Clinical best practices in interdisciplinary management of human epidermal growth factor receptor 2 antibody-drug conjugates-induced interstitial lung disease/pneumonitis: An expert consensus in China.

Antibody-drug conjugates (ADCs) have demonstrated effectiveness in treating various cancers, particularly exhibiting specificity in targeting human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Recent advancements in phase 3 clinical trials have broadened current understanding of ADCs, especially trastuzumab deruxtecan, in treating other HER2-expressing malignancies. This expansion of knowledge has led to the US Food and Drug Administration's approval of trastuzumab deruxtecan for HER2-positive and HER2-low breast cancer, HER2-positive gastric cancer, and HER2-mutant nonsmall cell lung cancer. Concurrent with the increasing use of ADCs in oncology, there is growing concern among health care professionals regarding the rise in the incidence of interstitial lung disease or pneumonitis (ILD/p), which is associated with anti-HER2 ADC therapy. Studies on anti-HER2 ADCs have reported varying ILD/p mortality rates. Consequently, it is crucial to establish guidelines for the diagnosis and management of ILD/p in patients receiving anti-HER2 ADC therapy. To this end, a panel of Chinese experts was convened to formulate a strategic approach for the identification and management of ILD/p in patients treated with anti-HER2 ADC therapy. This report presents the expert panel's opinions and recommendations, which are intended to guide the management of ILD/p induced by anti-HER2 ADC therapy in clinical practice.

Gold brocade coated CoFe PBA with enhanced peroxidase-like activity for a chemiluminescent imaging immunoassay.

Traditional chemiluminescence (CL) imaging immunoassays usually rely on natural enzymes as catalytic probes, which has hampered their extensive application due to the susceptibility to inactivation of natural enzymes. In response, a gold brocade coated CoFe Prussian blue analogue (CoFe PBA@Au brocade) with enhanced peroxidase-like activity was synthesized and utilized as a powerful label probe for constructing a highly sensitive CL imaging immunosensor targeting disease biomarkers with excellent performance. This research offers a universal strategy for enhancing the sensitivity of CL imaging immunoassays and further expands the application of PBA nanozymes.

An Au bipyramids@CuZn MOF core-shell nanozyme enables universal SERS and a colorimetric dual-model bioassay.

In this study, a new type of gold nano-bipyramids@CuZn bimetallic organic framework (AuNBPs@CuZn MOF) nanozyme with high peroxidase (POD)-like activity and surface enhanced Raman scattering (SERS) activity was constructed with a special core-shell structure, which can catalyze the oxidation of TMB (colourless and Raman-inactive) into ox-TMB (blue and Raman-active). An AuNBPs@CuZn MOF-enabling universal SERS and colorimetric dual-model bioassay was thus developed for biomolecules with excellent performance, and has promising application prospects in the biosensing fields.

Neurofibromatosis type 1 with huge intrathoracic meningoceles misdiagnosed as pleural effusion: A case report and literature review.

BACKGROUND: Neurofibromatosis type 1 is a genetic disease that affects multiple organs and systems, leading to various clinical manifestations. In Neurofibromatosis type 1, rare intrathoracic meningoceles often occur alongside bone dysplasia. These meningoceles contain cerebrospinal fluid and can be mistakenly diagnosed as 'pleural effusion'. CASE PRESENTATION: In this case report, we mistakenly identified 'cerebrospinal fluid' as 'pleural effusion' and proceeded with drainage. This error posed significant risks to the patient and holds valuable implications for the future diagnosis and treatment of similar patients. CONCLUSIONS: In patients with Neurofibromatosis type 1 complicated by spinal deformity, there is a high incidence of intrathoracic meningoceles. Treatment strategies may differ based on the specific features of the lesions, and collaboration among multiple disciplines can significantly improve patient outcomes.

Expert Consensus on the Diagnosis and Treatment of NRG1/2 Gene Fusion Solid Tumors.

The fusion genes NRG1 and NRG2 , members of the epidermal growth factor (EGF) receptor family, have emerged as key drivers in cancer. Upon fusion, NRG1 retains its EGF-like active domain, binds to the ERBB ligand family, and triggers intracellular signaling cascades, promoting uncontrolled cell proliferation. The incidence of NRG1 gene fusion varies across cancer types, with lung cancer being the most prevalent at 0.19 to 0.27%. CD74 and SLC3A2 are the most frequently observed fusion partners. RNA-based next-generation sequencing is the primary method for detecting NRG1 and NRG2 gene fusions, whereas pERBB3 immunohistochemistry can serve as a rapid prescreening tool for identifying NRG1 -positive patients. Currently, there are no approved targeted drugs for NRG1 and NRG2 . Common treatment approaches involve pan-ERBB inhibitors, small molecule inhibitors targeting ERBB2 or ERBB3, and monoclonal antibodies. Given the current landscape of NRG1 and NRG2 in solid tumors, a consensus among diagnostic and treatment experts is proposed, and clinical trials hold promise for benefiting more patients with NRG1 and NRG2 gene fusion solid tumors.

Burden of silica-attributed pneumoconiosis and tracheal, bronchus & lung cancer for global and countries in the national program for the elimination of silicosis, 1990-2019: a comparative study.

BACKGROUND: In industries worldwide, crystalline silica is pervasive and poses risks of pneumoconiosis and respiratory malignancies, with the latter being a knowledge gap in disease burden research that this study aims to address. By integrating both diseases, we also seek to provide an in-depth depiction of the silica-attributed disease burden. METHODS: Data from the Global Burden of Disease 2019 were extracted to analyze the disease burden due to silica exposure. The trends of age-standardized mortality rate (ASMR) and age-standardized DALY rate (ASDR) from 1990 to 2019, as well as the age-specific number and rate of deaths and disability-adjusted life years (DALYs) in 1990 and 2019, were presented using GraphPad Prism software. The average annual percentage changes (AAPCs) on ASMR and ASDR were calculated using joinpoint regression models. RESULTS: The global trends of disease burden due to silica exposure from 1990 to 2019 showed a significant decrease, with AAPCs on ASMR and ASDR of -1.22 (-1.38, -1.06) and - 1.18 (-1.30, -1.05), respectively. Vietnam was an exception with an unprecedented climb in ASMR and ASDR in general over the years. The age-specific deaths and DALYs mainly peaked in the age group 60-64. In comparison to 1990, the number of deaths and DALYs became higher after 45 years old in 2019, while their rates stayed consistently lower in 2019. Males experienced an elevated age-specific burden than females. China's general age-standardized burden of pneumoconiosis and tracheal, bronchus & lung (TBL) cancer ranked at the forefront, along with the highest burden of pneumoconiosis in Chilean males and South African females, as well as the prominent burden of TBL cancer in Turkish males, Thai females, and overall Vietnamese. The age-specific burden of TBL cancer surpassed that of pneumoconiosis, and a delay was presented in the pneumoconiosis pinnacle burden compared to the TBL cancer. Besides, the burden of pneumoconiosis indicated a sluggish growth trend with advancing age. CONCLUSION: Our research highlights the cruciality of continuous enhancements in occupational health legislation for countries seriously suffering from industrial silica pollution and the necessity of prioritizing preventive measures for male workers and elderly retirees.

Expert consensus on the diagnosis and treatment of RET gene fusion non-small cell lung cancer in China.

The rearranged during transfection (RET) gene is one of the receptor tyrosine kinases and cell-surface molecules responsible for transmitting signals that regulate cell growth and differentiation. In non-small cell lung cancer (NSCLC), RET fusion is a rare driver gene alteration associated with a poor prognosis. Fortunately, two selective RET inhibitors (sRETi), namely pralsetinib and selpercatinib, have been approved for treating RET fusion NSCLC due to their remarkable efficacy and safety profiles. These inhibitors have shown the ability to overcome resistance to multikinase inhibitors (MKIs). Furthermore, ongoing clinical trials are investigating several second-generation sRETis that are specifically designed to target solvent front mutations, which pose a challenge for first-generation sRETis. The effective screening of patients is the first crucial step in the clinical application of RET-targeted therapy. Currently, four methods are widely used for detecting gene rearrangements: next-generation sequencing (NGS), reverse transcription-polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC). Each of these methods has its advantages and limitations. To streamline the clinical workflow and improve diagnostic and treatment strategies for RET fusion NSCLC, our expert group has reached a consensus. Our objective is to maximize the clinical benefit for patients and promote standardized approaches to RET fusion screening and therapy.

Chinese expert consensus on the diagnosis and treatment of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a malignant tumor originating from the pleura, and its incidence has been increasing in recent years. Due to the insidious onset and strong local invasiveness of MPM, most patients are diagnosed in the late stage and early screening and treatment for high-risk populations are crucial. The treatment of MPM mainly includes surgery, chemotherapy, and radiotherapy. Immunotherapy and electric field therapy have also been applied, leading to further improvements in patient survival. The Mesothelioma Group of the Yangtze River Delta Lung Cancer Cooperation Group (East China LUng caNcer Group, ECLUNG; Youth Committee) developed a national consensus on the clinical diagnosis and treatment of MPM based on existing clinical research evidence and the opinions of national experts. This consensus aims to promote the homogenization and standardization of MPM diagnosis and treatment in China, covering epidemiology, diagnosis, treatment, and follow-up.

Comparison of High-Flow Nasal Cannula with Conventional Oxygen Therapy in Patients with Hypercapnic Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis.

Purpose: This study aimed to evaluate the clinical outcomes of high-flow nasal cannula (HFNC) compared with conventional oxygen therapy (COT) in patients with hypercapnic chronic obstructive pulmonary disease (COPD), including arterial partial pressure of carbon dioxide (PaCO2), arterial partial pressure of oxygen (PaO2), respiratory rate (RR), treatment failure, exacerbation rates, adverse events and comfort evaluation. Patients and Methods: PubMed, EMBASE and the Cochrane Library were retrieved from inception to September 30, 2022. Eligible trials were randomized controlled trials and crossover studies comparing HFNC and COT in hypercapnic COPD patients. Continuous variables were reported as mean and standard derivation and calculated by weighted mean differences (MD), while dichotomous variables were shown as frequency and proportion and calculated by odds ratio (OR), with the 95% confidence intervals (Cl). Statistical analysis was performed using RevMan 5.4 software. Results: Eight studies were included, five with acute hypercapnia and three with chronic hypercapnia. In acute hypercapnic COPD, short-term HFNC reduced PaCO2 (MD -1.55, 95% CI: -2.85 to -0.25, I² = 0%, p <0.05) and treatment failure (OR 0.54, 95% CI: 0.33 to 0.88, I² = 0%, p<0.05), but there were no significant differences in PaO2 (MD -0.36, 95% CI: -2.23 to 1.52, I² = 45%, p=0.71) and RR (MD -1.07, 95% CI: -2.44 to 0.29, I² = 72%, p=0.12). In chronic hypercapnic COPD, HFNC may reduce COPD exacerbation rates, but there was no advantage in improving PaCO2 (MD -1.21, 95% CI: -3.81 to 1.39, I² = 0%, p=0.36) and PaO2 (MD 2.81, 95% CI: -1.39 to 7.02, I² = 0%, p=0.19). Conclusion: Compared with COT, short-term HFNC reduced PaCO2 and the need for escalating respiratory support in acute hypercapnic COPD, whereas long-term HFNC reduced COPD exacerbations rates in chronic hypercapnia. HFNC has great potential for treating hypercapnic COPD.

Effects of awake prone position vs. usual care on acute hypoxemic respiratory failure in patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials.

Background: Previous studies have shown that an awake prone position may be beneficial for the treatment of acute respiratory distress syndrome (ARDS) or acute hypoxic respiratory failure (AHRF) in patients with COVID-19, but the results are not consistent, especially in terms of oxygenation outcomes and intubation rate. This systematic review and meta-analysis assessed the effects of the awake prone position on AHRF in patients with COVID-19 with all randomized controlled trials (RCTs). Methods: An extensive search of online databases, including MEDLINE, Embase, Web of Science, and Cochrane Central Register of Controlled Trials from 1 December 2019 to 30 October 2022, with no language restrictions was performed. This systematic review and meta-analysis are based on the PRISMA statement. We only included RCTs and used the Cochrane risk assessment tool for quality assessment. Results: Fourteen RCTs fulfilled the selection criteria, and 3,290 patients were included. A meta-analysis found that patients in the awake prone position group had more significant improvement in the SpO2/FiO2 ratio [mean difference (MD): 29.76; 95% confidence interval (CI): 1.39-48.13; P = 0.001] compared with the usual care. The prone position also reduced the need for intubation [odd ratio (OR): 0.72; 95% CI: 0.61 to 0.84; P < 0.0001; I 2 = 0%]. There was no significant difference in mortality, hospital length of stay, incidence of intensive care unit (ICU) admission, and adverse events between the two groups. Conclusion: The awake prone position was a promising intervention method, which is beneficial to improve the oxygenation of patients with ARDS or AHRF caused by COVID-19 and reduce the need for intubation. However, the awake prone position showed no obvious advantage in mortality, hospital length of stay, incidence of ICU admission, and adverse events. Systematic review registration: International Prospective Register of Systematic Reviews (PROSPERO), identifier: CRD42022367885.

Chinese expert consensus on the diagnosis and treatment of thymic epithelial tumors.

Thymic epithelial tumors (TETs) are a relatively rare type of thoracic tumor, accounting for less than 1% of all tumors. The incidence of TETs is about 3.93/10000 in China, slightly higher than that of European and American countries. For resectable TETs, complete surgical resection is recommended. Radiotherapy or chemotherapy may be used as postoperative adjuvant treatment. Treatment for advanced, unresectable TETs consist mainly of radiotherapy and chemotherapy, but there is a lack of standard first- and second-line treatment regimens. Recently, targeted therapies and immune checkpoint inhibitors have shown promising outcomes in TETs. Based on the currently available clinical evidences and the opinions of the national experts, the Thymic Oncology Group of Yangtze River Delta Lung Cancer Cooperation Group (East China LUng caNcer Group, ECLUNG; Youth Committee) established this Chinese expert consensus on the clinical diagnosis and treatment of TETs, covering the epidemiology, diagnosis, treatment, prognosis and follow-up of TETs.

Chinese expert consensus on the diagnosis and treatment of HER2-altered non-small cell lung cancer.

Human epidermal growth factor receptor 2 (HER2) possesses tyrosine kinase activity and participates in cell growth, differentiation and migration, and survival. Its alterations, mainly including mutations, amplifications, and overexpression are associated with poor prognosis and are one of the major drivers in non-small cell lung cancer (NSCLC). Several clinical trials had been investigating on the treatments of HER2-altered NSCLC, including conventional chemotherapy, programmed death 1 (PD-1) inhibitors, tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs), however, the results were either disappointing or encouraging, but inconsistent. Trastuzumab deruxtecan (T-DXd) was recently approved by the Food and Drug Administration as the first targeted agent for treating HER2-mutant NSCLC. Effective screening of patients is the key to the clinical application of HER2-targeted agents such as TKIs and ADCs. Various testing methods are nowadays available, including polymerase chain reaction (PCR), next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), etc. Each method has its pros and cons and should be reasonably assigned to appropriate patients for diagnosis and guiding treatment decisions. To help standardize the clinical workflow, our expert group reached a consensus on the clinical management of HER2-altered NSCLC, focusing on the diagnosis and treatment strategies.

Chronic exposure to IQOS results in impaired pulmonary function and lung tissue damage in mice.

The use of IQOS brand heated tobacco products (HTPs) is increasing worldwide; however, little is known about the long-term effects of HTPs aerosol exposure on the lungs. Herein, we exposed C57BL/6 J mice for 24 weeks to clean air, IQOS aerosol, or cigarette smoke, and determined pulmonary function, lung tissue pathology, inflammation, and oxidative stress. Compared with the control group mice, IQOS group mice showed substantially decreased weight and lung function. Levels of IL-6 and TNF-a, as well as oxidative stress markers, were comparable to those found in the cigarette group. In addition, hematoxylin and eosin staining showed that the alveolar space was enlarged and that emphysema had formed in the IQOS group. Masson staining showed that collagen deposition areas were substantially increased in the airway walls in the IQOS group than in the control group. Immunohistochemical staining showed epithelial-mesenchymal transition in the airways of mice in the IQOS group. In conclusion, chronic exposure to IQOS aerosol results in impaired pulmonary function and lung tissue damage; hence, concern should be raised regarding the long-term safety of this product.

miR-137 represses migration and cell motility by targeting COX-2 in non-small cell lung cancer.

Background: Lung cancer is a common malignant tumor, with, non-small cell lung cancer (NSCLC) accounting for about 80-85% of cases. This study investigated the expression of miR-137 in NSCLC tissues and cells and its effects on the migration and invasion of NSCLC cells and related mechanisms. Methods: We collected the neoplastic and paracancerous tissues of NSCLC patients, detected the expression of miR-137 in NSCLC tissues and cell lines by real-time quantitative polymerase chain reaction (RT-qPCR), and analyzed the correlation between miR-137 expression and the clinicopathological features and survival of NSCLC. Following transfection with miR-137 mimic or inhibitor in NSCLC cell lines (A549 or H1299) to upregulate or downregulate the expression of miR-137, transwell assay was employed to detect the effects of miR-137 on migration or invasion. Online software was employed to predict and analyze the target gene of miR-137, and luciferase reporter gene system was adopted to validate it. The effects of miR-137 on the expressions of COX-2 and Epithelial-Mesenchymal Transition (EMT) related proteins were investigated by Western blot. Results: Compared to paracancerous tissues and BEAS-2B cells, the expressions of miR-137 in NSCLC tissues, A549 and H1299 cells were dramatically down-regulated (P<0.01). After transfection with miR-137 mimic or inhibitor in A549 and H1299 cells, the miR-137 expressions were markedly up-regulated or down-regulated (P<0.01), respectively. The number of migrating or invading cells was observably decreased or increased (P<0.01) after transfected with mimic or inhibitor, respectively, while relative luciferase activity was evidently decreased in cells co-transfected with miR-137 mimic and wild type recombined vector of 3'UTR of COX-2. While the expressions of COX-2 and E-cadherin were both substantially reduced in A549 cells treated with miR-137 mimic, that of vimentin was substantially raised. The expression of miR-137 correlated with smoking history, lymph node metastasis, and TNM clinical stage, and patients with high miR-137 expression had apparent longer survival. Conclusions: The expression of miR-137 was significantly down-regulated in NSCLC tissues and cells, and correlated with NSCLC progress. miR-137 suppressed the migration and invasion of NSCLC cells through regulating EMT relative proteins by targeting COX-2. miR-137 is expected to become a novel biomarker and therapeutic target of NSCLC.

Chinese expert consensus on the multidisciplinary management of pneumonitis associated with immune checkpoint inhibitor.

Immune checkpoint inhibitors (ICIs) have successfully treated a number of different types of cancer, which is of great significance for cancer treatment. With the widespread use of ICIs in clinical practice, the increasing checkpoint inhibitor pneumonia (CIP) will be a challenge to clinicians. To guide the diagnosis and treatment of CIP, we conducted in-depth discussions based on the latest evidence, forming a consensus among Chinese experts on the multidisciplinary management of CIP.

Expert consensus on the diagnosis and treatment of NTRK gene fusion solid tumors in China.

Gene fusions can drive tumor development for multiple types of cancer. Currently, many drugs targeting gene fusions are being approved for clinical application. At present, tyrosine receptor kinase (TRK) inhibitors targeting neurotrophic tyrosine receptor kinase (NTRK) gene fusions are among the first "tumor agnostic" drugs approved for pan-cancer use. Representative TRK inhibitors, including larotrectinib and entrectinib, have shown high efficacy for many types of cancer. At the same time, several second-generation drugs designed to overcome first-generation drug resistance are undergoing clinical development. Due to the rarity of NTRK gene fusions in common cancer types and technical issues regarding the complexity of fusion patterns, effectively screening patients for TRK inhibitor treatment in routine clinical practice is challenging. Different detection methods including immunohistochemistry, fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and (DNA and/or RNA-based) next-generation sequencing have pros and cons. As such, recommending suitable tests for individual patients and ensuring the quality of tests is essential. Moreover, at present, there is a lack of systematic review for the clinical efficacy and development status of first- and second-generation TRK inhibitors. To resolve the above issues, our expert group has reached a consensus regarding the diagnosis and treatment of NTRK gene fusion solid tumors, aiming to standardize clinical practice with the goal of benefiting patients with NTRK gene fusions treated with TRK inhibitors.

Clinicopathological characteristics, survival outcomes and prognostic factors in pleomorphic carcinoma: a SEER population-based study.

BACKGROUND: Pulmonary pleomorphic carcinoma (PPC) is a rare tumor, and it usually has an aggressive clinical course and poor prognosis. We aim to analyze the clinicopathological features, management and prognostic factors of pulmonary pleomorphic carcinoma. PATIENTS AND METHODS: Using the surveillance, epidemiology, and end results (SEER) database, we identified 461 patients of pulmonary pleomorphic carcinoma from 2004 to 2014 including clinicopathological characteristics, treatment modalities and outcome data. RESULTS: The mean age of all PPC patients was 66 years and 58% of the patients were male. Most patients (80%) were white people, 53% were found in the right lung, and lesions were mostly observed in upper lobe (56%). The median overall survival was 9 months and overall 1-, 3- and 5-year survival rate was 45%, 29%, 23%. In Kaplan-Meier analysis, age, marital status, tumor primary site, gender, laterality, SEER summary stage, chemotherapy and surgery were associated with overall survival. Patients received surgery or chemotherapy had a better OS for patients with PPC. Multivariate Cox analysis revealed that SEER summary stage, age, surgery and chemotherapy were found to be independently associated with the OS. Surgery could significantly prolong survival in patients with localized stage and regional stage (HR = 0.120, 95% CI 0.038-0.383, p < 0.001; HR = 0.351, 95% CI 0.212-0.582, p < 0.001) while it did not have great impact on survival in patients with distant stage (p = 0.192). Chemotherapy decreased risk of death by 46% (HR = 0.544, 95% CI 0.393-0.752, p < 0.001) for patients with distant stage, whereas chemotherapy did not confer survival benefits to patients with localized stage and regional stage. But radiation did not have great impact on survival of patients with different stages in this study. CONCLUSIONS: PPC mostly occurred in white people, with a median age of 66 years, and men were more susceptible to this disease. The SEER summary stage, age, surgery and chemotherapy were independently associated with prognosis. Surgery should be considered for the PPC patients with localized stage or regional stage, and chemotherapy should be recommended for the treatment of patients with distant stage.

Associative analysis of multi-omics data indicates that acetylation modification is widely involved in cigarette smoke-induced chronic obstructive pulmonary disease.

We aimed to study the molecular mechanisms of chronic obstructive pulmonary disease (COPD) caused by cigarette smoke more comprehensively and systematically through different perspectives and aspects and to explore the role of protein acetylation modification in COPD. We established the COPD model by exposing C57BL/6J mice to cigarette smoke for 24 weeks, then analyzed the transcriptomics, proteomics, and acetylomics data of mouse lung tissue by RNA sequencing (RNA-seq) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), and associated these omics data through unique algorithms. This study demonstrated that the differentially expressed proteins and acetylation modification in the lung tissue of COPD mice were co-enriched in pathways such as oxidative phosphorylation (OXPHOS) and fatty acid degradation. A total of 19 genes, namely, ENO3, PFKM, ALDOA, ACTN2, FGG, MYH1, MYH3, MYH8, MYL1, MYLPF, TTN, ACTA1, ATP2A1, CKM, CORO1A, EEF1A2, AKR1B8, MB, and STAT1, were significantly and differentially expressed at all the three levels of transcription, protein, and acetylation modification simultaneously. Then, we assessed the distribution and expression in different cell subpopulations of these 19 genes in the lung tissues of patients with COPD by analyzing data from single-cell RNA sequencing (scRNA-seq). Finally, we carried out the in vivo experimental verification using mouse lung tissue through quantitative real-time PCR (qRT-PCR), Western blotting (WB), immunofluorescence (IF), and immunoprecipitation (IP). The results showed that the differential acetylation modifications of mouse lung tissue are widely involved in cigarette smoke-induced COPD. ALDOA is significantly downregulated and hyperacetylated in the lung tissues of humans and mice with COPD, which might be a potential biomarker for the diagnosis and/or treatment of COPD.

Tripartite motif protein 11 (TRIM11), an oncogene for human lung cancer via the DUSP6-mediated ERK1/2 signaling pathway.

Evidence suggests that Tripartite Motif Containing 11 (TRIM11) has pro-tumor activity in human non-small cell lung cancer (NSCLC). However, the roles and underlying mechanisms of TRIM11 in NSCLC have not yet been fully elucidated. In this work, human lung cancer cell lines (A549, H446, and H1975) were transfected with siRNA or lentiviruses to knockdown or overexpress TRIM11 and dual-specificity phosphatase 6 (DUSP6). The cell tumor response was assessed by determining the rate of proliferation, apoptosis, the uptake of 2-[N-(7-nitrobenz-2-oxa-1, 3-diaxol-4-yl) amino]-2-deoxyglucose (2-NBDG), and the secretion of lactic acid (LD). Dominant-negative (dn)-MEK1 was used to block the ERK1/2 pathway. The mechanism was investigated by assessing the protein levels of pyruvate kinase isozymes M2 (PKM2) and DUSP6, as well as the activation of ERK1/2 pathway. Our data confirmed the anti-cancer effect of siTRIM11 in human lung cancer by demonstrating inhibition of cancer cell proliferation, induction of apoptosis, prevention of 2-NBDG uptake, suppression of LD production, and prevention of lung cancer cell (A549) tumorigenicity in nude mice. The underlying mechanism involved the up-regulation of DUSP6 and the inhibition of ERK1/2 activity. Overexpression of TRIM11 induced tumorigenesis of NSCLC in vitro, and the activation of ERK1/2 was significantly reversed by DUSP6 overexpression or additional dn-MEK1 treatment. Interestingly, we confirmed TRIM11 as a deubiquitinase that regulated DUSP6 accumulation, indicating that lung cancer progression is regulated via the DUSP6-ERK1/2 pathway. In conclusion, TRIM11 is an oncogene in NSCLC, likely through the DUSP6-mediated ERK1/2 signaling pathway.

AMPK α1 Downregulates ROS Levels Through Regulating Trx Leading to Dysfunction of Apoptosis in Non-Small Cell Lung Cancer.

PURPOSE: AMP-activated protein kinase α1 (AMPK α1) associates closely with cancers. However, the relationship between AMPK α1 and non-small cell lung cancer (NSCLC) is not fully understood. In this study, we aim to explore the role and mechanism of AMPK α1 in NSCLC initiation and progression. MATERIALS AND METHODS: A total of 165 clinical NSCLC specimens were included in the formalin-fixed and paraffin-embedded (FFPE) lung cancer tissue arrays. The expression levels of AMPK α1 and thioredoxin (Trx) in NSCLC cancer tissues and adjacent non-tumor lung tissues were measured through using immunohistochemistry. MTT assay was used to detect cell proliferation. Intracellular ROS levels were measured by using H2DCFDA reagent. Lentiviruses including LV-PRKAA1-RNAi, LV-PRKAA1 and a negative LV-control were used to infect A549 cells to modulate AMPK α1 expression in vitro. Immunoblotting was used to determine the modulation relationship between AMPK α1 and Trx. Log rank test and Kaplan-Meier survival analysis were performed to evaluate the significances of AMPK α1 and Trx expression levels on NSCLC patients' prognoses. RESULTS: AMPK α1 was highly expressed in NSCLC cancer tissues and correlated with poor prognosis in patients with NSCLC. In A549 cells, overexpression of AMPK α1 promoted proliferation, suppressed ROS levels and inhibited apoptosis. Moreover, inhibition of AMPK α1 expression achieved the opposite effects. Trx was significantly overexpressed in NSCLC cancer tissues; furthermore, Trx expressed much more in cytoplasm when compared with cell nucleus. Trx expression levels were positively correlated with AMPK α1 expression levels in NSCLC tissues. AMPK α1 could regulate Trx in A549 cells. No significant correlations were observed between Trx expression variances and prognoses in NSCLC patients. Combination of AMPK α1 and Trx had no advantage in predicting prognoses of NSCLC patients. CONCLUSION: These results suggest that AMPK α1 serves a carcinogenic role at least in part through the regulation of Trx expression, and thus represents a potential treatment target in patients with NSCLC.