Identification of WD-Repeat Protein 72 as a Novel Prognostic Biomarker in Non-Small-Cell Lung Cancer.

WD-repeat protein 72(WDR72; OMIM∗613214), a scaffolding protein lacking intrinsic enzymatic activity, produces numerous ß-propeller blade formations, serves as a binding platform to assemble protein complexes and is critical for cell growth, differentiation, adhesion, and migration. Despite evidence supporting a basic role of WDR72 in the tumorigenesis of particular cancers, the value of WDR72 in non-small-cell lung cancer (NSCLC), the tumor with the highest mortality rate globally, is undocumented. We investigated the prognostic value of WDR72 in NSCLC and studied its potential immune function and its correlation with ferroptosis. According to The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, Genotype-Tissue Expression, and Gene Set Cancer Analysis, we used multiple bioinformatic strategies to investigate the possible oncogenic role of WDR72, analyze WDR72 and prognosis, and immune cell infiltration in different tumors correlation. WDR72 exhibited a high expression in NSCLC and a positive association with prognosis. WDR72 expression was related to immune cell infiltration and tumor immune microenvironment in NSCLC. Finally, we validated WDR72 in human NSCLC; it has a predictive value in NSCLC related to its function in tumor progression and immunity. The significance of our study is that WDR72 can be used as a potential indicator of lung cancer prognosis. Helping physicians more accurately predict patient survival and risk of disease progression.

Comparison on the Effect and Complications of VATS and Radical Thoracotomy for Lung Cancer in the Treatment of Stages IIB-IIIA Non-Small Cell Lung Cancer.

Objective: Lung adenocarcinoma (NSCLC) is a common subtype of lung cancer, and its prevalence has gradually increased in recent years. There are various treatment methods for NSCLC, and surgical resection, as one of the important treatments, is crucial to improving the survival rate and quality of life of patients. To explore the effect and complications of video-assisted thoracic surgery (VATS) and radical thoracotomy for lung cancer (RTLC) in the treatment of stages IIB-IIIA non-small cell lung cancer (NSCLC). Methods: A total of 80 patients with NSCLC admitted to the hospital were enrolled between June 2019 and January 2021. According to the random number table method, they were divided into the VATS group (40 cases, VATS) and RTLC group (40 cases, RTLC). The operation time, intraoperative blood loss, postoperative drainage time, number of lymph node dissections, score of visual analogue scale (VAS) at 24 h after surgery, and hospitalization time were compared between the two groups. We chose specific inclusion criteria, including patients diagnosed with non-small cell lung cancer (NSCLC) who did not receive radiation therapy or chemotherapy before surgery, to ensure consistency and comparability across studies. We focused on indicators related to lung function and immune system, such as CD3+, CD4+ and CD8+ levels, as well as FEV1, FVC and MVV, to evaluate the impact of surgery on lung function and immune status. The levels of CD3+, CD4+, and CD8+ in both groups were detected by flow cytometry at 1 d before surgery and 3 d after surgery. The forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and maximal voluntary ventilation (MVV) in both groups were detected by spirometry before and at 1 month after surgery. The occurrence of postoperative complications in both groups was recorded. After 12 months of follow-up, survival rates in both groups were statistically analyzed. The progression-free survival (PFS) and 12-month overall survival (OS) in both groups were analyzed by the Kaplan-Meier method. Results: The incision length, operation time, intraoperative blood loss, postoperative drainage time, VAS score at 24 h after surgery, and hospitalization time in VATS group were significantly lower than those in RTLC group (P < .05). The two groups had no significant difference in the number of lymph node dissections (P > .05). At 3 d after surgery, levels of CD3+, CD4+ and CD8+ in VATS group were significantly higher than those in RTLC group (P < .05). At 1 month after surgery, FEV1, FVC, and MVV in VATS group operation were significantly higher than those in RTLC group (P < .05). The incidence of postoperative complications in VATS group was lower than that in RTLC group (5.00% vs. 20.00%) (P < .05). Kaplan-Meier survival analysis showed that there was no significant difference in 12-month OS or PFS between the two groups (P > .05). Conclusions: The long-term curative effect of VATS and RTLC is comparable on patients with stages IIB-IIIA NSCLC. The former has advantages such as less surgical injury, faster postoperative recovery, and higher safety, which can reduce the incidence of postoperative complications. This study provides clinicians with important information about the treatment of stage IIb ~ IIIa NSCLC and helps them choose surgical methods more wisely. These results also alert physicians to focus on operative time, blood loss, and complication risk to maximize patient outcomes.

Circadian clock gene Clock-Bmal1 regulates cellular senescence in Chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disease. COPD is associated with accelerated lung aging. Circadian clock is believed to play important roles in COPD. Although the circadian molecular clock regulates cellular senescence, there is no information available regarding the impact of COPD. The aim of this study is to investigate the role of the circadian clock protein BMAL1 and CLOCK in cellular senescence in order to understand the cellular mechanisms of accelerated aging of COPD. Bmal1 and Clock levels were assessed in the plasma samples of non-smokers, smokers, and patients with COPD. The regulation of ciracadian clock expression and cell senescence by cigarette smoke extract (CSE) was studied in vitro, and small interfering RNA (siRNA) and overexpression of Bmal1 or Clock were employed to investigate the role of circadian clock on cell senescence. Herein, patients with COPD showed lower Bmal1 and Clock expression in the plasma. Interestingly, CSE exposure contributed to the increased cell senescence, decreased Clock and Bmal1 in human bronchial epithelial cells (Beas-2B cells). We found that knockdown of Clock or Bmal1 lead to upregulation of cell senescence in Beas-2B cells, while overexpression of Clock or Bmal1 inhibited cell senescence in Beas-2B cells, which is through the MAPK pathways. Therefore, our findings indicated that Bmal1 or Clock deficiency may be a significant factor to increase cellular senescence of the lung to develop COPD.

Stromal-derived miR-486-5p promotes metastasis of non-small-cell lung cancer cells by targeting the CADM1/tight junctions axis in vascular endothelial cells.

Serum microRNA has been demonstrated as a noninvasive predictor for the progression of non-small-cell lung cancer (NSCLC). The role of microRNA-486-5p (miR-486-5p) in NSCLC seems to be paradoxical. On the one hand, elevated expression of miR-486-5p in serum is associated with unfavorable survival; on the other hand, miR-486-5p was notably reduced in NSCLC tissues and acted as a tumor-suppressor to inhibit NSCLC metastasis. The expression of miR-486-5p was analyzed in serum and tissue samples and their relationship was explored. The miR-486-5p-expressing cells were isolated by fluorescent-activated cell sorting. The downstream target of miR-486-5p was identified by bioinformatics prediction and experimental confirmation. Functional studies of miR-486-5p on NSCLC metastasis were determined by endothelial permeability assay and trans-endothelial invasion assay. We found that the expression of miR-486-5p was remarkably increased in serum, while dramatically downregulated in tumor tissues of NSCLC. However, the level of miR-486-5p in serum was positively correlated with that in tumor tissues. Next, we identified CD31+ vascular endothelial cells in the lung stroma as miR-486-5p-expressing cells. According to bioinformatics prediction, quantitative real-time reverse transcription PCR, luciferase reporter assay, and western blot, miR-486-5p directly targeted the cell adhesion molecule 1/tight junctions axis in vascular endothelial cells. In addition, endothelial permeability assay and trans-endothelial invasion assay confirmed that miR-486-5p promoted NSCLC metastasis. Highly elevated expression of miR-486-5p in CD31+ vascular endothelial cells increased vascular permeability and promoted NSCLC metastasis. In conclusion, stromal-derived miR-486-5p is responsible for the paradoxical effect of miR-486-5p in serum and tumor tissue.

Somatic and germline mutations in the tumor suppressor gene PARK2 impair PINK1/Parkin-mediated mitophagy in lung cancer cells.

PARK2, which encodes Parkin, is a disease-causing gene for both neurodegenerative disorders and cancer. Parkin can function as a neuroprotector that plays a crucial role in the regulation of mitophagy, and germline mutations in PARK2 are associated with Parkinson's disease (PD). Intriguingly, recent studies suggest that Parkin can also function as a tumor suppressor and that somatic and germline mutations in PARK2 are associated with various human cancers, including lung cancer. However, it is presently unknown how the tumor suppressor activity of Parkin is affected by these mutations and whether it is associated with mitophagy. Herein, we show that wild-type (WT) Parkin can rapidly translocate onto mitochondria following mitochondrial damage and that Parkin promotes mitophagic clearance of mitochondria in lung cancer cells. However, lung cancer-linked mutations inhibit the mitochondrial translocation and ubiquitin-associated activity of Parkin. Among all lung cancer-linked mutants that we tested, A46T Parkin failed to translocate onto mitochondria and could not recruit downstream mitophagic regulators, including optineurin (OPTN) and TFEB, whereas N254S and R275W Parkin displayed slower mitochondrial translocation than WT Parkin. Moreover, we found that deferiprone (DFP), an iron chelator that can induce mitophagy, greatly increased the death of A46T Parkin-expressing lung cancer cells. Taken together, our results reveal a novel mitophagic mechanism in lung cancer, suggesting that lung cancer-linked mutations in PARK2 are associated with impaired mitophagy and identifying DFP as a novel therapeutic agent for PARK2-linked lung cancer and possibly other types of cancers driven by mitophagic dysregulation.

Prognostic Significance of Right Bundle Branch Block for Patients with Acute Myocardial Infarction: A Systematic Review and Meta-Analysis.

BACKGROUND: The aim of the current meta-analysis was to assess the effect of right bundle branch block (RBBB) on mortality outcome in patients with acute myocardial infarction (AMI). MATERIAL/METHODS: Embase, PubMed, and Cochrane databases were searched through January 2015 using the keywords "RBBB", "mortality", "AMI", "Coronary Heart Disease", and "cardiovascular". An odds ratio (OR) of RBBB on mortality endpoints was calculated using random-effects models. RESULTS: RBBB was associated with significantly increased overall mortality in patients with AMI. The OR of RBBB for deaths was 1.56 [95% confidence interval (CI), 1.44 to 1.68, p<0.001]. Moreover, RBBB showed a considerable effect on both in-hospital mortality (OR: 1.94, 95% CI: 1.60 to 2.37, p=0.002) and long-term mortality (OR: 1.49, 95% CI: 1.37 to 1.62, p<0.001). CONCLUSIONS: RBBB is associated with an increased risk of all-cause mortality and indicates a poorer prognosis in patients with AMI.

Roles of interleukin (IL)-6 gene polymorphisms, serum IL-6 levels, and treatment in obstructive sleep apnea: a meta-analysis.

BACKGROUND: Inconsistent results regarding the relationship between interleukin (IL)-6 gene polymorphisms, serum IL-6 levels, and the treatment in obstructive sleep apnea (OSA) have been reported. This meta-analysis assessed the associations between IL-6 gene polymorphisms and OSA susceptibility, IL-6 levels in OSA, and CPAP (continuous positive airway pressure) and T&A (tonsillectomy and adenoidectomy) therapy for IL-6 in OSA. METHODS: Studies regarding IL-6 polymorphisms, serum IL-6 levels, and OSA treatment were identified using PubMed and Embase. The associations between IL-6 gene polymorphisms and OSA risk (estimated by pooling odds ratios (ORs) with 95 % confidence intervals (CIs)) were assessed using an allele model. The pooled standardized mean differences (SMDs) with 95 % CI of IL-6 were estimated using a random-effects model. Meta-regression, sensitivity analysis, and publication bias were also evaluated. RESULTS: In total, 53 studies were included. In adults, a significant association between -174 G/C and OSA susceptibility was observed (OR = 1.46, 95 % CI = 1.14-1.87) and IL-6 levels were higher in OSA compared to controls (SMD = 1.56, 95 % CI = 1.18-1.95); however, no association was observed for the -572 G/C allele (OR = 1.13, 95 % CI = 0.87-1.47) and OSA susceptibility and there was no significant change in IL-6 in pre- and post-CPAP therapy (SMD = -0.24, 95 % CI = -0.73 to 0.26). In children, IL-6 levels were also higher in OSA (SMD = 1.27, 95 % CI = 0.29-2.26) and T&A treatment significantly decreased them (SMD = -0.97, 95 % CI = -1.72 to -0.22). CONCLUSIONS: This meta-analysis indicates that the IL-6 gene polymorphism -174 G/C, and not -572 G/C, is associated with adult OSA risk. Although IL-6 levels increased in OSA, CPAP did not significantly suppress them in adults with OSA. In children with OSA, IL-6 levels also increased and T&A therapy significantly decreased them.

[Effects of soluble programmed death ligand 1 on regulating the proliferation of T lymphocytes and its mechanism].

OBJECTIVE: To explore the effects of soluble programmed death ligand 1 (sPD-L1) on the proliferation of T lymphocytes and its mechanism. METHODS: T lymphocytes were isolated from healthy human peripheral blood and activated by phytohemagglutinin (PHA). The experiment had group A: resting T lymphocytes, group B: activated T lymphocytes, group C: activated T lymphocytes+sPD-L1Ig, group D: activated T lymphocytes+sPD-L1Ig+membrance-bound immunoglobulin (mIgG) and group E: activated T lymphocytes+sPD-L1Ig+anti-PD-L1 antibody (2H11). The absorbance value (A) of T lymphocytes in each group was measured by cell counting kit (CCK-8). The cell cycle and apoptosis of T lymphocytes induced by sPD-L1 were measured by flow cytometry. And the phosphorylation level of programmed death 1 (PD-1) signaling motif tyrosine was measured by Western blot. Furthermore, the amounts of signal adaptor molecule Src homology 2 domain-containing tyrosine phosphatase (SHP)-1 and SHP-2 were quantified by immunoprecipitation. And the exciting mechanism of sPD-L1 was explored for PD-1 inhibitory signals. RESULTS: CCK-8 study showed that A values in each group were 0.42 ± 0.03, 1.20 ± 0.06, 0.87 ± 0.05, 0.78 ± 0.05 and 1.11 ± 0.09 respectively when the concentration of sPD-L1Ig was 250 ng/ml. The proliferation of T lymphocytes in group C significantly decreased compared with group B (t = 3.946, P = 0.017) while group E significantly increased compared with group D (t = 3.139, P = 0.035). The percentage of cell number in G1 phase of the above-mentioned 5 groups were (94.49 ± 0.50)%, (79.22 ± 0.50)%, (89.62 ± 0.33)%, (92.89 ± 0.80)% and (87.94 ± 0.87)% respectively and group C significantly increased compared with group B (t = 17.310, P < 0.001). The apoptotic rate of the above-mentioned five groups were (35.77 ± 1.82)%, (35.20 ± 2.70)%, (62.77 ± 0.24)%, (64.47 ± 0.44)% and (36.80 ± 3.53)% respectively. And apoptotic rate in group C significantly increased compared with group B (t = 10.160, P = 0.001) while group E significantly decreased compared with group D (t = 7.790, P = 0.002). The expressions of SHP-1 and SHP-2 showed no inter-group difference (all P > 0.05). However, the expressions of p-SHP-1 and p-SHP-2 in group C was higher than those in group B (t = 10.790, P < 0.001; t = 13.051, P < 0.001) while the expression of p-SHP-1 decreased in group E compared with group D (t = 3.361, P = 0.028). CONCLUSIONS: Soluble PD-L1 can effectively inhibit the proliferation of T lymphocytes. The phosphorylation of SHP-1 and SHP-2 contributes to the inhibitory signaling of PD-1/sPD-L1 pathway. And anti-PD-L1 blocking antibody may partially restore the proliferation of T lymphocytes through a down-regulated expression of p-SHP-1..

[Level of soluble programmed death ligand 1 in pleural effusion and peripheral blood of patients with tuberculous pleural effusion and its clinical implications].

OBJECTIVE: To explore the level of soluble programmed death ligand 1 (sPD-L1) in pleural effusion and peripheral blood of patients with tuberculous pleural effusion (TPE) and elucidate its clinical implications. METHODS: Patients with newly diagnosed pleural effusion at the Second Affiliated Hospital of Soochow University from June 2012 to March 2013 were enrolled and divided into 3 groups of TPE, malignant pleural effusion (MPE) and non-tuberculous non-malignant pleural effusion (non-TPE non-MPE) according to the nature of pleural effusion. The level of sPD-L1 in pleural effusion and peripheral blood was analyzed by enzyme linked immunosorbent assay (ELISA) kit. Flow cytometry was used to detect the changes of immune cell subsets in pleural effusion. And the gene expressions of programmed death ligand 1 (PD-L1) and matrix metalloproteinase-3 (MMP-3) were detected in different effusions by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: A total of 77 newly diagnosed patients with pleural effusion were enrolled, 24 patients with TPE, 39 patients with MPE, 14 patients with non-TPE non-MPE. The level of sPD-L1 in TPE was higher than that in MPE and non-TPE non-MPE (4.2 (2.6-6.3), 1.4 (0.8-2.1), 1.8 (1.2-2.6) µg/L, P < 0.001). No significant difference existed in the levels of sPD-L1 in peripheral blood samples (P = 0.811). The average content of sPD-L1 in pleural effusion in all patients was statistically higher than that in peripheral blood (2.0 (1.4-3.7), 1.5 (1.0-2.0) µg/L, P = 0.004). The proportion of CD8 subset, PD-L1 on CD14(+) monocytes and the mRNA level of PD-L1, MMP-3 in TPE were higher than in MPE and non-TPE non-MPE (P = 0.001, P < 0.001, P < 0.001), and the mRNA level of PD-L1 in TPE was positively correlated with the level of MMP-3 (r = 0.887, P < 0.001). Receiver operating characteristic (ROC) curve analysis showed that sPD-L1 had a sensitivity of 82.6%, a specificity of 83.8% and an area under curve (AUC) of 0.854 for differential diagnosis of TPE from other conditions. Combinations of sPD-L1, PD-L1 on CD14(+) monocytes and adenosine deaminase (ADA) measurements further increased the sensitivity up to 91.3%, specificity up to 89.2% and AUC up to 0.989. CONCLUSION: The elevated expression of sPD-L1 in tuberculous pleural effusion may aid the diagnosis of TPE.

[Effect of cisplatin alone or combined with monoclonal anti-programmed death ligand-1 antibody on lung adenocarcinoma cell line SPCA-1 and T lymphocytes].

OBJECTIVE: To observe the effect of cisplatin alone or combined with anti-programmed death ligand 1 monoclonal antibody (anti-PD-L1 mAb) on the co-culture system of lung adenocarcinoma SPCA-1 cells and T lymphocytes, and therefore to study the immunotherapeutic effect of anti-PD-L1 mAb on lung cancer. METHODS: Human adenocarcinoma SPCA-1 cell line was selected by flow cytometry (FCM) due to its high expression of membranous programmed death ligand-1 (PD-L1). The concentration of cisplatin was determined by CCK-8 method depending on the inhibition rate of SPCA-1 cell, which was set to less-than-or-equal-to 20% (IC20). After treatment with different concentrations of cisplatin, cell proliferation (A value) of SPCA-1 cells and T lymphocytes were detected by CCK-8 method and cell cycle of SPCA-1 cells and cell apoptosis of T lymphocytes were analyzed using PI staining. Treated with different concentrations of cisplatin alone or in combination with anti-PD-L1, T lymphocyte proliferation in co-culture system was determined by CCK-8 method, and cytokines such as IFN (interferon)-γ, IL-2, IL-10 and TNF-α were detected with enzyme linked immunosorbent assay (ELISA) method. RESULTS: The IC20 of cisplatin on SPCA-1 cells was ≤ 0.78 mg/L. The proliferation of SPCA-1 cells were inhibited with different concentrations of cisplatin in a concentration-dependent manner (0.78∼12.5 mg/L) (P < 0.001). Compared with the group treated with high-dose of cisplatin (12.5 mg/L), the proliferation of T lymphocytes treated with low-dose of cisplatin (0.78 mg/L) was higher (t = 3.508, P < 0.05) and the number of late apoptotic and dead T lymphocytes in the co-culture system was reduced (t = 17.55, P < 0.001). Compared with the group of co-culture system, cisplatin (0.78 mg/L) combined with anti-PD-L1 (1.5 mg/L) significantly enhanced the proliferation of T lymphocytes in the co-culture system (t = 4.419, P < 0.01). Also, the levels of T helper cell type-1 (Th1) cytokines such as IFN-γ, IL-2 and TNF-α were up-regulated (t = 25.79-55.15, P < 0.01) and the T helper cell type-2 (Th2) cytokine IL-10 was down-regulated (t = 18.38, P < 0.01). CONCLUSION: Low-dose of cisplatin combined with anti-PD-L1 could effectively promote the proliferation of T lymphocytes in the microenvironment and increase the secretion of Th1 type cytokines. This may reduce the toxic effect of high-dose antineoplastic agents on immune cells and help eradication of tumor cells.

Successful therapy of a critically ill non-small cell lung cancer patient with compound mutations in EGFR G719X and S768I genes using furmonertinib: A case report.

Background: Somatic mutations in epidermal growth factor receptor (EGFR) genes, such as G719X and S768I, and tyrosine kinase inhibitors (TKIs) have been confirmed to be promising for developing new targeted therapies against advanced non-small-cell lung cancer (NSCLC). The G719X and S768I mutations are uncommon and often occur in the form of compound mutations. However, the efficacy of furmonertinib in patients with these uncommon compound mutations has not yet been elucidated. Case presentation: In this study, the G719X/S768I compound mutations were detected in a critically ill NSCLC patient. This patient received furmonertinib for 14 months and successfully responded to the treatment. The present case report highlights the ideal clinical response, with ongoing follow-up. Conclusion: We report the successful treatment of a critically ill NSCLC patient carrying rare compound EGFR G719X and S768I mutations using furmonertinib. To the best of our knowledge, this is the first reported case of a successful furmonertinib treatment of compound EGFR G719X and S768I mutations. Furmonertinib, a third-generation EGFR-TKI, may be effective in controlling the EGFR G719X and S768I compound mutations in NSCLC.

Clinical features that predict the mortality risk in older patients with Omicron pneumonia: the MLWAP score.

In December 2022, the Chinese suffered widespread Omicron of SARS-CoV-2 with variable symptom severity and outcome. We wanted to develop a scoring model to predict the mortality risk of older Omicron pneumonia patients by analyzing admission data. We enrolled 227 Omicron pneumonia patients aged 60 years and older, admitted to our hospital from December 15, 2022, to January 16, 2023, and divided them randomly into a 70% training set and a 30% test set. The former were used to identify predictors and develop a model, the latter to verify the model, using the area under the receiver operating characteristic curve (AUC), the Hosmer-Lemeshow goodness-of-fit test, a calibration curve to test its performance and comparing it to the existing scores. The MLWAP score was calculated based on a multivariate logistic regression model to predict mortality with a weighted score that included immunosuppression, lactate ≥ 2.4, white blood cell count ≥ 6.70 × 109/L, age ≥ 77 years, and PaO2/FiO2 ≤ 211. The AUC for the model in the training and test sets was 0.852 (95% CI, 0.792-0.912) and 0.875 (95% CI, 0.789-0.961), respectively. The calibration curves showed a good fit. We grouped the risk scores into low (score 0-7 points), medium (8-10 points), and high (11-13 points). This model had a sensitivity of 0.849, specificity of 0.714, and better predictive ability than the CURB-65 and PSI scores (AUROC = 0.859 vs. 0.788 vs. 0.801, respectively). The MLWAP-mortality score may help clinicians to stratify hospitalized older Omicron pneumonia patients into relevant risk categories, rationally allocate medical resources, and reduce the mortality.

Metabolic reprogramming-related gene classifier distinguishes malignant from the benign pulmonary nodules.

The current existing classifiers for distinguishing malignant from benign pulmonary nodules is limited by effectiveness or clinical practicality. In our study, we aimed to develop and validate a gene classifier for lung cancer diagnosis. To identify the genes involved in this process, we used the weighted gene co-expression network analysis to analyze gene expression datasets from Gene Expression Omnibus (GEO). We identified the three most relevant modules associated with malignant nodules and performed functional enrichment analysis on them. The results indicated significant involvement in metabolic, immune-related, cell cycle, and viral-related processes. All three modules showed enrichment in metabolic reprogramming pathways. Based on these genes, we intersected genes from the three modules with metabolic reprogramming-related genes and further intersected with differentially expressed genes to get 78 genes. After machine learning algorithms and manual selection, we finally got a nine-gene classifier consisting of SEC24D, RPSA, PSME3, PSMD8, PSMB7, NCOA1, MED12, LPCAT1, and AKR1C3. Our developed and validated classifier-based model demonstrated good discrimination, with an area under the curve (AUC) of 0.763 in the development cohort, 0.744 in the internal validation cohort, and 0.718 in the external validation cohort, and outperformed previous clinical models. Moreover, the addition of nodule size improved the predictive capability of the classifier. We further verify the expression of the gene in the classifier using TCGA lung cancer samples and found eight of the genes showed significant differential expression in lung adenocarcinoma while all nine genes showed significant differential expression in lung squamous carcinoma. Our findings underscore the significance of metabolic reprogramming pathways in patients with malignant pulmonary nodules, and our gene classifier can assist clinicians in differentiating benign from malignant pulmonary nodules in clinical settings.

[Effect of soluble PD-L1 released by lung cancer cells in regulating the function of T lymphocytes].

OBJECTIVE: To explore the expression of soluble programmed death ligand-1 on lung cancer cells and to clarify its biological function through PD-1/PD-L1 pathway in regulating the function of T lymphocytes. METHODS: Labeled monoclonal antibody and flow cytometry were used to analyze the expression of PD-L1 and its receptor PD-l on lung cancer cells and human T lymphocytes, respectively. The level of sPD-L1 in the supernatant of lung cancer cells was determined with an ELISA kit. The inhibition of proliferation of T lymphocytes by mPD-L1 and sPD-L1 was studied using CCK-8 incorporation. RESULTS: Low or no expression [(16.08 ± 2.28)%] of PD-1 was found on resting T lymphocytes from human peripheral blood with flow cytometry, but up-regulated expression of PD-1 [(78.06 ± 7.21)%] was found on the surface of activated T lymphocytes. Soluble PD-L1 was found in supernatant of some lung cancer cell lines, such as H1299, HO8910, SPCA-1, H460, H446 cells, with PD-L1 expressing on their cell surface [(78.34 ± 10.25)%, (68.17 ± 11.56)%, (45.32 ± 7.98)%, (47.52 ± 9.62)% and (40.95 ± 8.56)%, respectively], but very low expression on A549 cells [(16.02 ± 6.28)%]. The level of mPD-L1 on H1299 cells was highest [(78.34 ± 10.25)%], compared with HO8910 cells (68.17 ± 11.56)%, SPCA-1 cells (45.32 ± 7.98)%, H446 cells (40.95 ± 8.56)%, and H460 cells (47.52 ± 9.62)%. At the same time, the sPD-L1 level on H1299 cells was low [(0.17 ± 0.01) ng/ml], compared with HO8910 cells (0.30 ± 0.03) ng/ml, SPCA-1cells (0.59 ± 0.03) ng/ml, H446 cells (0.34 ± 0.02) ng/ml, and H460 cells (0.57 ± 0.03) ng/ml, but not expressed on A549 cells. PD-L1 expressing H1299 cells inhibited the proliferation of T lymphocytes in the co-culture system. Supernatant of the cultured PD-L1(+) lung cancer cells also inhibited T cell proliferation. Anti-human PD-L1 blocking antibody could partly restore the proliferation capacity of T lymphocytes. CONCLUSIONS: Membrane-bound PD-L1 and soluble PD-L1 released from lung cancer cells can effectively inhibit the proliferation of T lymphocytes in mixed culture system and down-regulate cell-mediated immunity in vitro. This may lead to inactivation of tumor antigen-specific T cells and immune escape of lung cancer cells.

Characteristics and risk factors for advanced lung cancer with pulmonary embolism: A cross-sectional, case-control study.

OBJECTIVES: Pulmonary embolism (PE) is a life-threatening complication that can occur in patients with lung cancer. In this study, we aimed to identify risk factors and examine the clinical characteristics of advanced lung cancer patients with PE. METHODS: We conducted a retrospective review of patients admitted to our two hospitals between January 2020 and June 2022. The case group consisted of patients with lung cancer and PE, and a closely matched control group was included to identify risk factors. Statistical analysis was conducted using R language. RESULTS: A total of 4957 patients were reviewed, and 162 patients (comprising 54 cases and 108 controls) were included in this study. The prevalence of lung cancer with PE in the study population was 1.08%. The majority of patients were male, and the most common histological subtype was adenocarcinoma (67%), followed by squamous cell carcinoma, small cell carcinoma, and poorly differentiated non-small cell lung cancer. The majority of patients had a high performance status (PS) score, with 50% experiencing respiratory failure (mainly hypoxia) and 33% with deep vein thrombosis (DVT). Forty-eight percent of patients were diagnosed with concurrent PE. Further analysis showed that PE was an independent predictor of poor survival, and a PS score of >1 was an independent risk factor for PE in patients with lung cancer. CONCLUSION: Our study provides valuable insights into the epidemiology and prognosis of PE in lung cancer patients and suggests that a poor ECOG PS, which has not been previously reported, is an independent risk factor for PE.

POLRMT over-expression is linked to WNT/beta-catenin signaling, immune infiltration, and unfavorable outcomes in lung adenocarcinoma patients.

BACKGROUND: Mitochondrial RNA polymerase (POLRMT) is essential for the expression of mitochondrial genes. In recent studies, POLRMT expression promoted non-small cell cancer cell proliferation in cell lines and xenografts. The present study investigated the impact of POLRMT expression and function on lung adenocarcinoma (LUAD) patients. METHOD: Multi-omics data (genomics, transcriptomics, and proteomics) from publicly available databases were used to assess the role of POLRMT expression and function in LUAD. These findings were further verified using cancer tissues from clinical samples. RESULTS: POLRMT was over-expressed in LUADs, with mutation frequencies ranging from 1.30% to 5.71%. Over-expression of POLRMT was associated with an abnormal clinicopathological condition resulting in a decreased lifespan. Furthermore, gene sets enrich analysis revealed that POLRMT expression was linked to WNT/beta-catenin signaling; the expression of downstream target genes was positively correlated with POLRMT expression. Also, POLRMT expression was positively correlated with immunosuppressive genes, thereby affecting immune infiltration. CONCLUSION: POLRMT is over-expressed in LUAD, thereby impacting patient survival. It is also involved in WNT/beta-catenin signaling and may affect tumor infiltration.

Quantitative analysis of fucosylated glycoproteins by immobilized lectin-affinity fluorescent labeling.

Human biofluids are often used to discover disease-specific glycosylation, since abnormal changes in protein glycosylation can discern physiopathological states. Highly glycosylated proteins in biofluids make it possible to identify disease signatures. Glycoproteomic studies on saliva glycoproteins showed that fucosylation was significantly increased during tumorigenesis and that glycoproteins became hyperfucosylated in lung metastases, and tumor stage is associated with fucosylation. Quantification of salivary fucosylation can be achieved by mass spectrometric analysis of fucosylated glycoproteins or fucosylated glycans; however, the use of mass spectrometry is non-trivial for clinical practice. Here, we developed a high-throughput quantitative method, lectin-affinity fluorescent labeling quantification (LAFLQ), to quantify fucosylated glycoproteins without relying on mass spectrometry. Lectins with a specific affinity for fucoses are immobilized on the resin and effectively capture fluorescently labeled fucosylated glycoproteins, which are further quantitatively characterized by fluorescence detection in a 96-well plate. Our results demonstrated that serum IgG can be accurately quantified by lectin and fluorescence detection. Quantification in saliva showed significantly higher fucosylation in lung cancer patients compared to healthy controls or other non-cancer diseases, suggesting that this method has the potential to quantify stage-related fucosylation in lung cancer saliva.

The Clinical Impact of Metagenomic Next-Generation Sequencing (mNGS) Test in Hospitalized Patients with Suspected Sepsis: A Multicenter Prospective Study.

Background: Metagenomic Next Generation Sequencing (mNGS) has the potential to detect pathogens rapidly. We aimed to assess the diagnostic performance of mNGS in hospitalized patients with suspected sepsis and evaluate its role in guiding antimicrobial therapy. Methods: A multicenter, prospective cohort study was performed. We enrolled patients with suspected sepsis, collected clinical characteristics and blood samples, and recorded the 30-day survival. Diagnostic efficacy of mNGS test and blood culture was compared, and the clinical impact of mNGS on antibiotic regimen modification was analyzed. Results: A total of 277 patients were enrolled, and 162 were diagnosed with sepsis. The mortality was 44.8% (121/270). The mNGS test exhibited shorter turn-out time (27.0 (26.0, 29.0) vs. 96.0 (72.0, 140.3) hours, p < 0.001) and higher sensitivity (90.5% vs. 36.0%, p < 0.001) compared with blood culture, especially for fungal infections. The mNGS test showed better performance for patients with mild symptoms, prior antibiotic use, and early stage of infection than blood culture, and was capable of guiding antibiotic regimen modification and improving prognosis. Higher reads of pathogens detected by mNGS were related to 30-day mortality (p = 0.002). Conclusions: Blood mNGS testing might be helpful for early etiological diagnosis of patients with suspected sepsis, guiding the antibiotic regimen modification and improving prognosis.

Corrigendum: Advanced NSCLC patients with EGFR T790M harbouring TP53 R273C or KRAS G12V cannot benefit from osimertinib based on a clinical multicentre study by tissue and liquid biopsy.

[This corrects the article DOI: 10.3389/fonc.2021.621992.].

International expert consensus on diagnosis and treatment of lung cancer complicated by chronic obstructive pulmonary disease.

Background: Lung cancer combined by chronic obstructive pulmonary disease (LC-COPD) is a common comorbidity and their interaction with each other poses significant clinical challenges. However, there is a lack of well-established consensus on the diagnosis and treatment of LC-COPD. Methods: A panel of experts, comprising specialists in oncology, respiratory medicine, radiology, interventional medicine, and thoracic surgery, was convened. The panel was presented with a comprehensive review of the current evidence pertaining to LC-COPD. After thorough discussions, the panel reached a consensus on 17 recommendations with over 70% agreement in voting to enhance the management of LC-COPD and optimize the care of these patients. Results: The 17 statements focused on pathogenic mechanisms (n=2), general strategies (n=4), and clinical application in COPD (n=2) and lung cancer (n=9) were developed and modified. These statements provide guidance on early screening and treatment selection of LC-COPD, the interplay of lung cancer and COPD on treatment, and considerations during treatment. This consensus also emphasizes patient-centered and personalized treatment in the management of LC-COPD. Conclusions: The consensus highlights the need for concurrent treatment for both lung cancer and COPD in LC-COPD patients, while being mindful of the mutual influence of the two conditions on treatment and monitoring for adverse reactions.