Upregulated microRNA-125b-5p in patients with asthma-COPD overlap mediates oxidative stress and late apoptosis via targeting IL6R/TRIAP1 signaling.

BACKGROUND: Among patients with chronic obstructive pulmonary disease (COPD), some have features of both asthma and COPD-a condition categorized as asthma-COPD overlap (ACO). Our aim was to determine whether asthma- or COPD-related microRNAs (miRNAs) play a role in the pathogenesis of ACO. METHODS: A total of 22 healthy subjects and 27 patients with ACO were enrolled. We selected 6 miRNAs that were found to correlate with COPD and asthma. The expression of miRNAs and target genes was analyzed using quantitative reverse-transcriptase polymerase chain reaction. Cell apoptosis and intracellular reactive oxygen species production were evaluated using flow cytometry. In vitro human monocytic THP-1 cells and primary normal human bronchial epithelial (NHBE) cells under stimuli with cigarette smoke extract (CSE) or ovalbumin (OVA) allergen or both were used to verify the clinical findings. RESULTS: We identified the upregulation of miR-125b-5p in patients with ACO and in THP-1 cells stimulated with CSE plus OVA allergen. We selected 16 genes related to the miR-125b-5p pathway and found that IL6R and TRIAP1 were both downregulated in patients with ACO and in THP-1 cells stimulated with CSE plus OVA. The percentage of late apoptotic cells increased in the THP-1 cell culture model when stimulated with CSE plus OVA, and the effect was reversed by transfection with miR-125b-5p small interfering RNA (siRNA). The percentage of reactive oxygen species-producing cells increased in the NHBE cell culture model when stimulated with CSE plus OVA, and the effect was reversed by transfection with miR-125b-5p siRNA. In NHBE cells, siRNA transfection reversed the upregulation of STAT3 under CSE+OVA stimulation. CONCLUSIONS: Our study revealed that upregulation of miR-125b-5p in patients with ACO mediated late apoptosis in THP-1 cells and oxidative stress in NHBE cells via targeting IL6R and TRIAP1. STAT3 expression was also regulated by miR-125b-5p.

The importance of high total body water/fat free mass ratio and serial changes in body composition for predicting hospital mortality in patients with severe pneumonia: a prospective cohort study.

PURPOSE: This study aimed to investigate the impact of body composition variables on hospital mortality compared to other predictive factors among patients with severe pneumonia. Additionally, we aimed to monitor the dynamic changes in body composition variables over the course on days 1, 3, and 8 after intensive care unit (ICU) admission for each patient. METHODS: We conducted a prospective study, enrolling patients with severe pneumonia admitted to the medical intensive care unit at Kaohsiung Chang Gung Memorial Hospital from February 2020 to April 2022. We collected clinical data from all patients and assessed their body composition at 1, 3, and 8 days post-ICU admission. On day 1, we analyzed clinical and body composition variables to predict in-hospital mortality. RESULTS: Multivariate analysis identified the Modified Nutrition Risk in the Critically Ill (mNUTRIC) score and the ratio of total body water to fat-free mass (TBW/FFM) as independent factors associated with in-hospital mortality in severe pneumonia patients. Receiver operating characteristic analysis determined that the TBW/FFM ratio was the most reliable predictive parameter of in-hospital mortality, with a cutoff value of 0.74. General linear regression with repeated measures analysis showed that hospital non-survivors displayed notable fluctuations in body water, fat, and muscle variables over the course of days 1, 3, and 8 after ICU admission. CONCLUSIONS: The mNUTRIC score and TBW/FFM ratio emerged as independent factors for predicting hospital mortality, with the TBW/FFM ratio demonstrating the highest reliability as a predictive parameter.

E-cadherin expression in the tumor microenvironment of advanced epidermal growth factor receptor-mutant lung adenocarcinoma and the association with prognosis.

BACKGROUND: The expression of programmed death-ligand 1 (PD-L1), tumor-infiltrating lymphocytes (TILs), E-cadherin, and vimentin in lung cancer tumor microenvironment is known to impact patient survival or response to therapy. The expression of these biomarkers may also differ between primary lung tumors and brain metastatic tumors. In this study, we investigated the interaction between these biomarkers in lung tumors with or without concomitant brain metastasis and the interaction with paired brain metastatic tumors. METHODS: The study included 48 patients with stage IV epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma. Sixteen of the forty-eight patients were diagnosed with brain metastasis, while the remaining thirty-two were not. All sixteen patients with brain metastasis had brain tumors. The expression of PD-L1, TILs (CD8+ T lymphocytes and FOXP3+ regulatory T lymphocytes), E-cadherin, and vimentin were evaluated using immunohistochemical (IHC) staining. RESULTS: Patients with brain metastasis exhibited a higher frequency of exon 19 deletion and uncommon EGFR mutations, a higher lung tumor vimentin score, worse progression-free survival (PFS), and overall survival (OS) than patients without brain metastasis. IHC staining showed no difference between paired lung and brain tumors. Patients with low PD-L1 expression had better PFS and OS. After multivariate analysis, higher body mass index, the presence of brain metastasis, bone metastasis, and uncommon EGFR mutations were correlated with worse PFS, while the presence of brain metastasis and high lung tumor E-cadherin score was associated with worse OS. CONCLUSIONS: In patients with stage IV EGFR-mutant lung adenocarcinoma, high E-cadherin expression in the lung tumor might be associated with worse OS. Vimentin expression in the lung tumor was positively related to the risk of brain metastasis.

Impact of epidermal growth factor receptor gene expression level on clinical outcomes in epidermal growth factor receptor mutant lung adenocarcinoma patients taking first-line epidermal growth factor receptor-tyrosine kinase inhibitors.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are first-choice treatments for advanced non-small-cell lung cancer patients harboring EGFR mutations. Although EGFR mutations are strongly predictive of patients' outcomes and their response to treatment with EGFR-TKIs, early failure of first-line therapy with EGFR-TKIs in patients with EGFR mutations is not rare. Besides several clinical factors influencing EGFR-TKI efficacies studied earlier such as the Eastern Cooperative Oncology Group performance status or uncommon mutation, we would like to see whether semi-quantify EGFR mutation gene expression calculated by 2-ΔΔct was a prognostic factor in EGFR-mutant non-small cell lung cancer patients receiving first-line EGFR-TKIs. This retrospective study reviews 926 lung cancer patients diagnosed from January 2011 to October 2013 at the Kaohsiung Chang Gung Memorial Hospital in Taiwan. Of 224 EGFR-mutant adenocarcinoma patients, 148 patients who had 2-ΔΔct data were included. The best cutoff values of 2-ΔΔct for in-frame deletions in exon 19 (19 deletion) and a position 858 substituted from leucine (L) to an arginine (R) in exon 21 (L858R) were determined using receiver operating characteristic curves. Patients were divided into high and low 2-ΔΔct expression based on the above cutoff level. The best cutoff point of 2-ΔΔct value of 19 deletion and L858R was 31.1 and 104.7, respectively. In all, 92 (62.1%) patients showed high 2-ΔΔct expression and 56 patients (37.9%) low 2-ΔΔct expression. The mean age was 65.6 years. Progression-free survival of 19 deletion mutant patients with low versus high expression level was 17.07 versus 12.04 months (P = 0.004), respectively. Progression-free survival of L858 mutant patients was 13.75 and 7.96 months (P = 0.008), respectively. EGFR-mutant lung adenocarcinoma patients with lower EGFR gene expression had longer progression-free survival duration without interfering overall survival.

Time courses and value of circulating microparticles in patients with operable stage non-small cell lung cancer undergoing surgical intervention.

Microparticles (MPs) are substantially increased in patients with operable stage non-small cell lung cancer (NSCLC) prior to lung resection surgery. This study tested the hypothesis that there is a decrease in MPs after surgical intervention. Between March 2012 and January 2015, 33 patients who had operable stage NSCLC were consecutively and prospectively enrolled into the study. Additionally, 31 healthy subjects who were consecutively enrolled in the study period served as age- and gender-matched controls. Circulating MPs (EDAc-MPs, EDAp-MPs, PDAc-MPs, PDAp-MPs) were measured by flow cytometry once in control subjects and twice (i.e., prior to and three months later after surgical intervention) in NSCLC patients. Compared with control subjects, these four types of circulating MPs were significantly higher in NSCLC patients prior to operation (all P < 0.005), but did not differ among the controls and NSCLC patients at 3 months after surgery (all P > 0.2). Additionally, a receiver operating characteristic curve (ROC) showed that these four types of MPs were significantly valuable predictors for detecting early stage NSCLC (all P < 0.004). Circulating MPs which were remarkably increased in the operable stage of NSCLC prior to surgery were substantially decreased 3 months later after surgery. These findings show that circulating MPs might be an accessory biomarker for monitoring those of NSCLC after receiving lung resection surgery.

Impact of clinical parameters and systemic inflammatory status on epidermal growth factor receptor-mutant non-small cell lung cancer patients readministration with epidermal growth factor receptor tyrosine kinase inhibitors.

BACKGROUND: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) readministration to lung cancer patients is common owing to the few options available. Impact of clinical factors on prognosis of EGFR-mutant non-small cell lung cancer (NSCLC) patients receiving EGFR-TKI readministration after first-line EGFR-TKI failure and a period of TKI holiday remains unclear. Through this retrospective study, we aimed to understand the impact of clinical factors in such patients. METHODS: Of 1386 cases diagnosed between December 2010 and December 2013, 80 EGFR-mutant NSCLC patients who were readministered TKIs after failure of first-line TKIs and intercalated with at least one cycle of cytotoxic agent were included. We evaluated clinical factors that may influence prognosis of TKI readministration as well as systemic inflammatory status in terms of neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR). Baseline NLR and LMR were estimated at the beginning of TKI readministration and trends of NLR and LMR were change amount from patients receiving first-Line TKIs to TKIs readministration. RESULTS: Median survival time since TKI readministration was 7.0 months. In the univariable analysis, progression free survival (PFS) of first-line TKIs, baseline NLR and LMR, and trend of LMR were prognostic factors in patients receiving TKIs readministration. In the multivariate analysis, only PFS of first-line TKIs (p < 0.001), baseline NLR (p = 0.037), and trend of LMR (p = 0.004) were prognostic factors. CONCLUSION: Longer PFS of first-line TKIs, low baseline NLR, and high trend of LMR were good prognostic factors in EGFR-mutant NSCLC patients receiving TKI readministration.

Co-upregulation of Toll-like receptors 2 and 6 on peripheral blood cells in patients with obstructive sleep apnea.

PURPOSE: Toll-like receptor (TLR) 2 can heterodimerise with TLR6 to detect diacylated lipoproteins. Hypoxia inducible factor-1 α co-ordinates selective induction of TLR2 and TLR6 during persistent hypoxia. We hypothesized that TLR 2/6 co-expression may be upregulated by chronic intermittent hypoxia with re-oxygenation (IHR) in obstructive sleep apnea (OSA). METHODS: TLR2/6 expressions on blood immune cells were measured in 144 patients with sleep-disordered breathing (SDB), including primary snoring (PS, n = 24), moderate to severe OSA (MSO, n = 60), very severe OSA (VSO, n = 36), and very severe OSA on continuous positive airway pressure (CPAP) treatment (VSOC, n = 24). An in vitro IHR experiment was also undertaken. RESULTS: Patients in both the MSO and VSO groups had increased TLR2/6 co-expression on CD16(+) neutrophil than those in the PS group. Patients in the VSOC group had reduced TLR2/6 co-expression on neutrophil than those in either the MSO or VSO group. Blood absolute neutrophil count was positively but weakly correlated with TLR2/6 co-expression on neutrophil. TLR2/6 co-expressions on both CD14(+) monocyte and CD3(+)CD4(+)T helper cell, and TLR2 expressions on both monocyte and T helper cell in SDB patients with low Minimum SaO2 (≦70%) were all higher than those with high Minimum SaO2. In vitro IHR for 1-4 days resulted in TLR2/6 co-upregulation on both neutrophil and monocyte. CONCLUSIONS: OSA patients had increased TLR2/6 co-expressions on blood immune cells, which were related to their immune cell counts and could be reversed with CPAP treatment. In vitro IHR could induce TLR2/6 co-upregulation.

The influence of obesity on different genders in patients with obstructive sleep apnea.

Obesity is considered to be a major contributing factor to obstructive sleep apnea (OSA); however, there is limited evidence with regard to gender predominance. We analyzed 2345 patients (339 females) in correlation with body mass index (BMI) and OSA severity. Male AHIs were significantly higher than female AHIs in each BMI group. As the BMI increased, the AHI increased in both males and females, and this trend was more obvious in males. For BMI-matched male and female patients with OSA, the severity of OSA was higher in males. As BMI increased, the severity of OSA increased more obviously in males. Our findings suggest that increased body fat contributes to the pathogenesis of OSA more in males than in females and that obesity plays a more significant role in contributing to OSA in male patients.

Enhancing Outcomes in Chronic Fibrotic Interstitial Lung Disease Through Aggressive Management of Nintedanib-Induced Adverse Drug Reactions: A Retrospective Analysis.

BACKGROUND AND OBJECTIVES: Nintedanib, a tyrosine kinase inhibitor, is integral in slowing pulmonary fibrosis progression in chronic fibrotic interstitial lung disease (ILD). However, the occurrence of adverse drug reactions (ADRs) often limits its use, leading to treatment discontinuation, typically within 3-12 months. Discontinuation adversely affects patient outcomes. The study investigated whether aggressive ADR management can prolong nintedanib therapy and improve patient outcomes. METHODS: This retrospective, single-center study enrolled Taiwanese patients with chronic fibrotic ILD who were treated with nintedanib from January 2016 to December 2022 in Kaohsiung Chang Gung Memorial Hospital. Patients were categorized into those who discontinued treatment within 180 days and those continuing beyond. Management of ADRs was identified through concurrent prescriptions for symptoms such as nausea, vomiting, diarrhea, or hepatic dysfunction. Baseline demographics, comorbidities, pulmonary function tests, and instances of acute exacerbation were analyzed. RESULTS: The study enrolled 94 patients, with 71 (75.5%) experiencing ADRs. Among these, 41 (43.6%) discontinued nintedanib within 180 days. The administration of medications for managing nausea/vomiting [17 (41.5%) versus 36 (67.9%), p = 0.0103] and diarrhea [12 (29.3%) versus 33 (62.3%), p = 0.0015] was less frequent in the discontinued group compared with the continued group. Additionally, a higher incidence of acute exacerbation was observed in the discontinued group (34.1% versus 20.8%, p = 0.016). CONCLUSION: Aggressive management of ADRs may enhance patient tolerance to nintedanib, potentially prolonging treatment duration and improving outcomes in chronic fibrotic ILD.

A case report of drug interaction between co-packaged nirmatrelvir-ritonavir and tacrolimus causing hyponatremia in a lung transplant recipient.

BACKGROUND: Coronavirus disease 2019 (COVID-19) infection in lung transplant recipients can be lethal owing to the use of immunosuppressants. Antiviral agents may be administered to these patients. Co-packaged nirmatrelvir-ritonavir is a new agent currently being used in combination. CASE PRESENTATION: In this report, we present a case of a 64-year-old woman, a lung transplant recipient, who experienced hyponatremia and showed a high serum tacrolimus concentration following the administration of the co-packaged nirmatrelvir-ritonavir combination. CONCLUSION: Although the nirmatrelvir-ritonavir and tacrolimus combination is not contraindicated, other treatment strategies should be considered first, if available, and the dose of tacrolimus should be reduced when using the nirmatrelvir-ritonavir combination. In cases where combination therapy is necessary, serum tacrolimus levels should be closely monitored in lung transplant recipients. Documentation of more such reports is important to identify drug interactions between nirmatrelvir-ritonavir and other agents, with the aim of preventing severe adverse effects.

Double lung transplantation is better than single lung transplantation for end-stage chronic obstructive pulmonary disease: a meta-analysis.

BACKGROUND: Lung transplantation is one of the most common treatment options for patients with end-stage chronic obstructive pulmonary disease. However, the choice between single and double lung transplantation for these patients remains a matter of debate. Therefore, we performed a systematic search of medical databases for studies on single lung transplantation, double lung transplantation, and chronic obstructive pulmonary disease. METHODS: The rate ratio and hazard ratio of survival were analyzed. The meta-analysis included 15 case-control and retrospective registry studies. RESULTS: The rate ratios of the 3-year survival (0.937 and P = 0.041) and 5-year survival (0.775 and P = 0.000) were lower for single lung transplantation than for double lung transplantation. However, the hazard ratio did not differ significantly between the two. CONCLUSIONS: Double lung transplantation was found to provide better benefits than single lung transplantation in terms of the long-term survival in patients with chronic obstructive pulmonary disease.

Association of metabolic factors with high-sensitivity C-reactive protein in patients with sleep-disordered breathing.

Sleep-disordered breathing (SDB) such as snoring or obstructive sleep apnea and metabolic syndrome are both related to cardiovascular diseases. Being a surrogate marker of high risk for cardiovascular disorder, the high-sensitivity C-reactive protein (hs-CRP) level is thought to be elevated in patients with both SDB and metabolic syndrome. To understand better the development of cardiovascular disease in patients with SDB, we examined the association of metabolic variables with hs-CRP levels in adult patients with symptoms of SDB and without any previous treatment, who were selected to participate in the study. Metabolic parameters including fasting blood glucose, lipid profile and hs-CRP were measured following an overnight polysomnography. Laboratory and polysomnographic data were analyzed to identify variables related to high hs-CRP levels. A total of 309 patients with SDB participated in this study. Of these, 139 presented with hs-CRP <1 mg/L and 52 presented with hs-CRP >3 mg/L. Patients with high hs-CRP showed a higher apnea-hypopnea index (AHI), body mass index (BMI), fasting glucose, and triglyceride level, and a lower mean and minimal oxygen saturation and HDL-cholesterol level. However, ordinal regression analysis demonstrated that only a higher BMI and fasting glucose level and a lower HDL-cholesterol level were independent risk factors for cardiovascular diseases (OR = 1.076, 95 % CI = 1.009-1.147, p = 0.005; OR = 1.011, 95 % CI = 1.004-1.019, p = 0.008; OR = 0.966, 95 % CI = 0.947-0.984, p < 0.001, respectively). The results showed that elevated hs-CRP is common in patients with SDB but is not independently associated with the severity of SDB. Metabolic factors such as a higher BMI and fasting blood glucose and a lower HDL-cholesterol level were more strongly associated with elevated hs-CRP rather than with SDB severity, suggesting that metabolic parameters are important contributors to cardiovascular diseases and should be corrected in patients with SDB.

Delirium Care by Intensive Care Unit Nurses: Focus Group Studies in a Medical Center of Southern Taiwan.

OBJECTIVES: Studies have identified many nursing interventions that can prevent delirium and fall accidents in clinical patients, detect and treat delirium early to prevent functional decline in the patient, shorten hospitalization duration, and lower the death rate. This study aimed to explore delirium care by intensive care unit (ICU) nurses in a medical center of southern Taiwan. METHODS: This study conducted 3 semistructured focus group interviews, each for a single medical ICU, involving groups of 6 to 8 nurses each. The nurses were recruited through purposive sampling. This research was approved by an institutional review board in the medical center of southern Taiwan from March 31, 2020, to January 30, 2021. The co-principal investigator described the purpose and process of this study to the participants before they provided their written informed consents. The interviews were conducted in the meeting room and were audiotape recorded. The recordings were transcribed and subject to content analysis to identify the themes of delirium care. RESULTS: For nursing interventions of delirium, satisfying the patient's physical needs: comfort care, massages, and early rehabilitation; and psychological care: being presence, communication, and ensuring familial support were included. In terms of environmental interventions for delirium, providing reorientation, music, light, belongings with sentimental value, and audiovisual equipment were included. However, according to the recruited medical ICU nurses, these nonpharmacological interventions, although effective, do not have long-lasting effects. Finally, nurses reported themselves as having been attacked by patients with delirium. Thus, they all agreed that restraining patients with delirium may be necessary, but restraining is a double-edged sword for ICU delirium patients. CONCLUSIONS: Research team suggests for future studies to extend their evidence-based findings of physical, psychological, and environmental care for ICU delirium patients toward integrating the efforts of various health care professionals.

Do patient characteristics affect EGFR tyrosine kinase inhibitor treatment outcomes? A network meta-analysis of real-world survival outcomes of East Asian patients with advanced non-small cell lung cancer treated with first-line EGFR-TKIs.

BACKGROUND: Despite the well-established efficacies of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), there is limited real-world evidence comparing their effectiveness according to patients' clinical characteristics. This network meta-analysis (NMA) compared survival outcomes among first-line EGFR-TKIs in different subgroups of East Asian patients with advanced NSCLC. METHODS: This NMA included real-world observational studies reporting outcomes with TKIs in patients aged >65 years, with baseline brain metastasis, with different Eastern Cooperative Oncology Group (ECOG) statuses, or with different common EGFR mutation types. RESULTS: In patients with the EGFR L858R mutation, afatinib resulted in significantly longer progression-free survival (PFS) than erlotinib (hazard ratio [HR]: 0.59, 95% confidence interval [CI]: 0.46-0.75) and gefitinib (HR: 0.41, 95% CI: 0.32-0.53). Similarly, in patients with the EGFR Del19 mutation, afatinib and erlotinib resulted in significantly longer PFS than gefitinib (HR: 0.48 with 95% CI: 0.33-0.71 and HR: 0.54 with 95% CI: 0.36-0.80, respectively). Moreover, afatinib resulted in significantly longer PFS than gefitinib in patients with brain metastasis (HR: 0.53, 95% CI: 0.33-0.87) or ECOG status 0-1 (HR: 0.37, 95% CI: 0.23-0.59). CONCLUSION: This NMA suggests that afatinib results in similar PFS to erlotinib and superior PFS than gefitinib in patients with Del19 mutant NSCLC, aged ≥65 years, with ECOG scores of 0-1, and with baseline brain metastasis.

Early and Dose-Dependent Xenogeneic Mesenchymal Stem Cell Therapy Improved Outcomes in Acute Respiratory Distress Syndrome Rodent Through Ameliorating Inflammation, Oxidative Stress, and Immune Reaction.

This study tested whether human umbilical cord-derived mesenchymal stem cells (HUCDMSCs) treatment effectively protected the rat lung against acute respiratory distress syndrome (ARDS) injury, and benefits of early and dose-dependent treatment. Rat pulmonary epithelial cell line L2 (PECL2) were categorized into G1 (PECL2), G2 (PECL2 + healthy rat lung-derived extraction/50 mg/ml co-cultured for 24 h), G3 (PECL2 + ARDS rat lung-derived extraction/50 mg/ml co-cultured for 24 h), and G4 (condition as G3 + HUCDMSCs/1 × 105/co-cultured for 24 h). The result showed that the protein expressions of inflammatory (HMGB-1/TLR-2/TLR-4/MAL/TRAM/MyD88/TRIF/TRAF6/IkB/NF-κB/IL-1ß/TNF-α), oxidative-stress/mitochondrial-damaged (NOX-1/NOX-2/ASK1/p-MKK4/p-MKK7/JNKs/JUN/cytosolic-cytochrome-C/cyclophilin-D/DRP1), and cell-apoptotic/fibrotic (cleaved-caspase 3/cleaved-PARP/TGF-ß/p-Smad3) biomarkers were significantly increased in G3 than in G1/G2 and were significantly reversed in G4 (all P < 0.001), but they were similar between G1/G2. Adult male rats (n = 42) were equally categorized into group 1 (normal control), group 2 (ARDS only), group 3 [ARDS + HUCDMSCs/1.2 × 106 cells intravenous administration at 3 h after 48 h ARDS induction (i.e., early treatment)], group 4 [ARDS + HUCDMSCs/1.2 × 106 cells intravenous administration at 24 h after 48 h ARDS induction (late treatment)], and group 5 [ARDS + HUCDMSCs/1.2 × 106 cells intravenous administration at 3 h/24 h after-48 h ARDS induction (dose-dependent treatment)]. By day 5 after ARDS induction, the SaO2%/immune regulatory T cells were highest in group 1, lowest in group 2, significantly lower in group 4 than in groups 3/5, and significantly lower in group 3 than in group 5, whereas the circulatory/bronchioalveolar lavage fluid inflammatory cells (CD11b-c+/LyG6+/MPO+)/circulatory immune cells (CD3-C4+/CD3-CD8+)/lung-leakage-albumin level/lung injury score/lung protein expressions of inflammatory (HMGB-1/TLR-2/TLR-4/MAL/TRAM/MyD88/TRIF/TRAF6/IκB-ß/p-NF-κB/IL-1ß/TNF-α)/fibrotic (p-SMad3/TGF-ß), apoptosis (mitochondrial-Bax/cleaved-caspase-3)/oxidative-cell-stress (NOX-1/NOX-2/ASK1/p-MKK4/p-MKK7/p-JNKs/p-cJUN)/mitochondrial damaged (cyclophilin-D/DRP1/cytosolic-cytochrome-C) biomarkers displayed an opposite pattern of SaO2% among the groups (all P < 0.0001). Early administration was superior to and two-dose counterpart was even more superior to late HUCDMSCs treatment for protecting the lung against ARDS injury.

Survival outcomes of east Asian patients with advanced non-small cell lung cancer treated with first-line EGFR tyrosine kinase inhibitors: A network meta-analysis of real-world evidence.

BACKGROUND: The comparative efficacies of different generation tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC) remain largely unknown. Moreover, whether one EGFR-TKI confers superior survival remains unclear, especially in East Asians. We conducted a network meta-analysis (NMA) comparing the survival outcomes of East Asian patients with advanced NSCLC treated with first-line EGFR-TKIs. METHODS: The NMA included observational real-world evidence studies on adult patients with EGFR-mutated advanced NSCLC who received first (gefitinib and erlotinib), second (afatinib), or third (osimertinib) generation EGFR-TKIs as frontline therapy. Studies were identified through an online bibliographic search of Medline articles in the PubMed, SCOPUS, Web of Science, and Cochrane Library databases. RESULTS: For overall survival (OS), afatinib had significantly better hazard ratios (HRs) than osimertinib (HR: 0.46, 95% confidence interval [CI]: 0.23-0.91), gefitinib (HR: 0.56, 95% CI: 0.43-0.72), and erlotinib (HR: 0.71, 95% CI: 0.54-0.92). For progression-free survival (PFS), afatinib had significantly better HRs than gefitinib (HR: 0.45, 95% CI: 0.36-0.56) and erlotinib (HR: 0.63, 95% CI: 0.49-0.81). Moreover, afatinib was most likely to achieve the longest OS (81.3%), followed by erlotinib (13%), osimertinib, and gefitinib. Furthermore, afatinib was most likely to achieve the longest PFS (48.3%), followed by osimertinib (34.9%) and erlotinib. CONCLUSIONS: This real-world evidence shows that afatinib confers better survival than other first-line EGFR-TKIs in East Asian patients with advanced NSCLC.

Factors predicting ventilator dependence in patients with ventilator-associated pneumonia.

OBJECTIVES: To determine risk factors associated with ventilator dependence in patients with ventilator-associated pneumonia (VAP). STUDY DESIGN: A retrospective study was conducted at Chang Gung Memorial Hospital, Kaohsiung, from January 1, 2007 to January 31, 2008. METHODS: This study evaluated 163 adult patients (aged ≥ 18 years). Eligibility was evaluated according to the criterion for VAP, Sequential Organ Failure Assessment (SOFA) score, Acute Physiological Assessment and Chronic Health Evaluation II (APACHE II) score. Oxygenation index, underlying comorbidities, septic shock status, previous tracheostomy status, and factors related to pneumonia were collected for analysis. RESULTS: Of the 163 VAP patients in the study, 90 patients survived, yielding a mortality rate of 44.8%. Among the 90 surviving patients, only 36 (40%) had been weaned off ventilators at the time of discharge. Multivariate logistic regression analysis was used to identify underlying factors such as congestive cardiac failure (P = 0.009), initial high oxygenation index value (P = 0.04), increased SOFA scores (P = 0.01), and increased APACHE II scores (P = 0.02) as independent predictors of ventilator dependence. Results from the Kaplan-Meier method indicate that initial therapy with antibiotics could increase the ventilator weaning rate (log Rank test, P < 0.001). CONCLUSIONS: Preexisting cardiopulmonary function, high APACHE II and SOFA scores, and high oxygenation index were the strongest predictors of ventilator dependence. Initial empiric antibiotic treatment can improve ventilator weaning rates at the time of discharge.

Unraveling the Pathogenesis of Asthma and Chronic Obstructive Pulmonary Disease Overlap: Focusing on Epigenetic Mechanisms.

Asthma and COPD overlap (ACO) is characterized by patients presenting with persistent airflow limitation and features of both asthma and COPD. It is associated with a higher frequency and severity of exacerbations, a faster lung function decline, and a higher healthcare cost. Systemic inflammation in COPD and asthma is driven by type 1 T helper (Th1) and Th2 immune responses, respectively, both of which may contribute to airway remodeling in ACO. ACO-related biomarkers can be classified into four categories: neutrophil-mediated inflammation, Th2 cell responses, arachidonic acid-eicosanoids pathway, and metabolites. Gene-environment interactions are key contributors to the complexity of ACO and are regulated by epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs. Thus, this review focuses on the link between epigenetics and ACO, and outlines the following: (I) inheriting epigenotypes without change with environmental stimuli, or epigenetic changes in response to long-term exposure to inhaled particles plus intermittent exposure to specific allergens; (II) epigenetic markers distinguishing ACO from COPD and asthma; (III) potential epigenetic drugs that can reverse oxidative stress, glucocorticoid insensitivity, and cell injury. Improved understanding of the epigenetic regulations holds great value to give deeper insight into the mechanisms, and clarify their implications for biomedical research in ACO.

Comprehensive analysis of PD-L1 in non-small cell lung cancer with emphasis on survival benefit, impact of driver mutation and histological types, and archival tissue.

BACKGROUND: The aim of the study was to assess programmed death-ligand-1 (PD-L1) expression in different histological types and gene mutation status of patients with non-small cell lung cancer (NSCLC). METHODS: A total of 4062 pathology-confirmed lung cancer patients were retrospectively screened at Kaohsiung Chang Gung Memorial Hospital from November 2010 to June 2017. There were 699 NSCLC patients with confirmed PD-L1 expression level retrospectively enrolled for analysis. RESULTS: There was a trend of higher PD-L1 expression in squamous cell carcinoma and adenosquamous cell carcinoma than in adenocarcinoma (p = 063). Significant higher PD-L1 expression in EGFR wild-type was noted (p < 0.001). No significant differences in PD-L1 expression were found between ALK wild- and mutant types, but there seem was a trend of high PD-L1 level noted in ALK mutation patients (p = 0.069). In EGFR mutation patients, a higher time to treatment failure (TTF) duration was observed in no PD-L1 expression (p = 0.011). Longer tumor tissue storage time correlated with lower PD-L1 expression in lung cancer (p < 0.001 for linear trend). CONCLUSIONS: There were a trend or significant differences in PD-L1 expression between different histological types in NSCLC, different EGFR and ALK status, and different tumor tissue storage time. A higher survival benefit was observed in no PD-L1 expression than with PD-L1 expression in adenocarcinoma, EGFR and ALK mutation patients. We recommend that PD-L1 assay should be performed as early as possible if tissue is available.

The Impact of Intermittent Hypoxemia on Left Atrial Remodeling in Patients with Obstructive Sleep Apnea Syndrome.

Obstructive sleep apnea syndrome (OSAS) is a significant risk factor for left atrial (LA) remodeling. Intermittent hypoxemia occurs during the sleep cycle in patients with OSAS and plays a crucial role in cardiovascular pathologies such as stroke, arrhythmia, and coronary artery disease. However, there is very little information about the role of intermittent hypoxemia in LA remodeling in patients with OSAS. In total, 154 patients with sleep-related breathing disorders (SRBD) were prospectively recruited for this study. All enrolled SRBD patients underwent polysomnography and echocardiography. Significant OSAS was defined as an oxygen desaturation index (ODI) of ≥10 per hour. Intermittent hypoxia/reoxygenation (IHR) stimulation was used to test the effect of hypoxia on the viability, reactive oxygen species, apoptosis, and inflammation-associated cytokine expression in the HL-1 cell line. To investigate the effect of patients' exosomes on HIF-1 and inflammation-associated cytokine expression, as well as the relationship between ODI and their expression, exosomes were purified from the plasma of 95 patients with SRBD and incubated in HL-1 cells. The LA size was larger in patients with significant OSAS than in those without. There was a significant association between ODI, lowest SpO2, mean SpO2, and LA size (all p < 0.05) but not between the apnea-hypopnea index and LA size. IHR condition caused increased LDH activity, reactive oxygen species (ROS) levels, and apoptosis in HL-1 cells and decreased cellular viability (all p < 0.05). The expression of HIF-1α, TNF-α, IL-6, and TGF-ß increased in the IHR condition compared with the control (all p < 0.05). The expression of HIF-1α, IL-1ß, and IL-6 increased in the HL-1 cells incubated with exosomes from those patients with significant OSAS than those without (all p < 0.05). There was a significantly positive correlation between ODI and the expression of HIF-1α, TNF-α, IL-1ß, IL-6, and TGF-ß; a significantly negative correlation between mean SpO2 and IL-6 and TGF-ß; and a significantly negative correlation between the lowest SpO2 and HIF-1α (all p < 0.05). In conclusion, intermittent hypoxemia was strongly associated with LA remodeling, which might be through increased ROS levels, LDH activity, apoptosis, and the expression of HIF-1α and inflammation-associated cytokines.