Search

Yin-Han Wang,1 Tsung-Ming Yang,2,3 Ming-Szu Hung,2– 4 Yu-Ching Lin,2– 4 Tien-Pei Fang,1,3 Tzu-Tzu Kuo,5,* Mark D Griffiths,6 Chung-Ying Lin7– 10,* 1Department of Respiratory Therapy, Chang Gung Memorial Hospital, Chiayi, Taiwan; 2Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi, Taiwan; 3Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi, Taiwan; 4Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 5Division of Respiratory Medicine, Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung City, Taiwan; 6International Gaming Research Unit, Psychology Department, Nottingham Trent University, Nottingham, UK; 7Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 8Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 9Biostatistics Consulting Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 10Department of Occupational Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan*These authors contributed equally to this workCorrespondence: Chung-Ying Lin, Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Tel +886-6-2353535 ext. 5106, Fax +886-6-2367981, Email cylin36933@gmail.com Tzu-Tzu Kuo, Division of Respiratory Medicine, Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung City, Taiwan, Email ed101231@gmail.comPurpose: Inhaled medication adherence is an important issue for patients with chronic obstructive pulmonary disease (COPD) because adhering to inhaled medications could substantially improve their health. However, patients with COPD may not be always adhere to the prescribed inhaled medications. Therefore, understanding the underlying reasons for patients with COPD adhering to inhaled medications is important. The present study used Theory of Planned Behavior (TPB) as a theoretical framework to develop the Intention of Inhaled Medication Adherence Scale (IMAS) and assess its psychometric properties.Patients and Methods: After reviewing papers using the TPB to design psychometric scales and the TPB scale development guidelines, 28 items were generated for expert evaluation. Eight experts reported that the 28 items all had good content validity (content validity index ranged from 0.88 to 1.00 at item-level; and from 0.981 to 0.987 at scale-level) comprising four factors. Following initial development, 235 patients with COPD (mean age 73.12 years; 93.6% males) completed the IMAS via interview with a respiratory therapist and a research assistant. The four-factor structure of the IMAS was evaluated using confirmatory factor analysis (CFA).Results: Nine IMAS items were removed because of low factor loadings or offending estimates. The 19-item IMAS was confirmed as having a four-factor structure supported by the CFA results (comparative fit index=1.00; Tucker-Lewis index=1.00; root mean square error of approximation=0.00; standardized root mean square residual=0.06).Conclusion: The 19-item IMAS had satisfactory psychometric properties in construct validity. The 19-item IMAS is an instrument that could help healthcare providers understand potential factors associated with adherence to inhaled medications among people with COPD.Keywords: adherence, confirmatory factor analysis, COPD, psychometrics

The California Medical Supervision Program is designed to protect agricultural workers from overexposure to Toxicity Category I and II organophosphate (OP) and carbamate (CB) pesticides by routinely monitoring their blood cholinesterase (ChE) activity levels. ChE testing is conducted at State-approved laboratories and electronically reported to the Department of Pesticide Regulation (DPR) and the Office of Environmental Health Hazard Assessment (OEHHA) for review. In 2015, OEHHA and DPR evaluated the effectiveness of the Program by analyzing ChE data from pesticide handlers performed between 2011 and 2013, which revealed issues with the data quality that hindered the evaluation process. Several interventions have been implemented since then to improve data quality and the overall function of the Program. A new evaluation was conducted in 2020 to 2021 using data from 2014 to 2019 to determine the effectiveness of the Program, Program compliance, and efficacy of the interventions. The analysis revealed similar data quality issues identified in the last evaluation, however, an improvement in data quality was observed. The number of individuals with ChE depression below the action level threshold have decreased in recent years, corresponding to the implementation of certain interventions, indicating that the effectiveness of the Program has improved. Spatial and temporal analysis showed the proportion of pre-exposure baseline tests inversely correlated with pesticide use data while routine follow-up ChE test results showed a positive correlation, indicating a high degree of Program compliance across the state. Major improvements in the data cleaning and analysis since the last evaluation have also improved the evaluation: pesticide handlers under the Program were able to be identified with more certainty and ChE depressions were able to be calculated with increased accuracy. However, further improvements to the data collection process could enhance future evaluations of the Program.

Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. Critically ill patients with COPD exacerbations may require invasive mechanical ventilation (IMV). Ventilator-associated pneumonia (VAP) commonly occurs in the intensive care unit (ICU) and is usually associated with high mortality. Current studies on the relationship between COPD and VAP are limited. This work compares the etiology and clinical outcomes of VAP between patients with and without COPD in Taiwan., Methods: This retrospective observational study was conducted at the Chiayi Chang Gung Memorial Hospital. Patients with VAP were enrolled between January 2015 and December 2019. The COPD diagnosis was based on post-bronchodilator pulmonary function tests. We compared the bacterial etiology, ICU and hospital stay length, IMV duration, and mortality., Results: A total of 175 patients with VAP were enrolled, 44% of whom presented pre-existing COPD. The disease severity on the day of admission was similar in both groups. Microorganisms were identified in 83 (47%) patients, with Pseudomonas aeruginosa, Acinetobacter spp., and Klebsiella pneumoniae being the most common pathogens. The proportion of multi-drug resistant isolates showed no significant differences between groups. Most patients underwent antibiotic treatment before VAP onset. The length of ICU and hospital stays and IMV duration after VAP onset were similar between groups, as well as ICU mortality, in-hospital mortality and 14-day mortality., Conclusion: Our study revealed that COPD was not associated with worse clinical outcomes in patients with VAP. No significant differences in bacterial etiology were observed between the two groups., Competing Interests: Conflicts of interest: Dr. Yi-Tsung Lin, an editorial board member at Journal of the Chinese Medical Association, had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

Introduction: While nutrition's critical role in enhancing respiratory health is acknowledged, the specific impacts of vitamins A and K on lung function remain largely unexplored. The study aimed to evaluate the relationships between vitamins A and K intake and lung function., Methods: The cross-sectional study focused on adults aged 20-79 with utilizing data from US National Health and Nutrition Examination Survey (NHANES) 2007-2012. Lung function was assessed by measuring forced expiratory volume (FEV1), forced vital capacity (FVC), and the ratio of these two values (FEV1/FVC). Regression model was performed to determine the associations between intake of vitamins A and K and outcomes., Results: Data of 10,034 participants (representing 142,965,892 adults in the US) were analyzed. After adjusting for relevant confounders, multivariable analysis revealed 1 μg/day increase of vitamin A intake was significantly associated with 0.03 ml increased FEV1 ( p = 0.004) and 0.04 ml increased forced vital capacity (FVC) ( p < 0.001). In addition, 1 μg/day increase in vitamin K intake was significantly associated with 0.11 ml increased FEV1 ( p = 0.022). Neither vitamin A and K intake was associated with FEV1/FVC or presence of airway obstruction., Conclusions: In relatively healthy population of the US, greater vitamin A or K intake was independently associated with better lung function assessed by spirometry. Benefits of such vitamins for pulmonary health should be confirmed in future randomized controlled trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen and Hung.)

The association between influenza infection and thromboembolism (TE) events, including cardiovascular events, cerebrovascular events, pulmonary embolism, and deep vein thrombosis, is supported by compelling evidence. However, there is a disparity in the risk factors that impact the outcomes of severe influenza-complicated TE in intensive care unit (ICU) patients. The objective of this study was to evaluate the outcomes of severe influenza-complicated TE in ICU patients and identify any associated risk factors., Methods: A retrospective cohort study was conducted, recruiting consecutive patients with TE events admitted to the ICU between December 2015 through December 2018 at our institution in Taiwan. The study included a group of 108 patients with severe influenza and a control group of 192 patients with severe community-acquired pneumonia. Associations between complicated TE, length of ICU stay, and 90-day mortality were evaluated using logistic regression analysis, and risk factors were identified using univariate and multivariate generalized linear regression analyses., Results: TE event prevalence was significantly higher in ICU patients with severe influenza than in ICU patients with severe CAP (21.3% vs. 5.7%, respectively; p < 0.05). Patients with severe influenza who developed TE experienced a significant increase in the ratio of mechanical ventilation use, length of mechanical ventilation use, ICU stay, and 90-day mortality when compared to patients without TE (all p < 0.05). The comparison of severe CAP patients with and without TE revealed no significant differences (p > 0.05). The development of thromboembolic events in patients with severe influenza or severe noninfluenza CAP is linked to influenza infection and hypertension (p < 0.05). Furthermore, complicated TE and the severity of the APACHE II score are risk factors for 90-day mortality in ICU patients with severe influenza (p < 0.05)., Conclusions: Patients with severe influenza and complicated TE are more likely to have an extended ICU stay and 90-day mortality than patients with severe CAP. The risk is significantly higher for patients with a higher APACHE II score. The results of this study may aid in defining better strategies for early recognition and prevention of severe influenza-complicated TE., (© 2024 The Author(s). Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Yu-Hung Fang,1 Meng-Jer Hsieh,2,3 Ming-Szu Hung,1,4,5 Yu-Ching Lin,1,3– 5 Liang-Tseng Kuo,5,6 Mong-Liang Lu,7 Bor-Show Tzang,8– 10 Vincent Chin-Hung Chen5,11 1Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan; 2Department of Respiratory Therapy, College of Medicine, Chang Gung University, Chiayi, Taiwan; 3Division of Pulmonary Infection and Critical Care Medicine, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan; 4Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi, Taiwan; 5Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 6Division of Sports Medicine, Department of Orthopaedic Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan; 7Department of Psychiatry, Wan Fang Hospital, and School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 8Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan; 9Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan; 10Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 11Department of Psychiatry, Chang Gung Memorial Hospital, Chiayi, TaiwanCorrespondence: Vincent Chin-Hung ChenDepartment of Psychiatry, Chang Gung Memorial Hospital, Chiayi Branch, No. 6, W. Sec., Jiapu Road, Puzi City, Chiayi County 61363, Taiwan, Republic of ChinaTel +886-5-3621000 ext. 2315Email cch1966@gmail.comBackground: Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) concentrations were reported to decrease in patients with advanced cancer. However, the clinical significance of DHEA and DHEAS concentrations in patients with NSCLC receiving chemotherapy (CT) has not been sufficiently documented.Objective: To evaluate the correlation between mental health and hormone concentrations on patients with advanced non-small-cell lung cancer (NSCLC).Materials and Methods: The present study was a cross-sectional analysis based on a self-reported psychological investigation. Salivary samples were collected from 22 patients with advanced NSCLC after CT and 17 healthy controls. The concentrations of DHEA, DHEAS, and cortisol were analyzed to investigate their associations with the results of self-reported questionnaires on psychological health.Results: Patients with advanced NSCLC exhibited significantly higher Patient Health Questionnaire (PHQ-9) and Startle, Physiological arousal, Anger, and Numbness-Chinese version (SPAN-C) scores, poorer health conditions, lower sleep quality, and more severe fatigue after CT than did healthy controls, and salivary concentrations of DHEA and DHEAS were significantly lower among patients after CT than among controls. DHEAS concentrations were negatively associated with depression scores (PHQ-9, r = − 0.496, P = 0.019) and fatigue scores (Brief Fatigue Inventory-Taiwan, r = − 0.562, P = 0.006).Conclusion: Patients with advanced NSCLC after CT had lower DHEA and DHEAS concentrations than did controls. Lower DHEAS concentrations were associated with higher fatigue and depression scores.Keywords: cancer-related fatigue, chemotherapy, DHEA, DHEAS, lung cancer

Ming-Szu Hung,1– 3 Yi-Chuan Chen,2,4 Tsung-Yu Huang,5– 7 Dong-Ru Ho,6,8,9 Chuan-Pin Lee,10 Pau-Chung Chen,11,12 Yao-Hsu Yang10,13,14 1Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi, Taiwan; 2Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi, Taiwan; 4Department of Emergency Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi, Taiwan; 5Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi, Taiwan; 6Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 7Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan; 8Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi, Taiwan; 9Department of Nursing, Chang Gung University of Science and Technology, Chiayi, Taiwan; 10Health Information and Epidemiology Laboratory, Chang Gung Memorial Hospital, Chiayi, Taiwan; 11Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health, Taipei, Taiwan; 12Department of Environmental and Occupational Medicine, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan; 13Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi, Taiwan; 14School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, TaiwanCorrespondence: Yao-Hsu Yang Email r95841012@ntu.edu.twBackground: Sexual problems are common in male lung cancer survivors. However, the development of erectile dysfunction (ED) in lung cancer patients after surgery has been rarely explored. In this study, we aimed to explore the incidence and risk factors of ED after lung cancer surgery.Methods: From 2000 to 2012, 6025 and 24,100 male patients were included in each matched cohort of lung cancer and non-lung cancer patients, respectively. Poisson regression analysis was used to calculate the incidence rate ratio (IRR) and 95% confidence interval (CI).Results: The incidence of ED was higher in the lung cancer cohort compared to the non-lung cancer cohort (38.47 vs 28.28 per 10,000 person-years) with an adjusted IRR (aIRR) of 1.34 (95% CI: 1.06– 1.70, p=0.014) after the confounders were adjusted for. An increased incidence of ED was observed in the lung cancer cohort aged 40– 54 years (aIRR: 5.44, 95% CI: 2.25– 13.15, p< 0.001), 55– 64 years (aIRR: 3.62, 95% CI: 1.61– 8.17, p=0.002) years, and anxiety (aIRR: 2.99, 95% CI: 1.81– 4.94, p< 0.001). In addition, a higher incidence of emergency room (ER) visits (aIRR: 2.19, 95% CI: 1.98– 2.42, p< 0.001) was observed in lung cancer patients with ED compared to those without ED.Conclusion: Our study results suggested that early surveillance and intervention of ED should be advocated in lung cancer patients after surgery.Keywords: lung cancer, surgery, erectile dysfunction

© 2015 The Authors. Background: Lung cancer is the leading cause of morbidity and death worldwide. Although the available lung cancer animal models have been informative and further propel our understanding of human lung cancer, they still do not fully rec

Yu-Hung Fang,1 Yao-Hsu Yang,2–5 Meng-Jer Hsieh,6,7 Ming-Szu Hung,8,9 Yu-Ching Lin1,8 1Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Puzi City, Chiayi County, Taiwan, R.O.C; 2Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Puzi City, Chiayi County, Taiwan, R.O.C; 3Center of Excellence for Chang Gung Research Datalink, Chang Gung Memorial Hospital, Chiayi Branch, Puzi City, Chiayi County, Taiwan, R.O.C; 4Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health, Taipei City, Taiwan, R.O.C; 5School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Guishan Township, Taoyuan County, Taiwan, R.O.C; 6Department of Respiratory Therapy, College of Medicine, Chang Gung University, Guishan Township, Taoyuan County, Taiwan, R.O.C; 7Division of Pulmonary Infection and Critical Care Medicine, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Puzi City, Chiayi County, Taiwan, R.O.C; 8Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi Campus, Puzi City, Chiayi County, Taiwan, R.O.C; 9School of Medicine, College of Medicine, Chang Gung University, Guishan Township, Taoyuan County, Taiwan, R.O.CCorrespondence: Yu-Ching LinDivision of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, No.6, W. Sec., Jiapu Road, Puzi City, Chiayi County 61363, Taiwan, R.O.CTel +886 5 362 1000 Ext 2762Fax +886 5 362 3005Email lin0927@cgmh.org.twPurpose: Concurrent proton pump inhibitor (PPI) use might reduce the plasma concentration of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Clinically, the adverse effect of PPIs on patients with non-small cell lung cancer (NSCLC) treated with first-line EGFR TKIs remains controversial. This study was conducted to evaluate whether the combined use of gefitinib with PPIs affected NSCLC outcomes.Patients and methods: We performed a nationwide cohort study of patients newly diagnosed with NSCLC between 1997 and 2013 using the Taiwan Cancer Registry and Taiwan National Health Insurance databases. We identified patients who were treated with first-line EGFR TKIs and analyzed the association between use of PPIs and TKI treatment outcome. We defined the coverage ratio of PPIs as duration of PPI treatment in days divided by duration of TKIs in days. Patients who exhibited an overlap of >20% between PPI and TKI usage days were defined as having a high coverage ratio.Results: A total of 1278 patients were treated with first-line gefitinib, 309 of which took PPIs at the same time and 145 had a high PPI coverage ratio. Patients had similar time to failure regardless of their PPI coverage ratio during gefitinib treatment. However, higher PPI coverage ratio significantly decreased overall survival (OS) compared with that of patients with a lower PPI coverage ratio or no PPI treatment in univariate analysis (median OS, 13.5, 16.7, and 21.8 months, respectively, p

Casein kinase II (CK2) inhibitors suppress cancer cell growth. In this study, we examined the inhibitory effects of a novel CK2 inhibitor, hematein, on tumor growth in a murine xenograft model. We found that in lung cancer cells, hematein inhibited cancer

Background: A 2-level factorial pilot study was conducted in 2007 just before starting a randomized clinical trial comparing tomotherapy and conventional radiotherapy (CR) to reduce cardiac and pulmonary adverse effects in breast cancer, considering tumor laterality (left/right), target volume (with/without nodal irradiation), surgery (tumorectomy/mastectomy), and patient position (prone/supine). The study was revisited using a penalty score based on the recently developed mean absolute dose deviation (MADD). Methods: Eight patients with a unique combination of laterality, nodal coverage, and surgery underwent dual tomotherapy and CR treatment planning in both prone and supine positions, providing 32 distinct combinations. The penalty score was applied using the weighted sum of the MADDs. The Lenth method for unreplicated 2-level factorial design was used in the analysis. Results: The Lenth analysis identified nodal irradiation as the active main effect penalizing the dosimetry by 1.14 Gy (P = 0.001). Other significant effects were left laterality (0.94 Gy), mastectomy (0.61 Gy), and interactions between left mastectomy (0.89 Gy) and prone mastectomy (0.71 Gy), with P-values between 0.005 and 0.05. Tomotherapy provided a small reduction in penalty (reduction of 0.54 Gy) through interaction with nodal irradiation (P = 0.080). Some effects approached significance with P-values > 0.05 and ≤ 0.10 for interactions of prone × mastectomy × left (0.60 Gy), nodal irradiation × mastectomy (0.59 Gy), and prone × left (0.55 Gy) and the main effect prone (0.52 Gy). Conclusions: The historical dosimetric analysis previously revealed the feasibility of tomotherapy, but a conclusion could not be made. The MADD-based score is promising, and a new analysis highlights the impact of factors and hierarchy of priorities that need to be addressed if major gains are to be attained.

Molecular techniques that recover unknown sequences next to a known sequence region have been widely applied in various molecular studies, such as chromosome walking, identification of the insertion site of transposon mutagenesis, fusion gene partner, and chromosomal breakpoints, as well as targeted sequencing library preparation. Although various techniques have been introduced for efficiency enhancement, searching for relevant single molecular event present in a large-sized genome remains challenging. Here, the optimized ligation-mediated polymerase chain reaction (PCR) method was developed and successfully identified chromosomal breakpoints far away from the exon of the new exon junction without the need for nested PCR. In addition to recovering unknown sequences next to a known sequence region, the high efficiency of the method could also improve the performance of targeted  next-generation sequencing (NGS)., Competing Interests: All authors declare that there is no competing interests for the study., (© The Author(s) 2024. Published by Oxford University Press.)

Rationale: The prevalence, clinical characteristics, and outcomes of invasive pulmonary aspergillosis in patients with severe community-acquired pneumonia (CAP) in intensive care units remain underestimated because of the lack of a disease-recognition scheme and the inadequacy of diagnostic tests., Objectives: To identify the prevalence, risk factors, and outcomes of severe CAP complicated with invasive pulmonary aspergillosis (IPA) in intensive care units (ICUs)., Methods: We conducted a retrospective cohort study including recruited 311 ICU-hospitalized patients with severe CAP without influenza or with influenza. Bronchoalveolar lavage fluid (BALF) samples were from all patients and subjected to mycological testing. Patients were categorized as having proven or probable Aspergillus infection using a modified form of the AspICU algorithm comprising clinical, radiological, and mycological criteria., Measurements and Main Results: Of the 252 patients with severe CAP and 59 influenza patients evaluated, 24 met the diagnostic criteria for proven or probable Aspergillus infection in the CAP group and 9 patients in the influenza group, giving estimated prevalence values of 9.5% and 15.3%, respectively. COPD and the use of inhaled corticosteroids were independent risk factors for IPA. IPA in patients with severe CAP was significantly associated with the duration of mechanical support, the length of ICU stay, and the 28-day mortality., Conclusions: An aggressive diagnostic approach for IPA patients with severe CAP and not only influenza or COVID-19 should be pursued. Further randomized controlled trials need to evaluate the timing, safety, and efficacy of antifungal therapy in reducing IPA incidence and improving clinical outcomes., (© 2024. The Author(s).)

Jrhau Lung,1 Kuan-Liang Chen,2 Chien-Hui Hung,3 Chih-Cheng Chen,4,5 Ming-Szu Hung,5–7 Yu-Ching Lin,5–7 Ching-Yuan Wu,8 Kuan-Der Lee,9 Neng-Yao Shih,10 Ying Huang Tsai11,12 1Department of Medical Research and Development, Chang Gung Memorial Hospital, Chiayi, 2Department of Endodontics, ChiMei Medical Center, Tainan, 3Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, 4Division of Hematology and Oncology, Chang Gung Memorial Hospital, Chiayi, 5Department of Medicine, Chang Gung University, Taoyuan, 6Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi, 7Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, 8Department of Chinese Medicine; Chang Gung Memorial Hospital, Chiayi, 9Department of Hematology and Oncology, Taipei Medical University Hospital, Taipei, 10National Institute of Cancer Research, National Health Research Institutes, Tainan, 11Department of Respiratory Care, College of Medicine, Chang Gung University, Taoyuan, 12Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan Abstract: Unlimited growth of cancer cells requires an extensive nutrient supply. To meet this demand, cancer cells drastically upregulate glucose uptake and metabolism compared to normal cells. This difference has made the blocking of glycolysis a fascinating strategy to treat this malignant disease. α-enolase is not only one of the most upregulated glycolytic enzymes in cancer cells, but also associates with many cellular processes or conditions important to cancer cell survival, such as cell migration, invasion, and hypoxia. Targeting α-enolase could simultaneously disturb cancer cells in multiple ways and, therefore, is a good target for anticancer drug development. In the current study, more than 22 million chemical structures meeting the criteria of Lipinski’s rule of five from the ZINC database were docked to α-enolase by virtual screening. Twenty-four chemical structures with docking scores better than that of the enolase substrate, 2-phosphoglycerate, were further screened by the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties prediction. Four of them were classified as non-mutagenic, non-carcinogenic, and capable of oral administration where they showed steady interactions to α-enolase that were comparable, even superior, to the currently available inhibitors in molecular dynamics (MD) simulation. These compounds may be considered promising leads for further development of the α-enolase inhibitors and could help fight cancer metabolically. Keywords: α-enolase inhibitor, virtual screening, molecular dynamics simulation, glycolysis, metabolism

The drug discovery of G protein-coupled receptors (GPCRs) superfamily using computational models is often limited by the availability of protein three-dimensional (3D) structures and chemicals with experimentally measured bioactivities. Orphan GPCRs without known ligands further complicate the process. To enable drug discovery for human orphan GPCRs, multitask models were proposed for predicting half maximal effective concentrations (EC 50 ) of the pairs of chemicals and GPCRs. Protein multiple sequence alignment features, and physicochemical properties and fingerprints of chemicals were utilized to encode the protein and chemical information, respectively. The protein features enabled the transfer of data-rich GPCRs to orphan receptors and the transferability based on the similarity of protein features. The final model was trained using both agonist and antagonist data from 200 GPCRs and showed an excellent mean squared error (MSE) of 0.24 in the validation dataset. An independent test using the orphan dataset consisting of 16 receptors associated with less than 8 bioactivities showed a reasonably good MSE of 1.51 that can be further improved to 0.53 by considering the transferability based on protein features. The informative features were identified and mapped to corresponding 3D structures to gain insights into the mechanism of GPCR-ligand interactions across the GPCR family. The proposed method provides a novel perspective on learning ligand bioactivity within the diverse human GPCR superfamily and can potentially accelerate the discovery of therapeutic agents for orphan GPCRs., (© 2024. The Author(s).)

Objective: To explore the short- and long-term effects of lower-limb endurance training on chronic obstructive pulmonary disease outpatients., Design: Prospective quasi-experimental study., Setting: 1383-bed teaching hospital in Taiwan., Participants: Overall, 69 outpatients diagnosed with chronic obstructive pulmonary disease were enrolled. A total of 60 patients completed the study., Intervention: Training group: Lower-limb endurance training; control group: Education only., Main Measures: The modified medical research council score, chronic obstructive pulmonary disease assessment test score, pulmonary function test, and number of acute exacerbation within a year., Results: The training group showed significant improvement in the chronic obstructive pulmonary disease assessment test total score, modified medical research council score (both P  < 0.001) at third month sustaining to 12th month ( P  < 0.001) and presented less events of acute exacerbation ( P  = 0.011) at 12th month. The chronic obstructive pulmonary disease assessment test decreased by 8 points sustaining to 12th month. The training group presented significant post-training functional capacity improvements in 6-min walking distance, lowest oxygen saturation during 6-min walking test, peak workload, maximum inspiratory/ expiratory pressures, and calf circumference., Conclusions: The lower-limb endurance training improved perceived dyspnea in daily activity and health status after completion of training and sustaining for a year. The lower-limb endurance training alleviated disease impacted on reduced acute exacerbations., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Fucoidans are a class of long chain sulfated polysaccharides and have multiple biological functions. Herein, four natural fucoidans extracted from Fucus vesiculosus, F. serratus, Laminaria japonica and Undaria pinnatifida, were tested for their HCoV-OC43 inhibition and found to demonstrate EC 50 values ranging from 0.15 to 0.61 µg/mL. That from U. pinnatifida exhibited the most potent anti-HCoV-OC43 activity with an EC 50 value of 0.15 ± 0.02 µg/mL, a potency largely independent of its sulfate content. Comparison of the gene expression profiles of fucoidan-treated and untreated cells infected with HCoV-OC43 revealed that fucoidan treatment effectively diminished HCoV-OC43 gene expressions associated with induced chemokines, cytokines and viral activities. Further studies using a highly fucoidan-resistant HCoV-OC43 determined that fucoidan inhibited HCoV-OC43 infection via interfering with viral entry and led to the identification of the specific site on the N-terminal region of spike protein, that located adjacent to the host cell receptor binding domain, targeted by the virus. Furthermore, in a SARS-CoV-2 pseudovirus neutralization assay, fucoidan also blocked SARS-CoV-2 entry. In vitro and in vivo, fucoidan decreased SARS-CoV-2 viral loads and inhibited viral infection in Calu-3 or Vero E6 cells and SARS-CoV-2 infected hamsters, respectively. Fucoidan was also found to inhibit furin activity, and reported furin inhibitors were found to inhibit viral infection by wild type HCoV-OC43 or SARS-CoV-2. Accordingly, we conclude that fucoidans inhibit coronaviral infection by targeting viral spike protein and host cell furin to interfere with viral entry., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Positive fluid balance and tissue fluid accumulation are associated with adverse outcomes in sepsis. Vascular endothelial growth factor (VEGF) increases in sepsis, promotes vascular permeability, and may affect tissue fluid accumulation and oxygenation. We used near-infrared spectroscopy (NIRS) to estimate tissue hemoglobin (Hb) oxygenation and water (H 2 O) levels to investigate their relationship with serum VEGF levels., Material and Methods: New-onset severe sepsis patients admitted to the intensive care unit were enrolled. Relative tissue concentrations of oxy-Hb ([HbO 2 ]), deoxy-Hb ([HbR]), total Hb ([HbT]), and H 2 O ([H 2 O]) were estimated by near-infrared spectroscopy (NIRS) for three consecutive days and serum VEGF levels were measured. Comparisons between oliguric and non-oliguric patients were conducted and the correlations between variables were analyzed., Results: Among 75 eligible patients, compared with non-oliguric patients, oliguric patients were administrated more intravascular fluids (median [IQR], 1926.00 [1348.50-3092.00] mL/day vs. 1069.00 [722.00-1486.75] mL/day, p < 0.001) and had more positive daily net intake and output (mean [SD], 1,235.06 [1303.14] mL/day vs. 313.17 [744.75] mL/day, p = 0.012), lower [HbO 2 ] and [HbT] over the three-day measurement (analyzed by GEE p = 0.01 and 0.043, respectively) and significantly higher [H 2 O] on the third day than on the first two days (analyzed by GEE p = 0.034 and 0.018, respectively). Overall, serum VEGF levels were significantly negatively correlated with [HbO 2 ] and [HbT] (rho = - 0.246 and - 0.266, p = 0.042 and 0.027, respectively) but positively correlated with [H 2 O] (rho = 0.449, p < 0.001). Subgroup analysis revealed a significant correlation between serum VEGF and [H2O] in oliguric patients (rho = 0.532, p = 0.003). Multiple regression analysis determined the independent effect of serum VEGF on [H 2 O] (standardized coefficient = 0.281, p = 0.038)., Conclusions: In severe sepsis, oliguria relates to higher positive fluid balance, lower tissue perfusion and oxygenation, and progressive tissue fluid accumulation. Elevated serum VEGF is associated with worsening tissue perfusion and oxygenation and independently affects tissue fluid accumulation., (© 2023. The Author(s).)

B cells have recently become a focus in breast cancer pathology due to their influence on tumour regression, prognosis, and response to treatment, besides their contribution to antigen presentation, immunoglobulin production, and regulation of adaptive responses. As our understanding of diverse B cell subsets in eliciting both pro- and anti-inflammatory responses in breast cancer patients increases, it has become pertinent to address the molecular and clinical relevance of these immune cell populations within the tumour microenvironment (TME). At the primary tumour site, B cells are either found spatially dispersed or aggregated in so-called tertiary lymphoid structures (TLS). In axillary lymph nodes (LNs), B cell populations, amongst a plethora of activities, undergo germinal centre reactions to ensure humoral immunity. With the recent approval for the addition of immunotherapeutic drugs as a treatment option in the early and metastatic settings for triple-negative breast cancer (TNBC) patients, B cell populations or TLS may resemble valuable biomarkers for immunotherapy responses in certain breast cancer subgroups. New technologies such as spatially defined sequencing techniques, multiplex imaging, and digital technologies have further deciphered the diversity of B cells and the morphological structures in which they appear in the tumour and LNs. Thus, in this review, we comprehensively summarise the current knowledge of B cells in breast cancer. In addition, we provide a user-friendly single-cell RNA-sequencing platform, called "B singLe cEll rna-Seq browSer" (BLESS) platform, with a focus on the B cells in breast cancer patients to interrogate the latest publicly available single-cell RNA-sequencing data collected from diverse breast cancer studies. Finally, we explore their clinical relevance as biomarkers or molecular targets for future interventions.

Cannabinoid receptor 1 (CB1) is a G protein-coupled receptor and a therapeutic target for metabolic disorders. Numerous CB1 antagonists have been developed, but their functional selectivities and bias towards G protein or β-arrestin signaling have not been systemically characterized. In this study, we analyzed the binding affinities and downstream signaling of two series of pyrazole derivatives bearing 1-aminopiperidine (Series I) or 4-aminothiomorpholine 1,1-dioxide (Series II) moieties, as well as the well-known CB1 antagonists rimonabant and taranabant. Analyses of the results for the Series I and II derivatives showed that minor structure modifications to their functional groups and especially the incorporation of 1-aminopiperidine or 4-aminothiomorpholine 1,1-dioxide motifs can profoundly affect their bias toward G protein or β-arrestin signaling, and that their binding affinity and functional activity can be disassociated. Docking and molecular dynamics simulations revealed that the binding modes of Series I and II antagonists differed primarily in that Series I antagonists formed an additional hydrogen bond with the receptor, whereas those in Series II formed a water bridge., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Aim: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs)-associated Clostridioides difficile infection (CDI) among lung cancer patients have been reported in case reports and adverse events reporting system databases in the United States and Japan, but clinical data remained insufficient. This study aims to evaluate CDI in lung cancer patients receiving EGFR-TKIs., Methods: We conducted a retrospective cohort study using multi-institutional electronic medical records database. We included patients aged older than 20 years diagnosed with lung cancer and treated with EGFR-TKIs (gefitinib, erlotinib, afatinib). We defined EGFR-TKI initiation date as the index date and occurrence of diarrhea with CDI or without CDI as the event date. We followed patients from the index date until the event date, ICU admission, death, or 12/31/2019., Results: We included 2242 diarrhea patients, 51 were EGFR-TKI with CDI cohort, and 2191 were diarrhea without CDI cohort. Patients who were concurrently taking antibiotics (hazard ratio [HR], 3.30; 95% CI, 1.67-6.5) and systemic steroids (HR, 4.9; 95% CI, 2.65-9.06) had an increased risk of CDI. First-generation EGFR-TKIs tended to be associated with an increased risk of CDI compared with afatinib (HR, 1.81, 95% CI, 0.94-3.47). EGFR-TKI with CDI had a higher ICU admission rate (HR, 3.42, 95% CI, 1.98-5.91) and mortality rate (HR, 2.34, 95% CI, 1.67-3.28) than diarrhea without CDI., Conclusion: Patients with CDI had higher ICU admission rates and mortality rates than those without CDI. Concurrent use of antibiotics and systemic steroids were risk factors for CDI among patients with lung cancer receiving EGFR-TKIs. Afatinib was not associated with a higher risk of CDI than first-generation EGFR-TKIs., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2022 Chung et al.)

Purpose: Previous retrospective studies reported that proton-pump inhibitors (PPIs) may decrease the efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) including gefitinib and erlotinib. Afatinib had a wider soluble pH range, with possible fewer interactions with antacids. However, clinical data were limited. Thus, this study aimed to evaluate the negative impact of PPIs on afatinib., Patients and Methods: This retrospective cohort study included patients who are newly diagnosed with non-small cell lung cancer (NSCLC) from 2014 to 2019 using the Chang Gung Research Database. We identified patients who were treated with first-line afatinib and analyzed the association between the PPI and afatinib treatment outcomes., Results: A total of 1418 patients were treated with first-line afatinib and followed up for 6 years. First-line afatinib was administered to 918 eligible patients, and 330 had afatinib with PPIs. The combination use of PPIs and afatinib significantly decreased the overall survival (OS) compared with that of patients using afatinib only (median OS: 33.2 and 25.1 months, p < 0.01) and multivariate analyses (Combination use: hazard ratio: 1.29; 1.05-1.59, p = 0.01). The percentages of patients who were able to receive 2nd line therapy also significantly decreased in afatinib with PPI cohort., Conclusion: The concurrent use of PPIs was associated with lower OS in patients with EGFR-mutant lung cancer under the first-line afatinib treatment but not associated with TTF., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2022 Ho et al.)

Purposes: This study investigated the prevalence and clinical outcomes of pulmonary bacterial co-infections and secondary bacterial infections in patients with severe influenza pneumonitis., Methods: We retrospectively analyzed the data of adult patients with severe influenza pneumonitis admitted to medical ICUs. Bacterial co-infections and secondary bacterial infections were identified. The risk factors of bacterial infection were evaluated. The outcomes of patients regarding co-infection or secondary bacterial infection were analyzed., Results: We identified 117 critically ill patients with laboratory-confirmed influenza pneumonitis admitted to the medical ICUs. Klebsiella pneumoniae (31.4%) and Staphylococcus aureus (22.8%) were the most identified bacteria in patients with bacterial co-infection. A high proportion of methicillin-resistant Staphylococcus aureus (17.1%) was noted. Liver cirrhosis and diabetes mellitus were the independent risk factors for bacterial co-infection. Acinetobacter baumannii (30.7%) and S. aureus (23.1%) were the most often identified bacteria in patients with secondary bacterial pneumonia. Patients with secondary bacterial infections had a longer duration of mechanical ventilation, and longer ICU and hospital stay., Conclusions: High rates of drug-resistant bacterial co-infections and secondary bacterial infections were identified in patients with severe influenza pneumonitis requiring ICU care and were associated with more morbidity in these patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Breast cancer is one of the most important medical problems. In this paper, we report the results of using neural networks for breast cancer diagnosis. The theoretical advantage is that posterior probabilities of malignancy can be estimated directly, and coupled with resampling techniques such as the bootstrap, distributions of the probabilities can also be obtained. These allow a researcher much more insight into the variability of estimated probabilities. Another contribution is that we present an integrative approach to building neural network models. The issues of model selection, feature selection, and function approximation are discussed in some detail and illustrated with the application to breast cancer diagnosis. Journal of the Operational Research Society (2002) 53, 222-231. DOI: 10.1057/sj/jors/2601276 Keywords: neural networks; artificial intelligence; medicine; statistics

Actions that do not have instrumental goals can communicate social goals that are not rituals. Many non-instrumental actions such as bowing or kissing communicate a commitment to or roles in dyadic relationships. What is unclear is when people understand such actions in terms of ritual and when they understand them in terms of relationships.

For rapid and unlimited cell growth and proliferation, cancer cells require large quantities of nutrients. Many metabolic pathways and nutrient uptake systems are frequently reprogrammed and upregulated to meet the demand from cancer cells, including the demand for lipids. The lipids for most adult normal cells are mainly acquired from the circulatory system. Whether different cancer cells adopt identical mechanisms to ensure sufficient lipid supply, and whether the lipid demand and supply meet each other, remains unclear, and was investigated in lung cancer cells. Results showed that, despite frequent upregulation in de novo lipogenesis and the lipid transporter system, different lung cancer cells adopt different proteins to acquire sufficient lipids, and the lipid supply frequently exceeds the demand, as significant amounts of lipids stored in the lipid droplets could be found within lung cancer cells. Lipid droplet surface protein, PLIN3, was found frequently overexpressed since the early stage in lung cancer tissues. Although the expression is not significantly associated with a specific gender, age, histology type, disease stage, and smoking habit, the frequently elevated expression of PLIN3 protein indicates the importance of lipid droplets for lung cancer. These lipid droplets are not only for nutrient storage, but are also crucial for tumor growth and proliferation, as well as survival in starvation. These results suggest that manipulation of lipid droplet formation or TG storage in lung cancer cells could potentially decrease the progression of lung cancer. Further exploration of lipid biology in lung cancer could help design novel treatment strategies.

Background: Tissue oedema affects tissue perfusion and interferes with the monitoring of tissue oxygenation in patients with severe sepsis. However, the underlying mechanisms remain unclear. We used a wireless near-infrared spectroscopy (NIRS) device that transmits tri-wavelength light to quantify tissue haemoglobin (Hb) and water (H 2 O) content. We estimated tissue H 2 O in severe sepsis patients and healthy controls, compared their difference, and investigated the correlation of tissue H 2 O with systemic haemodynamics and its impact on tissue oxygenation., Methods: Seventy-seven adult patients with new-onset severe sepsis admitted to the intensive care unit within 72 h and 30 healthy volunteers (controls) were enrolled. The NIRS device was placed on the participant's leg to estimate the relative tissue concentrations of oxy-Hb ( [HbO 2 ] ), deoxy-Hb ( [HbR] ), total Hb ( [HbT] ), and H 2 O ( [H 2 O] ) at rest for three consecutive days. Two-sample t -test or Mann-Whitney U test, chi-square test, and generalised estimating equations (GEEs) were used for comparisons., Results: In severe sepsis patients, the [H 2 O] in the anterior tibia was higher [mean (standard deviation, 95% confidence interval), 10.57 (3.37, 9.81-11.34) vs. 7.40 (1.89, 6.70-8.11)] and the [HbO 2 ] , [HbT] , and tissue Hb oxygen saturation (StO 2 ) were lower [0.20 (0.01, 0.20-0.20) vs. 0.22 (0.01, 0.22-0.23), 0.42 (0.02, 0.42-0.43) vs. 0.44 (0.02, 0.44-0.45), and 47.25% (1.97%, 46.80-47.70%) vs. 49.88% (1.26%, 49.41-50.35%), respectively] than in healthy controls in first-day measurements. GEE analysis revealed significant differences in [H 2 O] , [HbO 2 ] , [HbT] , and StO 2 between groups over three consecutive days (all P≤0.001) . In addition, [HbO 2 ] and StO 2 levels gradually decreased over time in the patient group. A negative correlation was observed between [H 2 O] and [HbO 2 ] and StO 2 , which became more obvious over time (day 1: r=-0.51 and r=-0.42, respectively; both P<0.01; day 3: r=-0.67 and r=-0.63, respectively, both P<0.01). Systolic arterial pressure was positively related to [H 2 O] (r=0.51, P<0.05, on day 1) but was not associated with tissue oxygenation parameters., Conclusions: NIRS can be used to quantify tissue H 2 O. Severe sepsis patients have increased tissue H 2 O, which responds to changes in arterial blood pressure and affects tissue oxygenation., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-22-127/coif). CKL received grants from the Chang Gung Medical Foundation of Taiwan (Nos. CORPG6E0111, CORPG6E0112, and CORPG6E0113) for the study. The other authors have no conflicts of interest to declare., (2022 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

ROS1 fusion genes are rare but important driver genes in lung cancer. Owing to their rarity, many clinicopathological features and treatment responses for each ROS1 fusion variant are still largely unknown and require further investigation. RNA is the preferable template for the ROS1 fusion gene screening, but deterioration of RNA in FFPE often makes the detection challenging. To resolve the difficulty, a targeted chromosomal breakpoint sequencing method was developed for searching the ROS1 fusion gene, and was compared with fluorescence in situ hybridization, immunohistochemistry, RT-qPCR using 260 lung cancer samples of Southern Taiwan. The results showed that ROS1 -altered cases were present at low frequencies, did not share distinct clinicopathological features, and often carried other driver mutations. The performance of the targeted sequencing assay was superior to the RT-qPCR in ROS1 fusion gene identification when the cDNAs were from FFPE samples, but long-read DNA sequencing and fresh-frozen samples would be better to revolve all fusion genes. Precise determination of all ROS1 fusion variants and concomitant driver mutations using both genomic DNA and RNA would be required to help improve the treatment of patients with ROS1 alterations., Competing Interests: None., (AJCR Copyright © 2022.)

This study aims to investigate the role of 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) in early prediction of response and survival following epithelial growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy in patients with advanced lung adenocarcinomas and EGFR mutations. Thirty patients with stage IIIB/IV lung adenocarcinomas and EGFR mutations receiving first-line EGFR-TKIs were prospectively evaluated between November 2012 and May 2015. EGFR mutations were quantified by delta cycle threshold (dCt). 18 F-FDG PET/CT was performed before and 2 weeks after treatment initiation. PET response was assessed based on PET Response Criteria in Solid Tumors (PERCIST). Baseline and percentage changes in the summed standardized uptake value, metabolic tumor volume (bsumMTV and ΔsumMTV, respectively), and total lesion glycolysis of ≤5 target lesions/patient were calculated. The association between parameters (clinical and PET) and non-progression disease after 3 months of treatment in CT based on the Response Evaluation Criteria in Solid Tumors Version 1.1 (nPD 3mo ), progression-free survival (PFS), and overall survival (OS) were tested. The median follow-up time was 19.6 months. The median PFS and OS were 12.0 and 25.3 months, respectively. The PERCIST criteria was an independent predictor of nPD 3mo ( p = 0.009), dCt ( p = 0.014) and bsumMTV ( p = 0.014) were independent predictors of PFS, and dCt ( p = 0.014) and ΔsumMTV ( p = 0.005) were independent predictors of OS. 18 F-FDG PET/CT achieved early prediction of outcomes in patients with advanced lung adenocarcinomas and EGFR mutations receiving EGFR-TKIs.

Indoleamine 2,3-dioxygenase-1 (IDO1) is a potential target for the next generation of cancer immunotherapies. We describe the development of two series of IDO1 inhibitors incorporating a N-hydroxy-thiophene-carboximidamide core generated by knowledge-based drug design. Structural modifications to improve the cellular activity and pharmacokinetic (PK) properties of the compounds synthesized, including extension of the side chain of the N-hydroxythiophene-2-carboximidamide core, resulted in compound 27a, a potent IDO1 inhibitor which demonstrated significant (51%) in vivo target inhibition on IDO1 in a human SK-OV-3 ovarian xenograft tumor mouse model. This strategy is expected to be applicable to the discovery of additional IDO1 inhibitors for the treatment of other diseases susceptible to modulation of IDO1., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Part of this work was financially supported by RDD Lab, Inc. The authors declare the following competing financial interest(s): Chia-Hwa Chang is a current employee in RDD Lab, Inc. Jin-Chen Yu is a current employee in Bio-Thera Solutions Ltd., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: Studies have indicated that individuals taking aspirin have a reduced risk of cancers and have also established chemo-preventive benefit of aspirin in colorectal cancer. However, research on the association between aspirin use and the survival in patients with lung cancer has revealed inconsistent results. In this study, we investigated the effect of aspirin use on the survival of inoperable non-small cell lung cancer (NSCLC) patients., Methods: We identified a cohort of 38,842 patients diagnosed with NSCLC between 2000 and 2012 using the Taiwan's National Health Insurance Research Database and used propensity score matching to reduce possible confounding factors. In total, 9864 patients (4932 matched pairs) were included in the matched cohort. Aspirin exposure was analyzed to identify a possible association with mortality in patients with inoperable NSCLC. Time-dependent Cox regression models were used to calculate the hazard ratios (HRs) and the 95% confidence intervals (95% CIs) that corresponded with aspirin exposure., Results: A total of 4979 patients used aspirin at the time of diagnosis of NSCLC. The median overall survival (OS) of the aspirin users was 1.73 (interquartile range, 0.94-3.53) years compared with the 1.30 (interquartile range, 0.69-2.62) years of the non-aspirin users. The Cox proportional hazard model with the time-dependent covariate revealed that aspirin use was associated with a significantly longer OS (HR: 0.83, 95.0% CI: 0.80-0.86). After controlling the sociodemographic characteristics (age, sex, income, and level of urbanization) and lung cancer treatments by propensity score matching, the aspirin users still had a significantly longer OS than the non-aspirin users (HR: 0.79, 95.0% CI: 0.75-0.83)., Conclusion: Aspirin use is associated with a longer OS in patients with inoperable NSCLC, suggesting that aspirin has a potential anticancer effect. These results warrant further randomized clinical trials to evaluate the actual role of aspirin in the treatment of NSCLC patients., (© 2021. The Author(s).)

Cullin 4A (Cul4A) reportedly has oncogenic roles in several cancer types by regulating tumor suppressors through the ubiquitination and proteolysis of the tumor suppressor. In addition, Cul4A is associated with chemosensitivity to chemotherapy drugs. This study investigated the association between Cul4A and lung cancer cell chemosensitivity to paclitaxel, particularly with respect to the role of the p33 inhibitor of the growth 1 (p33ING1b) tumor suppressor. The results showed that the Cul4A knockdown upregulated the p33ING1b expression in lung cancer cells and increased the lung cancer cell and mice tumor xenograft chemosensitivity to paclitaxel. The Cul4A knockdown also inhibited the growth and increased the apoptosis in the tumor xenografts treated with paclitaxel. Notably, the p33ING1b overexpression increased the lung cancer cell chemosensitivity to paclitaxel, but the p33ING1b knockdown reduced the chemosensitivity. A further analysis demonstrated that Cul4A regulates the expression of p33ING1b through protein-protein interactions, ubiquitination, and protein degradation. In conclusion, the present findings suggest that Cul4A mediates the chemosensitivity of lung cancer cells to paclitaxel by regulating p33ING1b. These findings may offer novel insights into future therapeutic strategies for lung cancer that target Cul4A., Competing Interests: None., (AJTR Copyright © 2021.)

Annexin A1 (ANXA1) has been reported to promote tumor growth and resistance to chemotherapy drugs in lung cancer cells. In this study, we focused on the association of ANXA1 and chemosensitivity with a third generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), Osimertinib, in lung cancer cells with EGFR mutations. The overexpression of ANXA1 was observed in the lung cancer cells studied. The downregulation of ANXA1 with small interference RNA (siRNA) decreased the growth of lung cancer cells. In lung cancer cells with EGFR mutations, the knockdown of ANXA1 increased the chemosensitivity to Osimertinib, and decreased the tumorigenesis, invasion and migration of lung cancer cells. Further study showed that the knockdown of ANXA1 inhibited the phosphorylation of EGFR and down-stream Akt pathways and promoted apoptosis in lung cancer cells treated with Osimertinib. A mice xenograft lung cancer model was established in our study and showed that ANXA1 siRNA enhanced the effects of Osimertinib in vivo. Our study results showed that ANXA1 plays critical roles in chemosensitivity to EGFR-TKI in lung cancer cells with the EGFR mutation. Our efforts may be used in the development of lung cancer treatment strategies in the future.

Genetic mutations accumulated overtime could generate many growth and survival advantages for cancer cells, but these mutations also mark cancer cells as targets to be eliminated by the immune system. To evade immune surveillance, cancer cells adopted different intrinsic molecules to suppress immune response. PD-L1 is frequently overexpressed in many cancer cells, and its engagement with PD-1 on T cells diminishes the extent of cytotoxicity from the immune system. To resume immunity for fighting cancer, several therapeutic antibodies disrupting the PD-1/PD-L1 interaction have been introduced in clinical practice. However, their immunogenicity, low tissue penetrance, and high production costs rendered these antibodies beneficial to only a limited number of patients. PD-L1 dimer formation shields the interaction interface for PD-1 binding; hence, screening for small molecule compounds stabilizing the PD-L1 dimer may make immune therapy more effective and widely affordable. In the current study, 111 candidates were selected from over 180,000 natural compound structures through virtual screening, contact fingerprint analysis, and pharmacological property prediction. Twenty-two representative candidates were further evaluated in vitro. Two compounds were found capable of inhibiting the PD-1/PD-L1 interaction and promoting PD-L1 dimer formation. Further structure optimization and clinical development of these lead inhibitors will eventually lead to more effective and affordable immunotherapeutic drugs for cancer patients.

Background: This study proposes a prediction model for the automatic assessment of lung cancer risk based on an artificial neural network (ANN) with a data-driven approach to the low-dose computed tomography (LDCT) standardized structure report., Methods: This comparative validation study analysed a prospective cohort from Chiayi Chang Gung Memorial Hospital, Taiwan. In total, 836 asymptomatic patients who had undergone LDCT scans between February 2017 and August 2018 were included, comprising 27 lung cancer cases and 809 controls. A derivation cohort of 602 participants (19 lung cancer cases and 583 controls) was collected to construct the ANN prediction model. A comparative validation of the ANN and Lung-RADS was conducted with a prospective cohort of 234 participants (8 lung cancer cases and 226 controls). The areas under the curves (AUCs) of the receiver operating characteristic (ROC) curves were used to compare the prediction models., Results: At the cut-off of category 3, the Lung-RADS had a sensitivity of 12.5%, specificity of 96.0%, positive predictive value of 10.0%, and negative predictive value of 96.9%. At its optimal cut-off value, the ANN had a sensitivity of 75.0%, specificity of 85.0%, positive predictive value of 15.0%, and negative predictive value of 99.0%. The area under the ROC curve was 0.764 for the Lung-RADS and 0.873 for the ANN (P = 0.01). The two most important predictors used by the ANN for predicting lung cancer were the documented sizes of partially solid nodules and ground-glass nodules., Conclusions: Compared to the Lung-RADS, the ANN provided better sensitivity for the detection of lung cancer in an Asian population. In addition, the ANN provided a more refined discriminative ability than the Lung-RADS for lung cancer risk stratification with population-specific demographic characteristics. When lung nodules are detected and documented in a standardized structured report, ANNs may better provide important insights for lung cancer prediction than conventional rule-based criteria.

Mutations that lead to constitutive activation of key regulators in cellular processes are one of the most important drivers behind vigorous growth of cancer cells, and are thus prime targets in cancer treatment. BRAF V600E mutation transduces strong growth and survival signals for cancer cells, and is widely present in various types of cancers including lung cancer. A combination of BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) has recently been approved and significantly improved the survival of patients with advanced NSCLC harboring BRAF V600E/K mutation. To improve the detection of BRAF V600E/K mutation and investigate the incidence and clinicopathological features of the mutation in lung cancer patients of southern Taiwan, a highly sensitive and specific real-time quantitative PCR (RT-qPCR) method, able to detect single-digit copies of mutant DNA, was established and compared with BRAF V600E-specific immunohistochemistry. Results showed that the BRAF V600E mutation was present at low frequency (0.65%, 2/306) in the studied patient group, and the detection sensitivity and specificity of the new RT-qPCR and V600E-specific immunohistochemistry both reached 100% and 97.6%, respectively. Screening the BRAF V600E/K mutation with the RT-qPCR and V600E-specific immunohistochemistry simultaneously could help improve detection accuracy.

We aimed to quantify Soft Mist Inhalers (SMI) delivery to spontaneous breathing model and compare with different adapters via endotracheal tube during mechanical ventilation or by manual resuscitation. A tiotropium SMI was used with a commercial in-line adapter and a T-adapter placed between the Y-adapter and the inspiratory limb of the ventilator circuit during mechanical ventilation. The SMI was actuated at the beginning of inspiration and expiration. In separate experiments, a manual resuscitator with T-adapter was attached to endotracheal tube, collecting filter, and a passive test lung. Drug was eluted from collecting filters with salt-based solvent and analyzed using high-performance liquid chromatography. Results showed the percent of SMI label dose inhaled was 3-fold higher with the commercial in-line adapter with actuation during expiration than when synchronized with inspiration. SMI with T-adapter delivery via ventilator was similar to inhalation (1.20%) or exhalation (1.02%), and both had lower delivery dose than with manual resuscitator (2.80%; p = 0.01). The inhaled dose via endotracheal tube was much lower than inhaled dose with spontaneous breathing (22.08%). In conclusion, the inhaled dose with the commercial adapter was higher with SMI actuated during expiration, but still far less than reported spontaneous inhaled dose.

Indoleamine 2,3-dioxygenase (IDO1) inhibitors are speculated to be useful in cancer immunotherapy, but a phase III clinical trial of the most advanced IDO1 inhibitor, epacadostat, did not meet its primary end point and was abandoned. In previous work, we identified the novel IDO1 inhibitor N -(4-chlorophenyl)-2-((5-phenylthiazolo[2,3- c ][1,2,4]triazol-3-yl)thio)acetamide 1 through high-throughput screening (HTS). Herein, we report a structure-activity relationship (SAR) study of this compound, which resulted in the potent IDO1 inhibitor 1-(4-cyanophenyl)-3-(3-(cyclopropylethynyl)imidazo[2,1- b ]thiazol-5-yl)thiourea 47 (hIDO IC 50 = 16.4 nM). X-ray cocrystal structural analysis revealed that the basis for this high potency is a unique sulfur-aromatic interaction network formed by the thiourea moiety of 47 with F163 and F226. This finding is expected to inspire new approaches toward the discovery of potent IDO1 inhibitors in the future.

Somatic mutations of MET gene are emerging as important driver mutations for lung cancers. To identify the common clinicopathological features of MET exon 14 skipping mutations and amplification and clarify whether the two MET gene alterations cause protein overexpression were investigated using 196 lung cancer samples of Taiwan through real time-qPCR/sequencing, fluorescence in situ hybridization, and immunohistochemistry. The two MET gene alterations are both present in low frequency, ~1%, in the studied lung cancer population of Taiwan. MET exon 14 skipping mutations were identified from two early-stage patients, who were both relatively advanced in age, and did not carry other driver mutations. One was an adenocarcinoma and the other was a rare carcinosarcoma. Three gene amplifications cases were identified. Neither of the two MET gene alterations would lead to protein overexpression; hence, direct detection in nucleic acid level would be a preferred and straightforward solution for the identification of skipping mutations. The presence of MET exon 14 mutations in minor histological types of lung cancers urge to extend screening scope of this mutation in lung cancer and treatment response evaluation in clinical trials. These would be important next steps for the success of MET target therapy in clinical practice., Competing Interests: The authors have declared that no competing interests exist.

Leptin is an adipokine predominantly secreted by adipocytes and has many physiological roles, including in energy homeostasis. We identified that AM630, a cannabinoid receptor 2 (CB2) antagonist, down-regulated leptin expression in mature adipocytes differentiated from either stromal vascular fractions isolated from inguinal fat pads of C57BL/6J mice or 3T3-L1 preadipocytes. However, the leptin-suppressive effects of AM630 preserved in CB2-deficient adipocytes indicated the off-target activity of AM630 in leptin expression. Pharmacological and genetic studies, cheminformatics, and docking simulation were applied to identify the potential protein target of AM630 that modulates leptin expression in differentiated primary preadipocytes. Screening of the reported off-targets of AM630 identified a synthetic cannabinoid WIN55212-2 exerting the same function. Target deconvolution and docking simulation suggested that AM630 and WIN55212-2 were both inhibitors of lipocalin-type prostaglandin D2 synthase (L-PGDS). Further studies showed that L-PGDS positively regulates leptin expression. Although glucocorticoid and aldosterone were previously reported to induce expression of both L-PGDS and leptin, our data demonstrated that L-PGDS mediates only glucocorticoid-induced leptin expression in differentiated primary preadipocytes. No effect was observed after aldosterone treatment. This newly discovered glucocorticoid - L-PGDS - leptin pathway may provide insights into current clinical use of glucocorticoid and management of their undesired effects such as obesity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: This meta-analysis compared radiotherapy (RT) versus concurrent chemoradiotherapy (RT+CT) in treating patients with inoperable stage III non-small-cell lung cancer (NSCLC)., Methods: Medline, Cochrane, EMBASE, Google Scholar databases were searched until July 28, 2015 using the following keywords non-small cell lung cancer, advanced cancer, incurable/inoperable/unresectable, chemotherapy, radiotherapy, chemoradiotherapy/chemoradiation. Randomized controlled trials (RCTs) and two-armed prospective studies that compared combined RT+CT with RT alone in patients with locally advanced (stage III) nonresectable NSCLC were eligible for inclusion. Treatment effect on overall survival, progression-free survival (PFS), and objective response rate (ORR) were evaluated., Results: Ultimately, 13 RCT studies were included in the systematic review and meta-analysis. The 13 studies included a total of 1936 patients with incurable/inoperable stage III NSCLC, of which 975 received RT alone and 961 received RT+CT combination therapy. The average age ranged from 54 to 77 years. At 1 and 2 years after treatment, the pooled data reveal that patients receiving CT+RT combination therapy had higher overall survival (pooled hazard ratio (HR), 0.72; 95% CI, 0.62-0.84; P < .001; 1-yr: HR, 0.67; 95% CI, 0.54-0.84; P < .001; 2-year: HR, 0.57; 95% CI, 0.45-0.73; P < .001), higher PFS (pooled HR, 0.73, 95% CI, 0.60-0.89; P = .002; 1-year: HR, 0.36; 95% CI, 0.24-0.53; P < .001; 2-year: HR, 0.38; 95% CI, 0.23-0.63; P < .001)., Conclusion: Our findings show higher efficacy for concurrent CT+RT over RT alone in treating locally-advanced, unresectable stage III NSCLC.

Mutations in the epidermal growth factor receptor ( EGFR ) are associated with various solid tumors. This study aimed to compare two methods for the detection of EGFR mutations in circulating tumor DNA (ctDNA) from lung adenocarcinoma (LUAD) patients and to evaluate the clinical significance of EGFR mutations in ctDNA. In this prospective cohort study, the EGFR mutation status of 77 patients with stage IIIB or IV LUAD was first determined using lung cancer tissue. The amplification refractory mutation system (ARMS) and single allele base extension reaction combined with mass spectroscopy (SABER/MassARRAY) methods were also used to detect EGFR mutations in plasma ctDNA from these patients and then compared using the EGFR mutation status in lung cancer tissue as a standard. Furthermore, the relationship between the presence of EGFR mutations in ctDNA after receiving first-line EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy and survival was evaluated. The overall sensitivity and specificity for the detection of EG F R mutations in plasma ctDNA by ARMS and SABER/MassARRAY were 49.1% vs. 56% and 90% vs. 95%, respectively. The agreement level between these methods was very high, with a kappa-value of 0.88 (95% CI 0.77-0.99). Moreover, 43 of the patients who carried EGFR mutations also received first-line EGFR-TKI therapy. Notably, patients with EGFR mutations in plasma ctDNA had significantly shorter progression-free survival (9.0 months, 95% CI 7.0-11.8, vs. 15.0 months, 95% CI 11.7-28.2; p = 0.02) and overall survival (30.6 months, 95% CI 12.4-37.2, vs. 55.6 months, 95% CI 25.8-61.8; p = 0.03) compared to those without detectable EGFR mutations. The detection of EGFR mutations in plasma ctDNA is a promising, minimally invasive, and reliable alternative to tumor biopsy, and the presence of EGFR mutations in plasma ctDNA after first-line EGFR-TKI therapy is associated with poor prognosis., Competing Interests: The authors declare no conflict of interest.

: Cullin 4A (Cul4A) is overexpressed in a number of cancers and has been established as an oncogene. This study aimed to elucidate the role of Cul4A in lung cancer invasion and metastasis. We observed that Cul4A was overexpressed in non-small cell lung cancer (NSCLC) tissues and the overexpression of Cul4A was associated with poor prognosis after surgical resection and it also decreased the expression of the tumor suppressor protein annexin A10 (ANXA10). The knockdown of Cul4A was associated with the upregulation of ANXA10, and the forced expression of Cul4A was associated with the downregulation of ANXA10 in lung cancer cells. Further studies showed that the knockdown of Cul4A inhibited the invasion and metastasis of lung cancer cells, which was reversed by the further knockdown of ANXA10. In addition, the knockdown of Cul4A inhibited lung tumor metastasis in mouse tail vein injection xenograft models. Notably, Cul4A regulated the degradation of ANXA10 through its interaction with ANXA10 and ubiquitination in lung cancer cells. Our findings suggest that Cul4A is a prognostic marker in NSCLC patients, and Cul4A plays important roles in lung cancer invasion and metastasis through the regulation of the ANXA10 tumor suppressor., Competing Interests: The authors declare no conflict of interest