A novel anoikis-related prognostic signature associated with prognosis and immune infiltration landscape in lung adenocarcinoma.

BACKGROUND: One of the most prevalent malignancies in the world is lung adenocarcinoma (LUAD), with a large number of people dying from lung cancer each year. Anoikis has a crucial function in tumor metastasis, promoting cancer cell shedding and survival from the primary tumor site. However, the role of anoikis in LUAD is still unclear. METHODS: The GeneCard database (https://www.genecards.org/) was utilized to obtain anoikis-related genes with correlation greater than 0.4. Differential analysis was employed to acquire differential genes. Univariate, multifactorial Cox analyses and the least absolute shrinkage and selection operator were then utilized to capture genes connected to overall survival time. These genes were used to build prognostic models. The predictive model was analyzed and visualized. Survival analysis was conducted on the model and risk scores were calculated. The TCGA samples were split into groups of low and high risk depending on risk scores. A Gene Expression Omnibus database sample was used for external verification. Immunization estimates were performed using ESTIMATE, CiberSort and single sample gene set enrichment analysis. The connection between the prognostic gene model and immune cells was analyzed. Drug susceptibility prediction analysis was performed. The clinical information for samples was extracted and analyzed. RESULTS: We selected six genes related to anoikis in LUAD to construct a prognosis model (CDC25C, ITPRIP, SLCO1B3, CDX2, CSPG4 and PIK3CG). Compared with cases of high-risk scores, the overall survival of those with low risk was significantly elevated based on Kaplan-Meier survival analysis. Immune function analysis exhibited that different risk groups had different immune states. The results of ESTIMATE, CiberSort and single sample gene set enrichment analysis showed great gaps in immunization between patients in the two groups. The normogram of the risk score and the LUAD clinicopathological features was constructed. Principal component analysis showed that this model could effectively distinguish the two groups of LUAD patients. CONCLUSIONS: We integrated multiple anoikis-related genes to build a prognostic model. This investigation demonstrates that anoikis-related genes can be used as a stratification element for fine therapy of individuals with LUAD.

Insights into the heterogeneity of the tumor microenvironment in lung adenocarcinoma and squamous carcinoma through single-cell transcriptomic analysis: Implications for distinct immunotherapy outcomes.

BACKGROUND: Immune checkpoint blockade has emerged as a key strategy to the therapy landscape of non-small cell lung cancer (NSCLC). However, notable differences in immunotherapeutic outcomes exist between the two primary NSCLC subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This disparity may stem from the tumor immune microenvironment's heterogeneity at the transcriptome level. METHODS: By integrative analysis of transcriptomic characterization of 38 NSCLC patients by single-cell RNA sequencing, the present study revealed a distinct tumor microenvironment (TME) between LUAD and LUSC, with relevant results further confirmed in bulk transcriptomic and multiplex immunofluorescence (mIF) validation cohort of neoadjuvant immunotherapy patients. RESULTS: LUAD exhibited a more active immune microenvironment compared to LUSC. This included highly expression of HLA I/II in cancer cells, reinforced antigen presentation potential of dendritic cells and enhanced cytotoxic activity observed in T/NK cells. In LUSC, cancer cells highly expressed genes belonging to the aldo-keto reductases, glutathione S-transferases and aldehyde dehydrogenase family, negatively correlating with immunotherapy outcomes in the validation cohort of our center. Further analysis revealed elevated infiltrated cancer-associated fibroblasts (CAFs) in LUSC, which was corroborated in The Cancer Genome Atlas cohort. Corresponding increased infiltration of ADH1B+ CAFs in major pathologic response (MPR) patients and the higher presence of FAP+ CAFs in non-MPR patients were demonstrated by multiplex mIF. Moreover, upregulating immunosuppressive extracellular matrix remodeling was identified in LUSC. CONCLUSIONS: These comprehensive analyses advance the understanding of the differences in TME between LUAD and LUSC, offering insights for patient selection and developing subtype-specific treatment strategies.

Rivaroxaban versus nadroparin for thromboprophylaxis following thoracic surgery for lung cancer: A randomized, noninferiority trial.

The benefit of rivaroxaban in thromboprophylaxis after oncologic lung surgery remains unknown. To evaluate the efficacy and safety of rivaroxaban, patients who underwent thoracic surgery for lung cancer were enrolled, and randomly assigned to rivaroxaban or nadroparin groups in a 1:1 ratio; anticoagulants were initiated 12-24 h after surgery and continued until discharge. Four hundred participants were required according to a noninferiority margin of 2%, assuming venous thromboembolism (VTE) occurrence rates of 6.0% and 12.6% for patients in the rivaroxaban and nadroparin groups, respectively. The primary efficacy outcome was any VTE during the treatment and 30-day follow-up periods. The safety outcome was any on-treatment bleeding event. Finally, 403 patients were randomized (intention-to-treat [ITT] population), with 381 included in per-protocol (PP) population. The primary efficacy outcomes occurred in 12.5% (25/200) of the rivaroxaban group and 17.7% (36/203) of the nadroparin group (absolute risk reduction, -5.2%; 95% confidence interval [CI], [-12.2-1.7]), indicating the noninferiority of rivaroxaban in ITT population. Sensitivity analysis was performed in the PP population and yielded similar results, confirming the noninferiority of rivaroxaban. In the safety analysis population, the incidence of any on-treatment bleeding events did not differ significantly between the groups (12.2% for rivaroxaban vs. 7.0% for nadroparin; relative risk [RR], 1.9; 95% CI, [0.9-3.7]; p = .08), including major bleeding (9.7% vs. 6.5%; RR, 1.6 [95% CI, 0.9-3.7]; p = .24), and nonmajor bleeding (2.6% vs. 0.5%; RR, 5.2 [95% CI, 0.6-45.2]; p = .13). Rivaroxaban for thromboprophylaxis after oncologic lung surgery was shown to be noninferior to nadroparin.

Bevacizumab-Laden Nanofibers Simulating an Antiangiogenic Niche to Improve the Submuscular Stability of Stem Cell Engineered Cartilage.

Bone marrow stem cells (BMSCs) engineered cartilage (BEC) is prone to endochondral ossification in a submuscular environment due to the process of vascular infiltration, which limits its application in repairing tracheal cartilage defects. Bevacizumab, an antitumor drug with pronounced antiangiogenic activity, is successfully laden into a poly(L-lactide-co-caprolactone) system to prepare bevacizumab-laden nanofiber (BevNF) characterized by 5% and 10% bevacizumab concentrations. The in vitro results reveal that a sustained release of bevacizumab can be realized from BevNF, exhibiting inhibitive cytotoxicity toward human umbilical vein endothelial cells whereas non-cytotoxicity toward BMSCs-induced chondrocytes. A model is also established by encapsulating BEC within BevNF, aiming to realize an antiangiogenic niche under conditions of sustained and localized release of bevacizumab to inhibit the process of vascular invasion, resulting in the eventual stabilization of the cartilaginous phenotype and promotion of the process of cartilage maturation in the submuscular environment. These results also confirm that the chondrogenesis stability of BEC increases with an increase in the bevacizumab concentration, and 10% BevNF is sufficient to protect BEC from vascularization. This demonstrates that the use of BevNF can potentially help develop an effective strategy for regulating the submuscular stability of BEC to repair the defects formed in tracheal cartilage.

Lymph Node Examination for Stage I Second Primary Lung Cancer Patients Who Received Second Surgical Treatment.

PURPOSE: This study aims to investigate the effect of lymph node examination on overall survival (OS) and lung cancer-specific survival (LCSS) in stage I second primary lung cancer (SPLC) patients who underwent second pulmonary resection. PATIENTS AND METHODS: We conducted a retrospective study with the Surveillance, Epidemiology, and End Results (SEER) database to identify stage I SPLC patients who received surgery from 1998 to 2015. The Kaplan-Meier method with landmark analysis and multivariable Cox regression analysis were performed to evaluate the prognostic value of lymph node examination. RESULTS: A total of 842 patients from the SEER database with stage I SPLC who underwent a second surgical treatment were included. The 5-year survival rate was 54.8% for the whole cohort. Multivariable analysis revealed that the number of lymph nodes examined (LNE) was associated with better OS and LCSS in SPLC patients after 12 months postoperatively. Patients with contralateral SPLC had significantly more nodes removed than those with ipsilateral SPLC. For contralateral SPLC, more than 10 LNE was correlated with improved long-term survival outcomes. Ipsilateral SPLC patients benefited from 4 or more LNE. However, the current analysis did not show a significant survival benefit from lymph node examination within 12 months after surgery. CONCLUSIONS: For stage I SPLC patients who received surgical treatment after initial resection, an adequate number of LNE would improve both OS and LCSS. We recommend more than 10 LNE for contralateral SPLC and at least 4 LNE for ipsilateral SPLC.

Aging-related Atg5 defect impairs neutrophil extracellular traps formation.

Formation of neutrophil extracellular traps (NETs) is an important function of the innate immune system against infections. It has been proven that aging dysregulates immunity and impairs neutrophil function. However, the influence of aging on the ability to produce NETs has yet to be fully addressed. In this study, we tested the hypothesis that a lower level of autophagy in neutrophils from aged mice was responsible for the decrease in NET formation. We demonstrated that a broad range of Toll-like receptor 2 (TLR2) ligands could efficiently induce reactive oxygen species (ROS) -dependent NET release in young mice, but not in aged ones. We further explored that the difference between young and aged mice in TLR2 ligand-induced NETosis is the result of an Atg5 defect and subsequent impaired autophagy. Furthermore, we found that lower autophagy capacity led to not only reduced NET formation, but also increased apoptosis. Our results suggest an important role of Atg5 and autophagy in maintaining the function of NETs formation in response to infection and in regulating neutrophil death. Targeting autophagy-promoted NETs may present a therapeutic strategy to improve infection defence in an aged population.

Identifying optimal surgical approach among T1N2-3M0 non-small cell lung cancer patients: a population-based analysis.

Background: Whether stage T1N2-3M0 non-small cell lung cancer (NSCLC) patients could benefit from surgery and the optimal surgical procedure have remained controversial and unclear. This study aimed to investigate whether stage T1N2-3M0 NSCLC can benefit from different surgery types and develop a tool for survival prediction. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients diagnosed with stage T1N2-3M0 NSCLC between 2000 and 2015. A 1:1 propensity score-matched (PSM) analysis was used to balance the distribution of clinical characteristics. Survival analyses were performed by using the Kaplan-Meier (KM) curves and Cox proportional hazards regression. All patients were randomly split at a ratio of 7:3 into training and validation cohorts. The nomogram was constructed by integrating all independent predictors for overall survival (OS) and cancer-specific survival (CSS). The model's performance was evaluated by discrimination, calibration ability, and risk stratification ability. Results: A total of 4,671 patients were enrolled. After 1:1 PSM, the distribution proportions of clinical characteristics in 1,146 patients were balanced (all P>0.05). The non-surgical approach was associated with worse survival compared with sublobectomy and lobectomy in the unmatched and matched cohorts. The multivariate Cox analysis showed that sublobectomy and lobectomy were both related to better OS and CSS rates compared with no surgery (P<0.001). Moreover, the results of subgroup analyses based on age, N stage, and radiotherapy or chemotherapy strategy were consistent. A total of 801 patients were included in the training cohort and 345 cases constituted the validation cohort. The nomogram constructed for the 1-, 3-, and 5-year OS and CSS prediction showed good discrimination, performance, and calibration both in the training and validation sets. Significant distinctions in survival curves between different risk groups stratified by prognostic scores were also observed (all P<0.001). Conclusions: Stage T1N2-3M0 NSCLC patients could benefit from sublobectomy or lobectomy, and lobectomy provides better survival benefits. We developed and validated nomograms, which could offer clinicians instructions for strategy making.

Study on Joint Connection Performance of an Innovative Tooth Groove Connection and Vertical Reinforcement Lapping in Reserved Hole.

In order to explore the horizontal joint connection performance of the innovative tooth groove connection and vertical reinforcement lapping in the reserved hole, five horizontal joint specimens were designed and constructed in this paper. Through the combination of monotonic horizontal load tests and finite element simulation analysis, the effects of axial compression ratio, vertical reinforcement connection degree, reserved hole type, mortar strength, and tooth groove depth on the horizontal joint connection performance of innovative tooth groove connections and vertical reinforcement lapping in reserved holes were comprehensively analyzed and discussed. The results indicated that the specimens were subjected to penetration failure at the tooth groove joint, but the vertical reinforcements and UHPC in reserved holes can effectively transfer the stress, ensuring satisfactory connection performance. With the increase in axial compression ratio and vertical reinforcement connection degree, the joint connection performance enhanced gradually, while the reserved hole type had little effect on the joint connection performance. In addition, it was found that increasing the mortar strength and the tooth groove depth can significantly improve the peak bearing capacity through finite element analysis. Finally, the optimization design suggestions for this innovative tooth groove connection and vertical reinforcement lapping in the reserved hole were given considering factors such as joint connection performance and construction assembly.

Prevention of new-onset atrial fibrillation in elderly patients undergoing anatomic pulmonary resection by infusion of magnesium sulfate: protocol for a randomized controlled trial.

Atrial fibrillation (AF) is the most commonly sustained arrhythmia after pulmonary resection, which has been shown to predict higher hospital morbidity and mortality. The lack of strong evidence-based medical evidence makes doctors have very few options for medications to prevent new-onset AF following thoracic surgery. Magnesium can prevent perioperative AF in patients undergoing cardiac surgery. However, this has not yet been fully studied in patients undergoing non-cardiac thoracic surgery, which is the aim of this study. This is a single-center, prospective, double-blind, randomized controlled trial. In total, 838 eligible patients were randomly assigned to one of two study groups, namely, the control group or the magnesium group. The patients in the magnesium group preoperatively received 80 mg magnesium sulfate/kg ideal weight in 100 ml normal saline 30 min. The control group received the same volumes of normal saline simultaneously. The primary outcome is the incidence of new-onset AF intra-operative and on the first, second, and third postoperative days. The secondary outcomes are bradycardia, hypertension, hypotension, and flushing. The occurrence of stroke or any other type of arrhythmia is also recorded. Postoperative respiratory suppression and gastrointestinal discomfort, intensive care unit stays and total duration of hospital stays, in-hospital mortality, and 3-month all-cause mortality are also recorded as important outcomes. This study aims to prospectively evaluate the prophylactic effects of magnesium sulfate against AF compared with a placebo control group during and following anatomic pulmonary resection. The results may provide reliable evidence for the prophylactic value of magnesium against AF in patients with lung cancer. The trial was approved by the Clinical Research Ethics Committee of Shanghai Pulmonary Hospital and has been registered at Chinese Clinical Trial Registry: www.chictr.org.cn, identifier: ChiCTR2300068046.

Identify the Clinicopathological Characteristics of Lung Carcinoma Patients Being False Negative in Folate Receptor Based Circulating Tumor Cell Detection.

In lung cancer diagnosis, folate receptor (FR)-based circulating tumor cell (CTC) has shown its ability to distinguish malignancy from benign disease to some extent. However, there are still some patients that cannot be identified by FR-based CTC detection. And studies comparing the characteristics between true positive (TP) and false negative (FN) patients are few. Thus, the study comprehensively analyzes the clinicopathological characteristics of FN and TP patients in the current study. According to inclusion and exclusion criteria, 3420 patients are enrolled. Combining the pathological diagnosis with CTC results, patients are divided into FN and TP groups, and clinicopathological characteristics are compared between two groups. Compared with TP patients, FN patients have smaller tumor, early T stage, early pathological stage, and without lymph node metastasis. Epidermal growth factor receptor (EGFR) mutation status is different between FN and TP group. And this result is also demonstrated in lung adenocarcinoma subgroup but not in lung squamous cell carcinoma subgroup. Tumor size, T stage, pathological stage, lymph node metastasis, and EGFR mutation status may influence the accuracy of FR-based CTC detection in lung cancer. However, further prospective studies are needed to confirm the findings.

Cellular biocompatibility and biomechanical properties of N-carboxyethylchitosan/nanohydroxyapatite composites for tissue-engineered trachea.

To prepare an NCECS/nHA composite for tissue-engineered trachea and investigate its biomechanical and biocompatibile properties. Biomechanical tests were performed on dry and wet NCECS/nHA composite specimens prepared in vitro. The cell adhesion rate on each composite surface after 2, 6, and 12 hours of culture was calculated, and cell proliferation activity was measured using an MTT assay. NCECS/nHA composites exhibited satisfactory tensile strength and Young's modulus values. The adhesion rate of rabbit tracheal chondrocytes on NCECS/nHA surfaces reached 88.4% after 12 hours of culture. NCECS/nHA composites are promising scaffold materials for tissue-engineered trachea owing to satisfactory biocompatible and biomechanical properties.

[Current status and progress of tracheal substitute].

According to the numerous experimental studies but limited clinical applications, the tracheal replacement is still far to be applied maturely. This should be attribute to the poor biocompatibility of the substitute and insufficient vascularization, even with added prosthetic migration and dislocation, epithelial ischemia and necrosis, as well as local infections, and so on. Here we present a review in the attempts to summarize the progress and prospective advances in tracheal substitute.

Experimental Study on Seismic Behavior of PC Walls with Alveolar-Type Horizontal Joint under Pseudo-Static Loading.

There are many horizontal joints on precast concrete (PC) wall panel structures, which certainly has a significant impact on the seismic behavior of structures. This paper proposes a novel alveolar-type horizontal joint, which has advantages of convenient and rapid assembly. Six precast concrete wall specimens with alveolar-type joints were designed and constructed, and they were weakly connected by spliced rebars anchored into grouted sleeves to meet the requirements of structural performance. The pseudo-static loading tests on these specimens were conducted to investigate the effects of influencing factors, such as the axial compression ratio, the thickness of wall (interface contact area), and the addition of a vertical grouted sleeve connection at the horizontal joint, on the seismic performance of PC walls. Analyses and comparisons were conducted in terms of the cracking propagation pattern, failure modes, force-displacement hysteretic curves, skeleton curves, bearing capacity, ductility factors, and energy dissipation of PC walls. It was concluded that the axial compression ratio and adding grouted sleeve connection had a significant influence on the cracking mode of PC walls, whereas the impact of the wall thickness was slight. The shear capacity and energy dissipation capacity of specimen dramatically enhanced by increasing the axial compression ratio or adding grouted sleeve connection. The PC wall exhibits good ductility after adding the vertical grouted sleeve connection at a horizontal joint. However, the ductility factor increases firstly and then decreases in the enhancement of the axial compression ratio. The reduction in wall thickness has remarkable impacts on the shear strength and energy dissipation capacity of specimens, but the influences on ductility were not significant. The prediction method for calculating the shear capacity of PC walls with alveolar-type horizontal joints was proposed based on the experimental data, and these calculated results are in good agreement with the experimental results.

Carbon Dioxide Blower Facilitates Visceral Pleurectomy in Malignant Pleural Mesothelioma.

Pleurectomy and decortication serves as a major component of therapy for malignant pleural mesothelioma (MPM), but the procedure is time consuming. We tentatively applied a carbon dioxide (CO2) blower into pleurectomy and decortication for a patient with local relapse of MPM. The blower can help increase the potential subpleural place thanks to the positive pressure by CO2, while the mist of saline could clean the potential bleeding to increase visibility. Thereby, the procedure was greatly facilitated in a more precise manner, with blood loss of 100 mL and acceptable postoperative air leak and thorax drainage. Therefore, a CO2 blower may be considered in pleurectomy and decortication for MPM.

Efficacy evaluation of surgery combined with chemotherapy for stage IIIA small cell lung cancer patients: a retrospective analysis.

Background: The efficacy of surgery in combination of chemotherapy for stage IIIA small cell lung cancer (IIIA-SCLC) is controversial. The aim of the present study was to analyze the efficacy of surgery combined with chemotherapy, especially in the setting of neoadjuvant chemotherapy (NAC) followed by surgery for IIIA-SCLC. Methods: Between 2004 and 2015, we reviewed 2,199 chemotherapy-treated stage IIIA (N1/2) SCLC cases in the Surveillance, Epidemiology, and End Results (SEER) database, and 32 NAC + intentional radical resection-treated, centrally-located IIIA-SCLC cases at Shanghai Pulmonary Hospital (SPH). Outcomes were compared between surgically and non-surgically treated patients from the SEER database after propensity score matching (PSM), and comparing lobectomy/bi-lobectomy and pneumonectomy patients from SPH. Prognostic factors were evaluated by Kaplan-Meier method and the Cox proportional hazards regression model. Results: There was significantly higher overall survival (OS) in surgically treated IIIA-SCLC patients (OS, 44.8 vs. 21.2 months, P=0.048), and similar efficacy was observed between sub-lobectomy and lobectomy/bi-lobectomy patients (OS: 55.6 vs. 30.3 months, P=0.167) in SEER database. At SPH, significantly higher OS was associated with T1 stage (before NAC: T1 vs. T2-4, 48.7 vs. 32.2 months, P=0.025; after NAC: T1 vs. T2-4, 42.7 vs. 21.3 months, P=0.048). Female sex [hazard ratio (HR): 0.078, P=0.009], T1 stage (HR: 13.048, P=0.026), and pneumonectomy (HR: 0.095, P=0.009) were independent prognostic factors for IIIA-SCLC patients who received NAC + intentional radical resection. Conclusions: For stage IIIA SCLC patients, complete resection combined with chemotherapy might improve the prognosis than patients without surgery. Post-NAC lobectomy was not found to be superior to sub-lobectomy, while pneumonectomy was considered suitable for central-type IIIA-SCLC patients after NAC treatment.

Memantine Alleviates Acute Lung Injury Via Inhibiting Macrophage Pyroptosis.

ABSTRACT: Acute lung injury (ALI) is caused by direct pulmonary insults and indirect systemic inflammatory responses that result from conditions such as sepsis and trauma. Alveolar macrophages are the main and critical leukocytes in the airspace, and through the synthesis and release of various inflammatory mediators critically influence the development of ALI following infection and non-infectious stimuli. There is increasing recognition that inflammation and cell death reciprocally affect each other, which forms an auto-amplification loop of these two factors, and in turn, exaggerates inflammation. Therefore, pharmacological manipulation of alveolar macrophage death signals may serve as a logical therapeutic strategy for ALI. In this study, we demonstrate that memantine, a N-methyl-D-aspartic acid receptor (NMDAR) antagonist, through suppressing Ca2+ influx and subsequent ASC oligomerization inhibits macrophage Nlrp3 inflammasome activation and pyroptosis, therefore, alleviates ALI in septic mice. This finding explores a novel application of memantine, an FDA already approved medication, in the treatment of ALI, which is currently lacking effective therapy.

Genomic and transcriptional alterations in first-line chemotherapy exert a potentially unfavorable influence on subsequent immunotherapy in NSCLC.

Background: Recent studies in non-small cell lung cancer (NSCLC) patients have demonstrated that first-line immunotherapy is associated with better therapeutic response than second-line treatment. So far, the mechanisms need to be explored. It prompted us to evaluate the association between first-line chemotherapy and subsequent immunotherapy in NSCLC as well as its underlying mechanisms at the genomic and transcriptomic level. Methods: We launched a prospective, observational clinical study, paired tumor biopsies before and after chemotherapy were collected from NSCLC patients without tyrosine kinase inhibitor (TKI)-related driver gene mutations. The analyses included genomic and transcriptional changes performed by next-generation sequencing (NGS)-based whole-exome sequencing (WES) and messager ribonucleic acid (mRNA) sequencing. Characteristic mutational alterations in 1574 genes were investigated based on mutational status, clinicopathological factors, and chemotherapy responses. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, neoantigen prediction and intratumoral heterogeneity evaluation were also performed. Results: Samples and information from 32 NSCLC patients without TKI-related driver gene mutations were obtained. We found that the total number of single nucleotide variants (SNV)/insertion-deletion (INDEL) mutations did not change significantly after chemotherapy. The tumor mutation burden (TMB) decreased significantly after chemotherapy in smoking patients and the decreased TMB correlated with a better survival of smoking patients. The change in copy number variations (CNVs) exhibited a decreasing trend during chemotherapy. Subsequent analysis at mRNA level revealed a significant decrease in the expression levels of genes related to antigen processing and presentation as well as other factors relevant for response to immunotherapy. Pathway enrichment analysis confirmed that the immune-related signaling pathways or biological processes were decreased after first-line chemotherapy. Conclusions: Our study presents an explanation for the unsatisfactory results of immunotherapy when given after chemotherapy, and suggests that first-line chemotherapy is able to influence the tumor microenvironment and decrease the efficacy of subsequent immunotherapy. The study was registered at ClinicalTrials.gov, number NCT03764917, and has completed enrolment; patients are still in follow-up.

Druggable driver gene alterations in redefined large cell carcinoma in Chinese patients: an observational study.

BACKGROUND: Few reports have investigated the genetic status of large cell carcinoma (LCC) in Chinese patients under the 2015 World Health Organization (WHO) classification. We aimed to analyze the distribution of druggable driver gene alterations, including mutations in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma 2 viral oncogene homolog (KRAS), proto-oncogene B-Raf (BRAF), and phosphatidylinositol-4,5 biphosphate 3-kinase catalytic subunit alpha (PIK3CA) and translocations in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) and ROS proto-oncogene 1 (ROS1), in a large population of patients with LCC under the 2015 WHO classification, and to assess the clinical outcomes of patients with LCC harboring these genetic alterations. METHODS: A cohort of 322 patients with LCC resected between June 2015 and December 2018 was included in this study. The clinical characteristics of the patients and data on the distribution of EGFR, KRAS, BRAF, PIK3CA, EML4-ALK, and ROS1 alterations were retrospectively collected. The disease-free survival (DFS) of patients with LCC was analyzed using the log-rank test. RESULTS: Among the patients with redefined LCC, the proportion of males was much higher than that of females. Detection of LCC was more frequent in patients >60 years of age (71.4%). Mutations of EGFR were found in 3.6% of the LCC participants, predominantly in non-smokers. Mutations in KRAS were observed in 7.8% of the LCC patients, mainly in males and smokers. Mutations in PIK3CA and EML4-ALK translocations comprised 2.1% and 0.52% of the identified alterations, respectively. No alterations were identified in ROS1 and BRAF. After molecular stratification, no significant difference in DFS was identified between wild-type (WT) and mutation groups (29.91±3.83 vs. 25.33±6.04 months, P=0.48). CONCLUSIONS: Under the 2015 WHO criteria, LCC was more frequently detected in elderly male patients with inferior prognoses. The frequency of EGFR and KRAS mutations was found to be the highest. Mutations in EGFR occurred more frequently in non-smokers, whereas KRAS mutations occurred predominantly in males and smokers. The PIK3CA mutations and EML4-ALK translocations were rare in patients with LCC. Our data revealed that the identification of clinically actionable molecular alterations in LCC may help guide personalized cancer treatment decisions in the future.

Inhibition of the endoplasmic reticulum (ER) stress-associated IRE-1/XBP-1 pathway alleviates acute lung injury via modulation of macrophage activation.

BACKGROUND: Both endoplasmic reticulum (ER) stress and macrophage diversity contribute to inflammatory processes in lung injury. However, the interaction between ER stress and macrophage M1/M2 imbalance in lung inflammation remains unclear. The present study, thus, aimed to evaluate the role of ER stress-mediated macrophage phenotype changes in lipopolysaccharide (LPS)-induced acute lung injury (ALI). METHODS: Lung inflammation and injury were examined in a murine model of LPS-induced ALI with or without ER stress inhibitors. Alveolar macrophage (AM) polarization was determined by flow cytometry. Bone marrow-derived macrophages (BMDMs) were treated with either an ER stress inducer, inhibitor, or an IRE-1 endonuclease inhibitor before being polarized to an M1 and M2 phenotype. The macrophage polarization status was examined via RT-PCR and flow cytometry. RESULTS: Our results indicated that ER stress and IRE-1/XBP-1 signaling are activated in LPS-induced ALI. Furthermore, we observed that AM polarizes to an inflammatory phenotype upon exposure to LPS in the induction phase and an anti-inflammatory phenotype in the resolution phase of lung inflammation. Inhibition of ER stress attenuated the pathophysiological features of LPS-induced lung inflammation/injury, as evidenced by a decrease in bronchoalveolar lavage (BAL) protein levels, the number of inflammatory cells, and the expression level of inflammatory mediators. In addition, the ER stress inducer promoted M1 polarization and the switch from M2 to M1 in BMDMs, whereas inhibition of ER stress and XBP-1 splicing suppressed M1 but did not promote M2, both in vivo and in vitro. CONCLUSIONS: Our results demonstrated that inhibition of the ER stress-associated IRE-1/XBP-1 signaling pathway suppresses M1 polarization and ameliorates LPS-induced lung injury. This indicates that the interaction between ER stress and macrophage polarization might be a novel therapeutic target for endotoxin-induced lung inflammatory disorders.

Correction to: EGFR signaling augments TLR4 cell surface expression and function in macrophages via regulation of Rab5a activation.

In the original publication the bands in Fig. 1J and Fig. 2B were not visible. The correct versions of Fig. 1J and Fig. 2B are provided in this correction.