The use of non-steroid anti-inflammatory drugs during radical resection correlated with the outcome in non-small cell lung cancer.

AIMS: The use of non-steroid anti-inflammatory drugs (NSAIDs) is conventional in management of postoperative pain in cancer patients, and further investigations have reported that some of these drugs correlated with the outcome in cancers. However, the prognostic value of the use of NSAIDs during surgery in non-small cell lung cancer (NSCLC) patients has been less addressed. METHODS: NSCLC patients staged I-III are retrospectively enrolled, and the data of the use of NSAIDs during surgery are collected. Patients are divided into two subgroups according to the use intensity (UI) (low or high) of the NSAIDs, which was calculated by the accumulate dosage of all the NSAIDs divided by the length of hospitalization. The differences of the clinical features among these groups were checked. And the disease-free survival (DFS) and overall survival (OS) differences in these groups were compared by Kaplan-Meier analysis; risk factors for survival were validated by using a Cox proportional hazards model. RESULTS: The UI was significant in predicting the DFS (AUC = 0.65, 95% CI: 0.57-0.73, P = 0.001) and OS (AUC = 0.70, 95% CI: 0.59-0.81, P = 0.001). Clinical features including type of resection (P = 0.001), N stages (P < 0.001), and TNM stages (P = 0.004) were significantly different in UI low (< 74.55 mg/day) or high (≥ 74.55 mg/day) subgroups. Patients in UI-high subgroups displayed significant superior DFS (log rank = 11.46, P = 0.001) and OS (log rank = 7.63, P = 0.006) than the UI-low ones. At last, the UI was found to be an independent risk factor for DFS (HR: 0.52, 95% CI: 0.28-0.95, P = 0.034). CONCLUSIONS: The use of NSAIDs during radical resection in NSCLC patients correlated with the outcome and patients with a relative high UI has better outcome.

Retracted: A Regulatory Axis of circ_0008193/miR-1180-3p/TRIM62 Suppresses Proliferation, Migration, Invasion, and Warburg Effect in Lung Adenocarcinoma Cells Under Hypoxia.

This publication has been retracted by the Editor due to non-original content and deficiencies in the conduct of the study. Reference: Minbiao Chen, Xiuming Huang, Liang Li, Mingfang Huang, Renzhong Cai, Xuqiang Liao.A Regulatory Axis of circ_0008193/miR-1180-3p/TRIM62 Suppresses Proliferation, Migration, Invasion, and Warburg Effect in Lung Adenocarcinoma Cells Under Hypoxia. Med Sci Monit, 2020; 26: e922900. DOI: 10.12659/MSM.922900.

The Immunosuppressive Niche Established with a Curcumin-Loaded Electrospun Nanofibrous Membrane Promotes Cartilage Regeneration in Immunocompetent Animals.

Inflammatory cells mount an immune response against in vitro engineered cartilage implanted into immunocompetent animals, consequently limiting the usage of tissue-engineered cartilage to repair cartilage defects. In this study, curcumin (Cur)-an anti-inflammatory agent-was mixed with poly(lactic-co-glycolic acid) (PLGA) to develop a Cur/PLGA nanofibrous membrane with nanoscale pore size and anti-inflammatory properties. Fourier-transform infrared spectroscopy and high-performance liquid chromatography analyses confirmed the successful loading of Cur into the Cur/PLGA nanofibrous membrane. The results of the in vitro assay demonstrated the sustained release kinetics and enhanced stability of Cur in the Cur/PLGA nanofibrous membrane. Western blotting and enzyme-linked immunosorbent assay analyses revealed that the Cur/PLGA nanofibrous membrane significantly downregulated the expression of inflammatory cytokines (IL-1ß, IL-6, and TNF-α). A chondrocyte suspension was seeded into a porous PLGA scaffold, and the loaded scaffold was cultured for 3 weeks in vitro to engineer cartilage tissues. The cartilage was packed with the in vitro engineered Cur/PLGA nanofibrous membrane and subcutaneously implanted into rats to generate an immunosuppressive niche. Compared with those in the PLGA-implanted and pure cartilage (without nanofibrous membrane package)-implanted groups, the cartilage was well preserved and the inflammatory response was suppressed in the Cur/PLGA-implanted group at weeks 2 and 4 post-implantation. Thus, this study demonstrated that packaging the cartilage with the Cur/PLGA nanofibrous membrane effectively generated an immunosuppressive niche to protect the cartilage against inflammatory invasion. These findings enable the clinical translation of tissue-engineered cartilage to repair cartilage defects.

Curcumin-loaded nanofilm generating avascular niche to stabilize in vivo ectopic chondrogenesis of BMSC.

Bone marrow stem cells (BMSCs) engineered cartilage (BEC) represent a promising substitute for cartilage repairment. However, the in vitro-generated BEC was prone to endochondral ossification after in vivo ectopic implantation, significantly hindering its clinical translation. Increasing evidence suggested that vascularization essentially led to endochondral ossification of BEC in the subcutaneous microenvironment. Herein, a potent antiangiogenic agent of curcumin (Cur) was successfully laden into a polycaprolactone (PCL) to prepare a Cur/PCL nanofilm. The in vitro findings of this study showed that after co-culturing with human umbilical vein endothelial cells, Cur was sustained-released from Cur/PCL and suppressed the formation of tubes. Further, the Cur/PCL nanofilm was cytocompatible when recolonized with BMSCs. BMSCs were seeded into a porous polyglycolic acid scaffold and underwent 4 weeks of in vitro chondrogenic culture to successfully produce BEC. Thereafter, the BEC is encapsulated by the Cur/PCL nanofilm and subcutaneously implanted into nude mice for 4 weeks. The localized and sustained Cur release could inhibit vascular invasion via the antagonization of vascular endothelial growth factor signal, and stabilizes the cartilaginous phenotype. The results confirmed that Cur/PCL nanofilms protected BEC from vascularization and endochondral ossification in vivo, thus, indicating that the encapsulation of BEC using an anti-angiogenic nanofilm could be used as a novel strategy for modulating the in vivo ectopic BEC stability to repair cartilage defects.

GPR78 Regulates Autophagy and Drug Resistance in Non-small Cell Lung Cancer.

Context: Lung cancer is one of the most common forms of cancer. Autophagy and apoptosis play an important role in the development of lung cancer. Researchers have found upregulation of GRP78 expression in cancer cells of various types. Objective: The study intended to explore the mechanism of G protein-coupled receptor 78(GPR78) in regulating autophagy and drug resistance in non-small cell lung cancer (NSCLC). Design: The research team performed a laboratory study. Setting: The study took place in the Department of Thoracic Surgery at Hainan General Hospital of the Hainan Affiliated Hospital of Hainan Medical University in Haikou, Hainan, China. Intervention: The research team cultured immortalized, normal, human bronchial epithelial cells C3 (HBEC3) lines and HBEC4 lines in a serum medium without keratinocytes and infected the expression of GPR78 in knockdown A549 cells using lentiviral agents. The team divided the cells into a control group and a shRNA-GPR78 group, the intervention group. The lentiviral silencing vector expressing shRNA targets human GPR78#1 and GPR78 #2aadam10. Outcome Measures: The research team analyzed the mRNA expression of GPR78 in the NSCLC cell lines H1975, H1299, and A549 and in HBEC3 and HBEC4 using a real time-polymerase chain reaction (RT-PCR) and measured the proliferation of A549 cells at 0h, 24h, 48h, 72h, and 96h using yellow tetrazolium salt (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The team also analyzed the migration and invasion ability of cells using wound healing and Transwell tests as well as measured the protein expression of the autophagy-related factors Beclin-1, microtubule-associated protein light chain 3-I/II (LC3-I/LC3-II), ubiquitin-binding protein p62 and c-Jun N-terminal kinase (JNK) using a Western blot test. The team also analyzed the protein expressions of caspase-9, caspase-3, and caspase-12 related to apoptosis using a Western blot. To detect the cell viability induced by cisplatin, the team used a Cell Counting Kit 8 (CCK-8) at the concentrations of 1µM, 3µM and 10µM. Results: The mRNA expression of GPR78 in the H1975, H1299, and A549 cell lines was significantly higher than that in the HBEC3 and HBEC4 cell lines (P < .05). At 48h, 72h, and 96h, the A549 cell proliferation in the shRNA-GPR78 group was significantly lower than that of the control group (P < .05). The cell migration and invasion of cells in the shRNA-GPR78 group was significantly lower than that in the control group (P < .05), and the cell viability of the shRNA-GPR78 group was significantly lower than that of control group (P < .05). The expression of Beclin-1 and JNK protein in shRNA-GPR78 group was significantly higher than that in the control group (P < .05), and the expression of LC3-I/LC3-II and p62 protein in shRNA-GPR78 group was significantly lower than that in the control group (P < .05). The protein expressions of caspase-9, caspase-3, and caspase-12 in the shRNA-GPR78 group were significantly higher than those of the control group (P < .05), and the protein activities of RhoA and Rac1 in the shRNA-GPR78 group were significantly lower than those in the control group (P < .05). Conclusion: NSCLC upregulated GPR78. The knockdown of GPR78 can attenuate the proliferation, migration, and invasion of NSCLC cells and increase the apoptosis and autophagy of NSCLC cells that cisplatin has induced. Therefore, targeting GPR78 may be a promising treatment strategy for NSCLC patients.

The efficacy of pulmonary rehabilitation exercise training on complications and mortality after lung cancer resection: a systematic review and meta-analysis.

Background: The efficacy of pulmonary rehabilitation exercise training for patients after lung cancer resection has been controversial. We sought to evaluate the efficacy of pulmonary rehabilitation on the incidence of complications and mortality in patients after lung cancer resection. Methods: Search English databases PubMed, EMBASE, Medline to obtain literature. The literature compared the effect of pulmonary rehabilitation exercise training intervention or not on the efficacy of patients after lung cancer resection, and the outcomes included postoperative complications and mortality. The quality of the included literature was assessed according to the Cochrane risk of bias assessment work. The chi-square test was used to test for heterogeneity. When there is heterogeneity, a random effect model is used; when there is no heterogeneity, a fixed effect model is used. Results: A total of 9 prospective clinical studies (comprising 1,338 patients) were included in this meta-analysis. Among the patients, there were 571 cases in the rehabilitation group and 767 cases in the control group. The incidence of postoperative complications in the rehabilitation group was lower than that in the control group. The odds ratio (OR) value was 0.66 and 95% confidence interval (CI) was 0.47-0.94 (P=0.02). There was no heterogeneity among studies and no publication bias. The incidence of postoperative pulmonary complications in the rehabilitation group was lower than that in the control group, OR =0.33 (95% CI: 0.22-0.50) (P<0.00001). There was no heterogeneity among studies and no publication bias. There was no significant difference in postoperative mortality between the 2 groups (OR =0.77; 95% CI: 0.26-2.30; P=0.65). There was no heterogeneity among studies and no publication bias. Discussion: Implementing pulmonary rehabilitation significantly reduced postoperative complications and the risk of pulmonary complications in lung cancer patients, but had no significant effect on mortality. Pulmonary rehabilitation exercise training is recommended for patients undergoing lung cancer resection.

A Review of Emerging Biomarkers for Immune Checkpoint Inhibitors in Tumors of the Gastrointestinal Tract.

In recent years, immune checkpoint inhibition (ICI) therapy has made a tremendous improvement in the treatment of malignant tumors of gastrointestinal tract, especially for those with metastatic or recurrent lesions. However, while some patients benefit from ICI, others do not. In fact, predictive biomarkers can play a crucial role in screening patients who may benefit from a selected or targeted treatment, including immunotherapies such as programmed death-1/programmed death-1 ligand 1 (PD-1/PD-L1) inhibitors. A variety of techniques can be used to detect and quantify tumor biomarkers, each of which has a specific clinical application scenario and limitations. Cancer biomarkers in the gastrointestinal system involve an extremely complex network that requires careful interpretation and analysis. Different prognostic or predictive biomarkers are playing important roles in various tumor types, stages, and pathology/molecular subgroups, sometimes overlapping. Expression levels of biomarkers vary between different tumor types and even between the different lesions in the same tumor, depending on the heterogeneity of the patient, the tumor types, and the techniques of detection. The present systematic review comprehensively summarizes the potential biomarkers of immunotherapy, such as PD-1/PD-L1, total mutation burden (TMB), and tumor-infiltrating lymphocytes (TILs) in various gastrointestinal tumors, including tumors of the colon, stomach, esophagus, liver, and pancreas, to assist future application of immunotherapy and patient selection in clinical practice.

Astragaloside IV enhances the sensibility of lung adenocarcinoma cells to bevacizumab by inhibiting autophagy.

Bevacizumab (BV) has an inhibitory effect on tumor growth including lung adenocarcinoma. However, its efficacy is greatly affected by drug resistance. Astragaloside IV (AST-IV) is effective in combination with other drugs is effective to treat cancer. This study aimed to investigate the effect of AST-IV on enhancing the sensibility of lung adenocarcinoma cells to BV. A549 cells were treated by different concentrations of BV and AST-IV. Cell viability, cell cycle, and apoptosis were detected by thiazolyl blue tetrazolium bromide (MTT) and flow cytometry, respectively. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting were performed to detect the expression levels of autophagy- and apoptosis-related proteins, protein kinase B (AKT), and mammalian target of rapamycin (mTOR). The results showed that BV or AST-IV could inhibit the viability and promote the apoptosis of A549 cells in a concentration-dependent manner. Moreover, BV or AST-IV inhibited Bcl-2 expression and increased the expressions of Bax and Cleaved caspase-3, and promoted apoptosis. BV and AST-IV in combination acted synergistically on viability and apoptosis of A549 cells. However, BV alone down-regulated P62 expression, LC3I/LC3II level, the number of cells arrested at S phase and the phosphorylation levels of AKT and mTOR, but upregulated the number of cells arrested at G0/G1 phase and Beclin1 expression, whereas AST-IV alone could reverse the effect of BV on autophagy-related proteins, the phosphorylation levels of AKT and mTOR. This paper demonstrates that AST-IV enhances the effect of BV on inhibiting proliferation and promoting apoptosis of lung adenocarcinoma cells through inhibiting autophagy pathway.

Raddeanin A induced apoptosis of non-small cell lung cancer cells by promoting ROS-mediated STAT3 inactivation.

PURPOSE: Non-small cell lung cancer (NSCLC) is a high-risk type of lung cancer. Raddeanin A exerts anti-tumor activity by regulating cell proliferation and apoptosis, but its role in NSCLC remains to be elucidated. This study was to investigate the effect of raddeanin A in NSCLC and its mechanism. METHODS: The effect of raddeanin A (2, 4, 8, 10 µmol/L) on the viability, proliferation and apoptosis of A549 and H1299 cells was determined by cell counting kit-8, colony formation and flow cytometry assays, respectively. Next, western blot was performed to examine the protein expressions of cleaved caspase-3, Bax, phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and STAT3. Subsequently, the intracellular reactive oxygen species (ROS) generation and mitochondrial membrane potential of NSCLC cells were detected by 2', 7'-dichlorofluorescein-diacetate (DCFH-DA) and JC-1 assay. Lastly, the effect of N-acetylcysteine (NAC) on the apoptosis, ROS generation, and STAT3 was evaluated by the above-mentioned assays again. RESULTS: Raddeanin A treatment had no obvious effect on 16HBE cells viability, but it inhibited viability and proliferation of A549 and H1299 cells, promoted the apoptosis, increased the protein expressions of cleaved caspase-3 and Bax, generated intracellular ROS, as well as decreased mitochondrial membrane potential and the expressions of p-STAT3 and STAT3 in A549 and H1299 cells. After cells treated with NAC, the effect of raddeanin A was reversed, as evidenced by the apoptosis and ROS generation were suppressed, and the expression of p-STAT3 was promoted. CONCLUSION: Raddeanin A suppressed the proliferation and induced apoptosis of NSCLC cells via promoting the ROS-mediated STAT3 inactivation.

A Regulatory Axis of circ_0008193/miR-1180-3p/TRIM62 Suppresses Proliferation, Migration, Invasion, and Warburg Effect in Lung Adenocarcinoma Cells Under Hypoxia.

BACKGROUND Expression profiles of circular ribonucleic acids (circRNAs) have been recently reported in lung cancers including lung adenocarcinoma (LUAD). Hypoxia is a hallmark of lung cancers. However, the role of hsa_circ_0008193 (circ_0008193) in LUAD under hypoxia remains to be illuminated. MATERIAL AND METHODS Gene expression levels were detected using real-time quantitative polymerase chain reaction and western blotting. Cell proliferation, migration, invasion, and Warburg effect were detected using 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide assay, transwell assays, special kits, and xenograft experiments. The relationship among circ_0008193, micro (mi)RNA (miR)-1180-3p, and tripartite motif containing 62 (TRIM62) was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation. RESULTS Expression of circ_0008193 was downregulated in human LUAD tumor tissues and cell lines (A549 and H1975), accompanied by miR-1180-3p upregulation and TRIM62 downregulation. Moreover, circ_0008193 downregulation was correlated with tumor size and lymph node metastasis. Functionally, circ_0008193 overexpression inhibited cell viability, glucose uptake, lactate production, migration, and invasion, as well as expression of hexokinase II, lactate dehydrogenase A, matrix metalloproteinase 2 (MMP2), and MMP9 in hypoxic LUAD cells in vitro. Furthermore, tumor growth of A549 cells in vivo was also hindered by circ_0008193 overexpression. Mechanically, circ_0008193 regulated TRIM62 expression via sponging miR-1180-3p, and TRIM62 was targeted by miR-1180-3p. Both miR-1180-3p upregulation and TRIM62 downregulation could abolish the suppressive role of circ_0008193 in LUAD cells. CONCLUSIONS Upregulating circ_0008193 inhibited LUAD cell proliferation, migration, invasion, and Warburg effect under hypoxia in vitro and in vivo through regulation of the miR-1180-3p/TRIM62 axis.