

FASEB J 2020 10 11;34(10):13317-13332. Epub 2020 Aug 11.

Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.

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.
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http://dx.doi.org/10.1096/fj.202000632RDOI Listing
October 2020

Plasma Level of Circular RNA hsa_circ_0000190 Correlates with Tumor Progression and Poor Treatment Response in Advanced Lung Cancers.

Cancers (Basel) 2020 Jun 30;12(7). Epub 2020 Jun 30.

School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.

Lung cancer (LC) causes the majority of cancer-related deaths. Circular RNAs (circRNAs) were reported to play roles in cancers by targeting pro- and anti-oncogenic miRNAs. However, the mechanisms of circRNAs in LC progression and their prognostic value of treatment response remain unclear. By using next generation sequencing (NGS) of LC cell lines' transcriptomes, we identified highly overexpressed hsa_circ_0000190 and hsa_circ_000164 as potential biomarkers. By using the highly sensitive RT-ddPCR method, these circRNAs were shown to be secreted by cell lines and were detected in human blood. Clinical validation by RT-ddPCR was carried out on 272 (231 LC patients and 41 controls) blood samples. Higher hsa_circ_0000190 levels were associated with larger tumor size ( < 0.0001), worse histological type of adenocarcinoma ( = 0.0028), later stage ( < 0.0001), more distant metastatic organs ( = 0.0039), extrathoracic metastasis ( = 0.0004), and poor survival ( = 0.047) and prognosis. Using liquid biopsy-based RT-ddPCR, we discovered the correlation between increased hsa_circ_0000190 plasma level ( < 0.0001) and higher programmed death-ligand 1 (PD-L1) level in tumor ( = 0.0283). Notably, long-term follow-up of the immunotherapy treated cases showed that upregulated plasma hsa_circ_0000190 level correlated with poor response to systemic therapy and immunotherapy ( = 0.0002, 0.0058, respectively). Secretory circRNAs are detectable in blood by LB-based RT-ddPCR and may serve as blood-based biomarkers to monitor disease progression and treatment efficacy.
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http://dx.doi.org/10.3390/cancers12071740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408140PMC
June 2020

Durvalumab-induced de novo annular psoriasiform drug eruption successfully treated with a combination of narrowband ultraviolet B phototherapy and topical treatment.

J Dermatol 2020 Sep 1;47(9):1041-1045. Epub 2020 Jul 1.

Department of Dermatology, Taipei Medical University- Shuang Ho Hospital, New Taipei City, Taiwan.

Immune checkpoint inhibitors, including anti-programmed death 1 and anti-programmed death ligand 1, have become prominent treatment options for various types of cancers. However, immune checkpoint inhibitors are associated with various cutaneous adverse events, one of which is psoriasiform drug eruption. Some cases of psoriasiform drug eruption can only be controlled through the cessation of immune checkpoint inhibitors and administration of systemic immunosuppressants, such as corticosteroids and methotrexate. However, no clear guideline is available on the management of this specific rash, and the use of systemic immunosuppressants is contraindicated in selected conditions. In this article, we report a case of annular psoriasiform drug eruption induced by an anti-programmed death ligand 1 monoclonal antibody, durvalumab. The patient responded well to the combination of phototherapy and topical treatment, which allowed continuation of durvalumab treatment without concomitant systemic immunosuppressants in a 2-year follow up.
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http://dx.doi.org/10.1111/1346-8138.15371DOI Listing
September 2020

Elevation of CD109 promotes metastasis and drug resistance in lung cancer via activation of EGFR-AKT-mTOR signaling.

Cancer Sci 2020 May 25;111(5):1652-1662. Epub 2020 Mar 25.

Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.

Lung cancer is the most commonly diagnosed cancer worldwide, and metastasis in lung cancer is the leading cause of cancer-related deaths. Thus, understanding the mechanism of lung cancer metastasis will improve the diagnosis and treatment of lung cancer patients. Herein, we found that expression of cluster of differentiation 109 (CD109) was correlated with the invasive and metastatic capacities of lung adenocarcinoma cells. CD109 is upregulated in tumorous tissues, and CD109 overexpression was associated with tumor progression, distant metastasis, and a poor prognosis in patient with lung adenocarcinoma. Mechanistically, expression of CD109 regulates protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling via its association with the epidermal growth factor receptor (EGFR). Inhibition of CD109 decreases EGFR phosphorylation, diminishes EGF-elicited activation of AKT/mTOR, and sensitizes tumor cells to an EGFR inhibitor. Taken together, our results show that CD109 is a potential diagnostic and therapeutic target in lung cancer patients.
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http://dx.doi.org/10.1111/cas.14373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226182PMC
May 2020

Schistosoma egg antigens suppress LPS-induced inflammation in human IMR-90 cells by modulation of JAK/STAT1 signaling.

J Microbiol Immunol Infect 2020 Jan 25. Epub 2020 Jan 25.

Department of Molecular Parasitology and Tropical Diseases, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Center for International Tropical Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address:

Background: The regulation of the balance between inflammatory and anti-inflammatory events during the treatment of pulmonary infection is very important. Soluble Schistosoma egg antigens (SEA) can effectively inhibit the expression of cytokines during hepatic acute inflammation. However, the mechanisms by which these proteins suppress the inflammatory responses in lung cells remain unclear. The purpose of this study was to investigate the ability of SEA to inhibit pulmonary inflammation.

Methods: The effects of SEA were investigated in LPS-treated lung IMR-90 cells. The involvement of the JAK/STAT-1 signaling pathway in these effects was evaluated by employing CBA assays, quantitative polymerase chain reaction, and western blotting experiments.

Results: Pretreatment of IMR-90 cells with appropriate concentrations of SEA protected cells against the cytotoxic effects of LPS-induced inflammation in a time-dependent manner. SEA pretreatment significantly attenuated the LPS-induced activation of the JAK/STAT1 signaling pathway, including the upregulation of JAK1/2 and STAT1, as well as the production of inflammatory cytokines. The level of phosphorylated STAT1 gradually declined in response to increasing concentrations of SEA. Based on these findings, we hypothesize that SEA-induced anti-inflammatory effects initiate with the downregulation of the IFN-γ-JAK-STAT1 signaling pathway, resulting in the attenuation of LPS-induced inflammation in IMR-90 cells.

Conclusion: Our study is the first to demonstrate the anti-inflammatory activity of SEA in an in vitro model of pulmonary inflammation, involving the modulation of JAK/STAT1 signaling. We propose SEA as potential therapeutic or preventive agents for the selective suppression of STAT1 and the control of inflammatory response in lung IMR-90 cells.
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http://dx.doi.org/10.1016/j.jmii.2019.12.001DOI Listing
January 2020

Nicotinic-nAChR signaling mediates drug resistance in lung cancer.

J Cancer 2020 1;11(5):1125-1140. Epub 2020 Jan 1.

Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan.

Lung cancer is the leading cause of cancer death worldwide. Cigarette smoking is the most common risk factor for lung carcinoma; other risks include genetic factors and exposure to radon gas, asbestos, secondhand smoke, and air pollution. Nicotine, the primary addictive constituent of cigarettes, contributes to cancer progression through activation of nicotinic acetylcholine receptors (nAChRs), which are membrane ligand-gated ion channels. Activation of nicotine/nAChR signaling is associated with lung cancer risk and drug resistance. We focused on nAChR pathways activated by nicotine and its downstream signaling involved in regulating apoptotic factors of mitochondria and drug resistance in lung cancer. Increasing evidence suggests that several sirtuins play a critical role in multiple aspects of cancer drug resistance. Thus, understanding the consequences of crosstalk between nicotine/nAChRs and sirtuin signaling pathways in the regulation of drug resistance could be a critical implication for cancer therapy.
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http://dx.doi.org/10.7150/jca.36359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959074PMC
January 2020

Influenza vaccination reduces dementia in patients with chronic obstructive pulmonary disease: a nationwide cohort study.

J Investig Med 2020 04 14;68(4):838-845. Epub 2020 Jan 14.

Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Shuang Ho Hospital, Ministry of Health and Welfare, New Taipei City, Taiwan

This study aimed to explore the protective potential of influenza vaccination against occurrence of dementia in patients with chronic obstructive pulmonary disease (COPD), who are expected to be more vulnerable to influenza infection. This nationwide retrospective cohort study enrolled patients with COPD (aged ≥60 years) from 1 January 2001 to 31 December 2012 by using the Taiwan National Health Insurance Research Database. By applying time-dependent Cox proportional hazard model, we used multivariate analysis to calculate the adjusted HR (aHR) with 95% CI of dementia in relation to influenza vaccination among patients with COPD. Besides, patients were partitioned into four groups according to the vaccination number (unvaccinated, 1, 2-3 and ≥4 total vaccinations) to investigate the dose-response effect of vaccinations on the dementia incidence. This cohort study included 19 848 patients with COPD, and 45% of them received influenza vaccination. The aHR of dementia was 0.68 (95% CI: 0.62 to 0.74, p<0.001) comparing vaccinated patients with unvaccinated ones. Furthermore, there was a trend of dementia risk reduction with the vaccination number. For patients who received 2-3 vaccinations, the aHR was 0.81 (95% CI: 0.73 to 0.90), and for those received 4 vaccinations, the aHR was 0.44 (95% CI: 0.40 to 0.50), with p for trend <0.001. In conclusion, annual influenza vaccination can reduce the risk of dementia in patient with COPD in a dose-dependent manner.
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http://dx.doi.org/10.1136/jim-2019-001155DOI Listing
April 2020

Effect of annual influenza vaccination on reducing lung cancer in patients with chronic obstructive pulmonary disease from a population-based cohort study.

Medicine (Baltimore) 2019 Nov;98(47):e18035

Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei.

Chronic obstructive pulmonary disease (COPD) patients are at a higher risk of development of lung cancer. Frequent exacerbations of COPD trigger the disease course to chronic inflammation which likely plays a role in the pathogenesis of lung cancer. Previous studies showed influenza virus infection is one of important causes for exacerbations of COPD. Therefore, the aim of this study was to know whether influenza vaccination could reduce the incidence of lung cancer in patients with COPD.This cohort study enrolled patients (≥55 years old) with a recorded diagnosis of COPD between January 1, 2000 and December 31, 2012 by using the Taiwan Health Insurance Database. A propensity score was calculated to reduce vaccine therapy selection bias. Cox proportional hazard regressions were used to investigate the association between the influenza vaccination and lung cancer incidence after adjusting for known confounding factors. Besides, we categorized the patients into 4 groups according to vaccination status (unvaccinated, total number of vaccinations: 1, 2-3, ≥4) to evaluate the dose-dependent effect on reducing lung cancer occurrence of lung cancer in COPD patients.Our study comprised of 28,752 eligible individuals from the COPD cohort database. Among them, 51% (14,630) received influenza vaccination; the rest (49%) of the COPD patients did not receive influenza vaccination. We observed that COPD patients receiving influenza vaccination had a lower risk of lung cancer (adjusted HR = 0.40, 95% CI (0.35-0.45), P < .001). We also founded comparable protective effect in both sexes and all age groups (55-64, 65-74, ≥75) regardless of influenza seasonality. Furthermore, dose-dependent protective effect could be seen after stratifying patients according to the total number vaccinations, the adjusted HRs for lung cancer risk were 0.48 (0.40-0.54) and 0.24 (0.20-0.29) for patients who received 2 to 3 and ≥4 vaccinations during the follow-up period.This population-based cohort study demonstrated that annual influenza vaccination administration could reduce incidence of lung cancer in COPD patients.
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http://dx.doi.org/10.1097/MD.0000000000018035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882634PMC
November 2019

The effects of fine and coarse particulate matter on lung function among the elderly.

Sci Rep 2019 10 15;9(1):14790. Epub 2019 Oct 15.

Department of Environmental and Occupational Medicine, National Taiwan University (NTU) College of medicine and NTU Hospital, Taipei City, Taiwan.

Impaired lung function is associated with morbidity and mortality in the elderly. However, there is a paucity of data regarding the long-term effects of particulate matter (PM) on lung function among the elderly. This study evaluated the exposure-response relationship between ambient PM and different lung function indices among the elderly in Taiwan. A cross-sectional survey of individuals aged ≥65 years was conducted in Taiwan from October 2015 to September 2016. Those who attended the annual health examination for the elderly in five hospitals of varying background PM concentrations were enrolled. The long-term (2015 annual mean concentration) exposure to air pollution was estimated by the Kriging method at the residence of each subject. The association between ambient PM exposure and lung function was evaluated by linear regression modeling, with adjustments for age, sex, height, weight, educational attainment, presence of asthma or chronic obstructive pulmonary disease, smoking status, season, and co-pollutants. There were 1241 subjects (mean age, 70.5 years). The mean residential PM and PM in 2015 was 26.02 and 18.01 μg/m, respectively. After adjustments for confounders and co-pollutants, the FVC decrease was best associated with fine particles (PM), whereas the FEV, FEF, FEF and FEF decreases were best associated with coarse particles (PM). An IQR (10 μg/m) increase in PM decreased FVC by 106.38 ml (4.47%), while an IQR (7.29 μg/m) increase in PM decreased FEV and FEF by 91.23 ml (4.85%) and 104.44 ml/s (5.58%), respectively. Among the Taiwanese elderly, long-term PM exposure mainly decreases the vital capacity of lung function. Moreover, PM has a stronger negative effect on the function of conductive airways than PM.
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http://dx.doi.org/10.1038/s41598-019-51307-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794286PMC
October 2019

(PG2) Enhances the M1 Polarization of Macrophages, Functional Maturation of Dendritic Cells, and T Cell-Mediated Anticancer Immune Responses in Patients with Lung Cancer.

Nutrients 2019 Sep 20;11(10). Epub 2019 Sep 20.

Division of Thoracic Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan.

Background: Recently, we demonstrated that (PG2), the active ingredient in dried roots of ameliorates cancer symptom clusters and improves quality of life (QoL) in patients with metastatic disease by modulating inflammatory cascade against the background roles of inflammatory cells, including macrophages, dendritic cells (DCs), and cytotoxic T lymphocytes (CTLs) in tumor initiation, metastasis, and progression. Nevertheless, the role of PG2 in the modulation of anticancer immunogenicity and therapeutic response remains relatively underexplored and unclear.

Purpose: The present study investigates how and to what extent PG2 modulates cellular and biochemical components of the inflammatory cascade and enhances anticancer immunity, as well as the therapeutic implication of these bio-events in patients with lung cancer.

Methods And Results: Herein, we demonstrated that PG2 significantly increased the M1/M2 macrophage polarization ratio in non-small cell carcinoma (NSCLC) H441 and H1299 cells. This PG2-induced preferential pharmacologic up-regulation of tumoral M1 population in vitro positively correlated with the downregulation of tumor-promoting IL-6 and IL-10 expression in NSCLC cell-conditioned medium, with concomitant marked inhibition of cell proliferation, clonogenicity, and tumorsphere formation. Our ex vivo results, using clinical sample from our NSCLC cohort, demonstrated that PG2 also promoted the functional maturation of DCs with consequent enhancement of T cell-mediated anticancer immune responses. Consistent with the in vitro and ex vivo results, our in vivo studies showed that treatment with PG2 elicited significant time-dependent depletion of the tumor-associated M2 population, synergistically enhanced the anti-M2-based anticancer effect of cisplatin, and inhibited xenograft tumor growth in the NSCLC mice models. Moreover, in the presence of PG2, cisplatin-associated dyscrasia and weight-loss was markedly suppressed.

Conclusion: These results do indicate a therapeutically-relevant role for PG2 in modulating the M1/M2 macrophage pool, facilitating DC maturation and synergistically enhancing the anticancer effect of conventional chemotherapeutic agent, cisplatin, thus laying the foundation for further exploration of the curative relevance of PG2 as surrogate immunotherapy and/or clinical feasibility of its use for maintenance therapy in patients with lung cancer.
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http://dx.doi.org/10.3390/nu11102264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836209PMC
September 2019

Effects of PM on Skeletal Muscle Mass and Body Fat Mass of the Elderly in Taipei, Taiwan.

Sci Rep 2019 08 1;9(1):11176. Epub 2019 Aug 1.

Department of Environmental and Occupational Medicine, National Taiwan University (NTU) College of medicine and NTU Hospital, Taipei, Taiwan.

Loss of skeletal muscle mass is common with aging and can cause morbidity and mortality in the elderly. The effects of particulate air pollution on skeletal muscle mass is not known. The study aims to assess the chronic effects of ambient fine particulates (PM) on the body composition of the elderly. From October 2015 to November 2016, a cross-sectional survey on 530 elderly (age > = 65 years) was conducted in the Taipei Basin, Taiwan. The body composition was measured by bioelectrical impedance analysis (InBody 120). One year exposure to air pollution was estimated using the Kriging method at the participant's residence. Multiple linear regression analysis, after adjustments for demographics and co-pollutants, was used to examine the effects of PM on body composition indices and force of handgrip. Changes in body composition for an interquartile (1.4 μm/m) increase in PM concentration included a 0.4 kg (95% confidence interval (CI): -0.31, -0.58; p < 0.0001) decrease in skeletal muscle mass (2.0%) and a 0.7 kg (95% CI: 0.47, 0.91; p < 0.0001) increase in body fat mass (3.6%). While PM reduced fat free mass in the upper extremities and trunk, but not in the lower extremities, it increased body fat mass in the three parts. There was no significant effect of PM on handgrip force. Higher physical activity (versus lower than median) was associated with less detrimental effect of PM on skeletal muscle mass and body fat mass (p values for interaction term: 0.009 and 0.013, respectively). Long-term PM exposure is associated with decreased skeletal muscle mass and increased body fat mass in the elderly, which can be ameliorated by physical activity.
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http://dx.doi.org/10.1038/s41598-019-47576-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6671961PMC
August 2019

(PG2) Ameliorates Cancer Symptom Clusters, as well as Improves Quality of Life in Patients with Metastatic Disease, through Modulation of the Inflammatory Cascade.

Cancers (Basel) 2019 Jul 25;11(8). Epub 2019 Jul 25.

Department of Radiation Oncology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan.

: Improving patients' quality of life (QoL) is a principal objective of all treatment in any clinical setting, including oncology practices. Cancer-associated inflammation is implicated in disease progression and worsening of patients' QoL. Conventional anticancer therapeutics while selectively eliminating cancerous cells, are evaded by stem cell-like cells, and associated with varying degrees of adverse effects, thus reducing patients' QoL. This necessitates novel therapeutic approaches with enhanced efficacy, minimal or no treatment-related adverse effects, and improved QoL in patients with cancer, especially those with metastatic/advance stage disease. : Sequel to our team's previous publication, the present study explores probable effects of (PG2) on cancer-related inflammatory landscape and known determinants of QoL, as well as the probable link between the two to provide mechanistic insight. In an exploratory double blind randomized controlled trial using patients with metastatic disease ( = 23), we comparatively evaluated the therapeutic efficacy of high (500 mg) or low (250 mg) dose PG2 administered intravenously (i.v.), with particular focus on its suggested anti-inflammatory function and the probable effect of same on QoL indices at baseline, then at weeks 4 and 8 post-PG2 treatment. : All 23 patients with metastatic disease treated with either low or high PG2 experienced reduced pain, nausea, vomiting, and fatigue, as well as better appetite and sleep, culminating in improved global QoL. This was most apparent in the high dose group, with significant co-suppression of pro-inflammatory interleukin (IL)-1β, IL-4, IL-6, IL-13, IL-17, monocytes chemotactic protein (MCP)1, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), tumor growth factor (TGF)-β1, interferon (IFN)-γ, and immune suppressors IL-10 and IL-12. Univariate and multivariate analyses revealed that IL-1β, IL-13 and GM-CSF are independent prognosticators of improved QoL. Conclusion: This proof-of-concept study provides premier evidence of functional association between PG2 anti-inflammatory effects and improved QoL in patients with advanced stage cancers, laying the groundwork for future larger cohort blinded controlled trials to establish the efficacy of PG2 as adjuvant anticancer therapy in metastatic or advanced stage clinical settings.
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http://dx.doi.org/10.3390/cancers11081054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721312PMC
July 2019

Chronic obstructive pulmonary disease patients have a higher risk of occurrence of pneumonia by air pollution.

Sci Total Environ 2019 Aug 26;677:524-529. Epub 2019 Apr 26.

School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address:

Epidemiological evidence has shown that air pollution is associated with chronic obstructive pulmonary disease (COPD). The objective of this study was to investigate the effects of air pollution on patients with COPD and pneumonia. A case-control study of patients who had undergone thoracentesis for pleural effusion drainage in a hospital was recruited for this study. COPD and non-COPD patients with pneumonia respectively served as the case and control groups. Increases in particulate matter of <2.5 μm in aerodynamic diameter (PM) and NO increased the risk of pneumonia in COPD patients (adjusted odd ratio (OR) = 4.136, 95% confidence interval (CI) = 1.740-9.832 for PM; adjusted OR = 1.841, 95% CI = 1.117-3.036 for NO). COPD patients with pneumonia had higher levels of CD14 in pleural effusion than did non-COPD with pneumonia (p < 0.05). An increase in CD14 of the pleural effusion increased the risk of pneumonia in COPD patients (adjusted OR = 1.126, 95% CI = 1.009-1.256). We further observed that an increase in Cu and a decrease in Zn in the pleural effusion increased the risk of pneumonia in COPD patients (adjusted OR = 1.005, 95% CI = 1.000-1.010 for Cu; adjusted OR = 0.988, 95% CI = 0.978-0.997 for Zn). In conclusion, our results suggest that COPD patients had a high risk of pneumonia occurring due to air pollution exposure.
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http://dx.doi.org/10.1016/j.scitotenv.2019.04.358DOI Listing
August 2019

Alterations by Air Pollution in Inflammation and Metals in Pleural Effusion of Pneumonia Patients.

Int J Environ Res Public Health 2019 02 27;16(5). Epub 2019 Feb 27.

School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.

Air pollution is known to increase the risk of pneumonia. However, the effects of air pollution on the pleural effusion of patients with pneumonia are unclear. The objective of this study was to investigate alterations in inflammatory⁻immune biomarkers by air pollution in patients with pneumonia by analyzing their pleural effusion. Patients who had undergone thoracentesis to drain their pleural effusion in a hospital were recruited for this study. Patients with pneumonia and those with congestive heart failure respectively served as the case and control groups. We observed that an increase of 1 ppb in one-year NO₂ was associated with a decrease of 0.105 ng/mL in cluster of differentiation 62 (CD62) (95% confidence interval (CI) = -0.085, -0.004, < 0.05) in the pleural effusion. Furthermore, we observed that an increase in one-year 1 ppb of NO₂ was associated with a decrease of 0.026 ng/mL in molybdenum (Mo) (95% CI = -0.138, -0.020, < 0.05). An increase in one-year 1 ppb of SO₂ was associated with a decrease of 0.531 ng/mL in zinc (95% CI = -0.164, -0.006, < 0.05). Also, an increase in one-year 1 ppb of O₃ was associated with a decrease of 0.025 ng/mL in Mo (95% CI = -0.372, -0.053, < 0.05). In conclusion, air pollution exposure, especially gaseous pollution, may be associated with the regulation of immune responses and changes in metal levels in the pleural effusion of pneumonia patients.
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http://dx.doi.org/10.3390/ijerph16050705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427250PMC
February 2019

Electrospun Polylactic Acid (PLLA) Microtube Array Membrane (MTAM)-An Advanced Substrate for Anticancer Drug Screening.

Materials (Basel) 2019 Feb 14;12(4). Epub 2019 Feb 14.

Graduate Institute of Biomedical Materials & Tissue Engineering, Taipei Medical University, Xinyi District, Taipei 11031, Taiwan.

The advent of personalized cancer treatment resulted in the shift from the administration of cytotoxic drugs with broad activity spectrum to a targeted tumor-specific therapy. Aligned to this development, the focus of this study revolved around the application of our novel and patented microtube array membrane (MTAM) in the US National Cancer Institute (NCI) developed an HFA (hollow fiber assay) assay; hereinafter known as MTAM/HFA. Electrospun poly-L-lactic acid (PLLA) MTAM was sterilized and loaded with cell lines/patient derived tumor cells (PDTC) and subcutaneously implanted into the backs of BALB/C mice. Anticancer drugs were administered at the respective time points and the respective MTAMs were retrieved and the viability tumor cells within were quantified with the MTT assay. Results revealed that the MTAMs were excellent culture substrate for various cancer cell lines and PDTCs (patient derived tumor cells). Compared to traditional HFA systems that utilize traditional hollow fibers, MTAM/HFA revealed superior drug sensitivity for a wide range of anticancer drug classes. Additionally, the duration for each test was <14 days; all this while capable of producing similar trend outcome to the current gold-standard xenograft models. These benefits were observed in both the in vitro and in vivo stages, making it a highly practical phenotypic-based solution that could potentially be applied in personalized medicine.
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http://dx.doi.org/10.3390/ma12040569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416630PMC
February 2019

FOSB⁻PCDHB13 Axis Disrupts the Microtubule Network in Non-Small Cell Lung Cancer.

Cancers (Basel) 2019 Jan 17;11(1). Epub 2019 Jan 17.

Marine Research Station, Institute of Cellular and Organismic Biology, Academia Sinica, Ilan 262, Taiwan.

Non-small cell lung cancer (NSCLC) is among the leading causes of human mortality. One reason for high rates of NSCLC mortality is that drug resistance is a major problem for both conventional chemotherapies and less-toxic targeted therapies. Thus, novel mechanistic insights into disease pathogenesis may benefit the development of urgently needed therapies. Here we show that FBJ murine osteosarcoma viral oncogene homolog B (FOSB) was induced by an antimicrobial peptide, tilapia piscidin-4 (TP4), through the dysregulation of mitochondrial Ca homeostasis in NSCLC cells. Transcriptomic, chromatin immunoprecipitation quantitative PCR, and immunocytochemical studies reveal that protocadherin-β13 () as a target of FOSB that was functionally associated with microtubule. Overexpression of either PCDHB13 or FOSB attenuated NSCLC growth and survival in vitro and in vivo. Importantly, downregulation of both FOSB and PCDHB13 was observed in NSCLC patients and was negatively correlated with pathological grade. These findings introduce the FOSB⁻PCDHB13 axis as a novel tumor suppressive pathway in NSCLC.
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http://dx.doi.org/10.3390/cancers11010107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357195PMC
January 2019