Plin2 inhibits autophagy via activating AKT/mTOR pathway in non-small cell lung cancer.

Perilipin 2 (Plin2) is known to be dysregulated in several human malignancies, which facilitates cancer progression. Recent studies have found that the abnormal expression of Plin2 is associated with poor prognosis of non-small cell lung cancer (NSCLC). However, the specific role of Plin2 and its underlying mechanism remain unclear. This study revealed that Plin2 expression was low in NSCLC tissues, and its relatively higher expression indicated larger tumor size and poorer prognosis. In vitro experiments proved that Plin2 promoted NSCLC cellular proliferation and inhibited autophagy by activating the AKT/mTOR pathway. Meanwhile, treatment with the AKT phosphorylation promoter or inhibitor neutralized the influence of Plin2 depletion or over-expression on proliferation and autophagy, respectively. In vivo study showed that Plin2 stimulated subcutaneous tumorigenesis of NSCLC cells in nude mice. Collectively, this study clarified the carcinogenic role of Plin2 and its molecular mechanism in NSCLC progression, which may facilitate a targeted therapy in the future.

Endostar (rh-endostatin) consolidation therapy after sequential chemoradiotherapy in stage III, unresectable lung adenocarcinoma with novel STK11, TP53 and ATM mutations: a case report.

Concurrent chemoradiotherapy (cCRT) has been predominantly used as the standard therapy for locally advanced or unresectable non-small cell lung cancer (NSCLC) patients with stage III disease. Based on the outstanding results of Phase III Pacific study, Programmed Death-Ligand 1 (PD-L1) inhibitor consolidation therapy after cCRT without progression disease (PD) has been recommended by National Comprehensive Cancer Network (NCCN) guideline as standard therapy for these patients. However, not all patients can tolerate a full course of cCRT due to the poor performance status, concurrent complications, or poor pulmonary function. Therefore, sequential chemoradiotherapy (sCRT) is often conducted for these selected patients who have been assessed as not suitable for cCRT. Moreover, not all patients are suitable for immunotherapy, especially for those with auto-immune disease or certain gene mutations associated with non-response of immunotherapy. Hence, we presented a case with both autoimmune disease and serine/threonine kinase 11 (STK11) mutation, who underwent angiogenesis inhibitor Endostar consolidation therapy after sCRT, and achieved a progression-free survival (PFS) more than 17 months and still in the process of follow-up. This case may offer an effective consolidation treatment for these patients with stage III disease unsuitable for immunotherapy. Further clinical trials are required to confirm this treatment option.

Electrochemical regulation of the band gap of single layer graphene: from semimetal to semiconductor.

As a semimetal with a zero band gap and single-atom-scale thickness, single layer graphene (SLG) has excellent electron conductivity on its basal plane. If the band gap could be opened and regulated controllably, SLG would behave as a semiconductor. That means electronic elements or even electronic circuits with single-atom thickness could be expected to be printed on a wafer-scale SLG substrate, which would bring about a revolution in Moore's law of integrated circuits, not by decreasing the feature size of line width, but by piling up the atomic-scale-thickness of an SLG circuit board layer by layer. Employing scanning electrochemical microscopy (SECM), we have demonstrated that the electrochemically induced brominating addition reaction can open and regulate the band gap of SLG by forming SLG bromide (SLGBr). The SLG/SLGBr/SLG Schottky junction shows excellent performance in current rectification, and the rectification potential region can be regulated by tuning the degree of bromination of SLG. This work provides a feasible and effective way to regulate the band gap of SLG, which would open new applications for SLG in micro-nano electronics and ultra-large-scale integrated circuits (ULSI).

Comparison of Intercostal Block and Epidural Analgesia for Post-thoracotomy: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Thoracotomy is associated with severe postoperative pain. Effective management of acute pain after thoracotomy may reduce complications and chronic pain. Epidural analgesia (EPI) is considered the gold standard for postthoracotomy analgesia; however, it is associated with complications and limitations. Emerging evidence suggests that an intercostal nerve block (ICB) has a low risk of severe complications. Anesthetists will benefit from a review that assesses the advantages and disadvantages associated with ICB and EPI in thoracotomy. OBJECTIVES: This meta-analysis aimed to evaluate the analgesic efficacy and adverse effects of ICB and EPI for pain treatment after thoracotomy. STUDY DESIGN: Systematic review. METHODS: This study was registered in the International Prospective Register of Systematic Reviews (CRD42021255127). Relevant studies were searched for in PubMed, Embase, Cochrane, and Ovid databases. Primary (postoperative pain at rest and during cough) and secondary (nausea and vomiting, morphine consumption, and length of hospital stay) outcomes were analyzed. The standard mean difference for continuous variables and the risk ratio for dichotomous variables were calculated. RESULTS: Nine randomized controlled studies with a total of 498 patients who underwent thoracotomy were included. The results of the meta-analysis demonstrated no statistically significant differences between the 2 methods in terms of the Visual Analog Scale scores for pain at 6-8, 12-15, 24-25, and 48-50 hours at rest and at 24 hours during coughing after surgery. There were no significant differences in nausea and vomiting, morphine consumption, or length of hospital stay between the ICB and EPI groups. LIMITATIONS: The number of included studies was small, and the quality of evidence was low. CONCLUSIONS: ICB may be as effective as EPI for pain relief after thoracotomy.

ER predicts poor prognosis in male lung squamous cell cancer of stage IIIA-N2 disease after sequential adjuvant chemoradiotherapy.

Introduction: The efficacy of postoperative radiotherapy (PORT) is still unclear in non-small cell lung cancer (NSCLC) patients with pIIIA-N2 disease. Estrogen receptor (ER) was proven significantly associated with poor clinical outcome of male lung squamous cell cancer (LUSC) after R0 resection in our previous study. Methods: A total of 124 male pIIIA-N2 LUSC patients who completed four cycles of adjuvant chemotherapy and PORT after complete resection were eligible for enrollment in this study from October 2016 to December 2021. ER expression was evaluated using immunohistochemistry assay. Results: The median follow-up was 29.7 months. Among 124 patients, 46 (37.1%) were ER positive (stained tumor cells≥1%), and the rest 78 (62.9%) were ER negative. Eleven clinical factors considered in this study were well balanced between ER+ and ER- groups. ER expression significantly predicted a poor prognosis in disease-free survival (DFS, HR=2.507; 95% CI: 1.629-3.857; log-rank p=1.60×10-5). The 3-year DFS rates were 37.8% with ER- vs. 5.7% with ER+, with median DFS 25.9 vs. 12.6 months, respectively. The significant prognostic advantage in ER- patients was also observed in overall survival (OS), local recurrence free survival (LRFS), and distant metastasis free survival (DMFS). The 3-year OS rates were 59.7% with ER- vs. 48.2% with ER+ (HR, 1.859; 95% CI: 1.132-3.053; log-rank p=0.013), the 3-year LRFS rates were 44.1% vs. 15.3% (HR=2.616; 95% CI: 1.685-4.061; log-rank p=8.80×10-6), and the 3-year DMFS rates were 45.3% vs. 31.8% (HR=1.628; 95% CI: 1.019-2.601; log-rank p=0.039). Cox regression analyses indicated that ER status was the only significant factor for DFS (p=2.940×10-5), OS (p=0.014), LRFS (p=1.825×10-5) and DMFS (p=0.041) among other 11 clinical factors. Conclusions: PORT might be more beneficial for ER negative LUSCs in male, and the examination of ER status might be helpful in identifying patients suitable for PORT.

Molecular understanding of the Helmholtz capacitance difference between Cu(100) and graphene electrodes.

Unraveling the origin of Helmholtz capacitance is of paramount importance for understanding the interfacial structure and electrostatic potential distribution of electric double layers (EDL). In this work, we combined the methods of ab initio molecular dynamics and classical molecular dynamics and modeled electrified Cu(100)/electrolyte and graphene/electrolyte interfaces for comparison. It was proposed that the Helmholtz capacitance is composed of three parts connected in series: the usual solvent capacitance, water chemisorption induced capacitance, and Pauling repulsion caused gap capacitance. We found the Helmholtz capacitance of graphene is significantly lower than that of Cu(100), which was attributed to two intrinsic factors. One is that graphene has a wider gap layer at interface, and the other is that graphene is less active for water chemisorption. Finally, based on our findings, we provide suggestions for how to increase the EDL capacitance of graphene-based materials in future work, and we also suggest that the new understanding of the potential distribution across the Helmholtz layer may help explain some experimental phenomena of electrocatalysis.

Effects of Camrelizumab Combined with First-Line Chemotherapy on Serum SCC, VEGF Levels, and Adverse Reactions in Patients with Advanced Squamous Cell Carcinoma of the Lung.

Objective: To study the effects of camrelizumab accompanied by first-line chemotherapy on serum SCC, VEGF levels, and adverse reactions in people undergoing advanced lung squamous cell carcinoma. Methods: Data sources of the study subjects were 60 people suffering from advanced squamous cell carcinoma of the lung hospitalized from January 2018 to October 2019. They were assigned to two groups, including the control group and the observation group in a random manner, and each consisted of 30 patients. Those in the observation group received camrelizumab (SHR-1210), and gemcitabine plus cisplatin (GP) chemotherapy were treated in the control group. Finally, according to the results, we compare the data of patients in both groups so as to find out the similarities and differences. Results: Among them, the effective efficiency of clinical treatment in the control group reached 36.67%, and that in the observation group reached 56.67%. Intuitively, it can be concluded that the control group showed lower results than the observed group. The observed group turned out to have higher periodic survival and progression free survival (PFS) of patients than the other group. During and after the cycle treatment, the data of SCC and VEGF were reduced to some extent, but the control group appeared to have a more evident reduction rate than the other group. Conclusion: SHR-1210 combined with chemotherapy has a considerable effect in practical application and has excellent clinical performance.

Survival analysis and development of a prognostic nomogram for patients with malignant mesothelioma in different anatomic sites.

Background: Malignant mesothelioma (MMe) is a rare and fatal cancer with a poor prognosis. Our study aimed to compare the overall survival (OS) of MMe patients across various sites and develop a prognostic model to provide a foundation for individualized management of MMe patients. Methods: From the Surveillance, Epidemiology, and End Results (SEER) database, 1,772 individuals with malignant mesothelioma (MMe) were identified. The X-tile software was used to identify the optimal cut-off point for continuous variables. The Kaplan-Meier method was employed to compare the survival of MMe across different sites. The Cox proportional hazards model was applied to identify the independent risk factors of overall survival (OS) and a nomogram was constructed. Results: In the survival analysis, MMe originating from the reproductive organs and hollow organs showed a relatively better prognosis than those originating from soft tissue, solid organs, and pleura. Age, gender, location, histological type, grade of differentiation, extent of disease, lymph node status, lymph node ratio (LNR), and chemotherapy were all found to be independent risk variables for the prognosis of MMe patients (P<0.05) in a multivariate Cox analysis and were included in the construction of nomogram. In the training and testing sets, the C-index of the nomogram was 0.701 and 0.665, respectively, and the area under the ROC curve (AUROC) of the 1-, 3-, and 5-year overall survival rate was 0.749, 0.797, 0.833 and 0.730, 0.800, 0.832, respectively. The calibration curve shows that the nomogram is well-calibrated. Conclusions: This is the first research to examine the prognosis of MMe patients based on the location. However, previous studies often focused on malignant pleural mesothelioma or malignant peritoneal mesothelioma with high incidence. Furthermore, a nomograph with good prediction efficiency was established according to the variables that influence patient survival outcomes, which provides us with a reference for clinical decision-making.

Necroptosis-Related Prognostic Signature and Nomogram Model for Predicting the Overall Survival of Patients with Lung Cancer.

Background: Necroptosis is a type of programmed cell death mode and it serves an important role in the tumorigenesis and tumor metastasis. The purpose of this study is to develop a prognostic model based on necroptosis-related genes and nomogram for predicting the overall survival of patients with lung cancer. Method: Differentially expressed necroptosis-related genes (NRDs) between lung cancer and normal samples were identified. Univariate and LASSO regression analyses were performed to establish a risk score (RS) model, followed by validation within TCGA and GSE37745. The correlation between RS model and tumor microenvironment, mutation status, or drug susceptibility was analyzed. By combining clinical factors, nomogram was developed to predict 1-, 3-, and 5-year survival probability of an individual. The biological function involved by different risk groups was conducted by GSEA. Results: A RS model containing six NRDs (FLNC, PLK1, ID1, MYO1C, SERTAD1, and LEF1) was constructed, and patients were divieded into low-risk (LR) and high-risk (HR) groups. Patients in HR group were associated with shorter survival time than those in the LR group; this model had better prognostic performance. Nomogram based on necroptosis score, T stage, and stage had been confirmed to predict survival of patients. The number of resting NK cells and M0 macrophages was higher in HR group. In addition, higher tumor mutational burden and drug sensitivity were observed in the HR group. Patients in HR group were involved in p53 signaling pathway and cell cycle. Conclusion: This study constructed a robust six-NRDs signature and established a prognostic nomogram for survival prediction of lung cancer.

ER expression associates with poor prognosis in male lung squamous carcinoma after radical resection.

BACKGROUND: Clinical options for lung squamous carcinoma (LUSC) are still quite limited. Carcinogenesis is an exceedingly complicated process involving multi-level dysregulations. Therefore, only looking into one layer of genomic dysregulation is far from sufficient. METHODS: We identified differentially expressed genes with consistent upstream genetic or epigenetic dysregulations in LUSC. Random walk was adopted to identify genes significantly affected by upstream abnormalities. Expression differentiation and survival analysis were conducted for these significant genes, respectively. Prognostic power of selected gene was also tested in 102 male LUSC samples through immunohistochemistry assay. RESULTS: Twelve genes were successfully retrieved from biological network, including ERα (ESRS1), EGFR, AR, ATXN1, MAPK3, PRKACA, PRKCA, SMAD4, TP53, TRAF2, UBQLN4 and YWHAG, which were closely related to sex hormone signaling pathway. Survival analysis in public datasets indicated ERα was significantly associated with a poor overall survival (OS) in male LUSC. The result of our immunohistochemistry assay also demonstrated this correlation using R0 resected tumors (n = 102, HR: 2.152, 95% CI: 1.089-4.255, p = 0.024). Although disease-free survival (DFS) difference was non-significant (n = 102, p = 0.12), the tendency of distinction was straight-forward. Cox analysis indicated ERα was the only independent prognostic factor for male patients' OS after R0 resection (HR = 2.152, p = 0.037). CONCLUSION: ERα was significantly related to a poor prognosis in LUSC, especially for male patients after radical surgery, confirmed by our immunohistochemistry data.

P3H4 Overexpression Serves as a Prognostic Factor in Lung Adenocarcinoma.

BACKGROUND: The present study is aimed at evaluating the functional and clinical values of P3H4 in lung adenocarcinoma. Moreover, we also investigated the downstream pathways that P3H4 might participate in. METHODS: The differential expression analysis was used to identify genes differentially expressed in lung adenocarcinoma tissues as compared with normal tissues. Survival analysis was used to test the association between P3H4 and survival time. Gene set enrichment analysis was conducted to explore the downstream pathways. CCK8 and transwell were employed to examine the impact of P3H4 on cell phenotypes. RESULTS: P3H4 was highly upregulated in LUAD tissues at both RNA and protein levels. Moreover, the LUAD patients, who had high expression of P3H4, were also observed to have shorter disease-free survival and overall survival. These results demonstrated that P3H4 could be used as a prognostic biomarker for LUAD. Moreover, we also found that it was the copy number alterations (CNAs), not DNA methylation, that regulated the RNA expression of P3H4, indicating that its upregulation might be partially resulted from the CNAs. Furthermore, functional experiments revealed that the A549 and H1299 cells with siRNA treatment (siP3H4) exhibited significantly decreased cell proliferation after 24 hours, migratory ability, and invasiveness. Functionally, the upregulated proteins in the P3H4 high expression group were mainly enriched in tumor microenvironment-related pathways such as phagosome, focal adhesion, and ECM-receptor interaction and cancer-related pathways such as bladder cancer pathway, proteoglycans in cancer, and hippo signaling pathway. CONCLUSION: The present study systematically evaluated the functional and clinical values of P3H4 in LUAD, and explored the related biological pathways. P3H4 might promote LUAD progression through regulating tumor microenvironment-related pathways.

Comprehensive analyses of PBRM1 in multiple cancer types and its association with clinical response to immunotherapy and immune infiltrates.

BACKGROUND: The prognostic value of polybromo 1 (PBRM1) gene mutations in clear cell renal carcinoma (CCRCC) with anti-programmed death-ligand 1 (PD-L1) therapy remains controversial, and few studies have reported the impact of PBRM1 mutations in other cancer types. METHODS: The patient information was obtained from cBioPortal and the Tumor Immune Estimation Resource (TIMER) databases. Mann-Whitney U test were used for correlation analysis. For survival analyses, Kaplan-Meier survival curves were used and compared using the log-rank test. Cox's regression model was used to perform univariable and multivariable analyses. RESULTS: Our study, for the first time, performed comprehensive analyses of PBRM1 mutation frequency, PBRM1 expression, relationship of PBRM1 mutations with clinical benefit from immunotherapy, and PBRM1 expression with immune infiltrates in diverse cancer types. The results showed that the expression of PBRM1 was significantly lower in diverse cancer types compared with normal tissues. Based on multivariable analysis, PBRM1 mutations trended towards worse clinical outcomes from anti-PD-L1 in CCRCC, lung adenocarcinoma (LUAD), bladder urothelial carcinoma (BLCA), and skin cutaneous melanoma (SKCM), and a significant association was observed in LUAD and BLCA. PBRM1 mutations were associated with higher TMB in diverse cancer types and significant associations were observed in LUAD and BLCA. The expression of PBRM1 was found to positively correlate with immune infiltrates in diverse cancer types. CONCLUSIONS: Our findings suggested caution in starting immunotherapy alone in PBRM1 mutant patients. Further studies are needed to improve treatment for PBRM1 mutant patients.

Identifying Actionable Variants Using Capture-Based Targeted Sequencing in 563 Patients With Non-Small Cell Lung Carcinoma.

Although the NSCLC diagnostic standards recommend the detection of driver gene mutation, comprehensive genomic profiling has not been used widely in clinical practice. As to the different mutation spectrum characteristics between populations, the research based on Chinese NSCLC cohort is very important for clinical practice. Therefore, we collected 563 surgical specimens from patients with non-small cell lung carcinoma and applied capture-based sequencing using eight-gene panel. We identified 556 variants, with 416 potentially actionable variants in 54.88% (309/563) patients. These single nucleotide variants, insertions and deletions were most commonly found in EGFR (55%), followed by ERBB2 (12%), KRAS (11%), PIK3CA (9%), MET (8%), BRAF (7%), DDR2 (2%), NRAS (0.3%). By using ten protein function prediction algorithms, we also identified 30 novel potentially pathogenic variants. Ninety-eight patients harbored EFGR exon 21 p.L858R mutation and the catalytic domain of the protein tyrosine kinase (PTKc) in EGFR is largely mutated. In addition, there were nine frequent pathogenic variants found in five or more patients. This data provides the potential molecular basis for directing the treatment of lung cancer.

MicroRNA-105 promotes epithelial-mesenchymal transition of nonsmall lung cancer cells through upregulating Mcl-1.

BACKGROUND: A growing number of microRNAs have been proved to play significant roles in limiting tumor growth and the epithelial-mesenchymal transition (EMT) process of nonsmall cell lung cancer (NSCLC). Present work aims to study the function of microRNA (miR)-105 in EMT of NSCLC cells, which is unrevealed yet. METHODS: Two NSCLC cell lines A549 and Calu-3 were transfected with miR-105 mimic, inhibitor, or scrambled control. And then the effects of miR-105 were evaluated by performing trypan blue staining, transwell assay, ANNEXIN-FITC/propidium iodide (PI) double staining and Western blot analysis. The expression levels of myeloid cell leukemia-1 (Mcl-1) after transfection were tested by real-time quantitative polymerase chain reaction and Western blot analysis. Whether Mcl-1 was a downstream effector of miR-105, and the involvement of mammalian target of Rapamycin (mTOR) and p38 mitogen-activated protein kinase (p38MAPK) signaling pathways were assessed. RESULTS: The overexpression of miR-105 significantly increased the viability and migration of A549 and Calu-3, but had no impacts on cell apoptosis. Meanwhile, E-cadherin was remarkably downregulated, and N-cadherin, Vimentin, ZEB1, and Snail were upregulated by miR-105 overexpression. Mcl-1 was positively regulated by miR-105, and the effects of miR-105 overexpression on A549 and Calu-3 cells viability, migration and EMT were all flattened by Mcl-1 silence. Both mTOR and p38MAPK pathways were activated in miR-105-overexpressing and Mcl-1-overexpressing cells. Besides, inhibition of mTOR and p38MAPK pathways by using Rapamycin and VX-702 abolished the regulatory effects of Mcl-1 on EMT. CONCLUSION: Our study underlines the importance of miR-105 in modulating NSCLC cells EMT. miR-105 promoted the EMT of NSCLC cells possibly via upregulation of Mcl-1 and thereby activation of mTOR and p38MAPK signaling.

External suction versus water seal after selective pulmonary resection for lung neoplasm: a systematic review.

OBJECTIVE: To evaluate whether external suction is more advantageous than water seal in patients undergoing selective pulmonary resection (SPR) for lung neoplasm. SUMMARY OF BACKGROUND DATA: Whether external suction should be routinely applied in postoperative chest drainage is still unclear, particularly for lung neoplasm patients. To most surgeons, the decision is based on their clinical experience. METHODS: Randomized control trials were selected. The participants were patients undergoing SPR with lung neoplasm. Lung volume reduction surgery and pneumothorax were excluded. Suction versus non-suction for the intervention. The primary outcome was the incidence of persistent air leak (PAL). The definition of PAL was air leak for more than 3-7 days. The secondary outcomes included air leak duration, time of drainage, postoperative hospital stay and the incidence of postoperative pneumothorax. Studies were identified from literature collections through screening. Bias was analyzed and meta-analysis was used. RESULTS: From the 1824 potentially relevant trials, 6 randomized control trials involving 676 patients were included. There was no difference between external suction and water seal in decreasing the incidence of PAL [95% confidence interval (CI) 0.81-2.16; z = 1.10; P = 0.27]. Regarding secondary outcomes, there were no differences in time of drainage (95% CI-0.36-1.56, P = 0.22), postoperative hospital stay (95% CI -.31-.54, P = 0.87) or incidence of postoperative pneumothorax (95% CI 0.18-.02, P = 0.05) between external suction and water seal. CONCLUSIONS: For participants, no differences are identified in terms of PAL incidence, drainage time, length of postoperative hospital stay or incidence of postoperative pneumothorax between external suction and water seal. The bias analysis should be emphasized. To the limitations of the bias and methodological differences among the included studies, we have no recommendation on whether external suction should be routinely applied after lung neoplasm SPR. More high-quality randomized controlled trials are needed. SYSTEMATIC REVIEW REGISTRATION: None.