Hsa_circ_0008133 contributes to lung cancer progression by promoting glycolysis metabolism through the miR-760/MEX3A axis.

BACKGROUND: Lung cancer is a very common cancer with poor prognosis and high mortality. Circular RNAs (circRNAs) have been confirmed to be related to the occurrence of lung cancer, and circ_0008133 has been found to be possibly related to lung cancer. METHODS: Expression of circ_0008133, miR-760, and mex-3 RNA binding family member A (MEX3A) messenger RNA (mRNA) was detected using quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability, colony number, migration, and invasion were assessed using cell counting kit-8 (CCK8), colony formation, wound healing, and transwell assays. Glucose consumption and lactate production were detected using commercial kits. Protein expression was measured using western blot. Dual-luciferase reporter assay and RNA pull-down assay were used to analyze the relationships between miR-760 and circ_0008133 or MEX3A. The effects of circ_0008133 knockdown on tumor growth in vivo were examined by the nude mice expriment. Immunohistochemistry (IHC) assay analyzed Ki-67 expression. RESULTS: Circ_0008133 and MEX3A were markedly boosted in lung cancer tissues and cells. Circ_0008133 knockdown decreased lung cancer cell viability, glucose consumption, lactate production, colony formation, migration, and invasion. In mechanism, circ_0008133 might positively regulate MEX3A expression by sponging miR-760. Additionally, knockdown of circ_0008133 inhibited tumor growth in vivo. CONCLUSION: Circ_0008133 accelerated the progression of lung cancer by promoting glycolysis metabolism through the miR-760/MEX3A axis.

Early postoperative endoscopy for predicting anastomotic leakage after minimally invasive esophagectomy: A large-volume retrospective study.

BACKGROUND: Anastomotic leakage is one of the most severe adverse events of minimally invasive esophagectomy for esophageal cancer. Early postoperative endoscopy is considered to be the most objective means to diagnose anastomotic leakage, but its safety is questioned by clinicians. This study aimed to evaluate the safety and effectiveness of early postoperative endoscopy in predicting anastomotic leakage. METHODS: Patients who underwent minimally invasive esophagectomy (from January 2017 to June 2021) in our center were identified and divided into early postoperative endoscopy and control groups according to whether they underwent early postoperative endoscopy within 72 hours after surgery. Propensity score matching was used to balance baseline characteristics. The incidence of postoperative adverse events was compared between the 2 groups, risk variables for anastomotic leakage were identified using logistic regression, and abnormal endoscopic findings related to anastomotic leakage occurrence were explored. RESULTS: A total of 436 patients were enrolled, of whom 134 underwent early postoperative endoscopy. One hundred and thirty-two pairs were matched by propensity score matching, and baseline characteristics were well-balanced. Both before and after propensity score matching, early postoperative endoscopy did not increase the incidence of postoperative adverse events (chyle leak, hypoproteinemia, pneumonia, etc) and in-hospital mortality. Notably, the incidence of anastomotic leakage (9.8% vs 22.7%) and the length of mean postoperative hospital stay (17.6 vs 20.9 days) was significantly decreased in the early postoperative endoscopy group. Finally, based on the findings under early postoperative endoscopy, we found that gastric graft ischemia is related to a higher incidence of anastomotic leakage (P = .023). CONCLUSION: Early postoperative endoscopy does not increase postoperative adverse events after minimally invasive esophagectomy and may guide early prediction and intervention strategies for anastomotic leakage in patients undergoing minimally invasive esophagectomy.

Mediastinal lymph node dissection versus spared mediastinal lymph node dissection in stage IA non-small cell lung cancer presented as ground glass nodules: study protocol of a phase III, randomised, multicentre trial (MELDSIG) in China.

INTRODUCTION: Radical surgery including mediastinal lymph node dissection is the standard treatment for early-stage non-small cell lung cancer (NSCLC). About 50% lung nodules are pure ground glass or part-solid nodules, which are predominantly clinical stage IA NSCLC. Non-solid nodules rarely develop mediastinal lymph node metastasis. METHOD AND ANALYSIS: A phase III study was started in China to evaluate the non-inferiority in overall survival of spared mediastinal lymph node dissection compared with mediastinal lymph node dissection in stage IA NSCLC. A total of 1362 patients will be enrolled from 4 institutions in 2-3 years. The second endpoints are relapse-free survival and perioperative data, including duration of hospitalisation, duration of chest tube placement, operation time, blood loss. ETHICS AND DISSEMINATION: This protocol has been reviewed and approved by the Clinical Research Review Board of Tianjin Medical University Cancer Institute and Hospital. The findings will be disseminated in peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT04631770.

Neoadjuvant Camrelizumab Plus Platinum-Based Chemotherapy vs Chemotherapy Alone for Chinese Patients With Resectable Stage IIIA or IIIB (T3N2) Non-Small Cell Lung Cancer: The TD-FOREKNOW Randomized Clinical Trial.

Importance: The benefit of neoadjuvant camrelizumab plus chemotherapy for resectable stage IIIA or IIIB non-small cell lung cancer (NSCLC) remains unknown. Objective: To assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy vs chemotherapy alone for patients with resectable stage IIIA or IIIB NSCLC. Design, Setting, and Participants: In this randomized phase 2 clinical trial conducted at 2 hospitals in China, patients aged 18 to 70 years with resectable stage IIIA or IIIB (T3N2) NSCLC were enrolled between April 7, 2020, and January 12, 2022. Interventions: Patients were randomly assigned to receive 3 cycles of camrelizumab (200 mg) plus chemotherapy (nab-paclitaxel, 130 mg/m2, and platinum [cisplatin, 75 mg/m2; carboplatin, area under the curve, 5; or nedaplatin, 100 mg/m2]) or chemotherapy alone, followed by surgery after 4 to 6 weeks. Main Outcomes and Measures: The primary end point was the pathologic complete response (pCR) rate. Secondary end points included the major pathologic response (MPR) rate, objective response rate (ORR), event-free survival (EFS), and safety. Disease-free survival (DFS, defined as the time from surgery to disease recurrence or death from any cause) was analyzed post hoc. Efficacy was assessed on a modified intention-to-treat basis. Results: Ninety-four Chinese patients were randomized, and 88 (93.6%; median age, 61 years [IQR, 54-65 years]; 74 men [84.1%]) received allocated neoadjuvant treatment (43 received camrelizumab plus chemotherapy, and 45 received chemotherapy alone). Among these 88 patients, the pCR rate was 32.6% (14 of 43; 95% CI, 19.1%-48.5%) with camrelizumab plus chemotherapy vs 8.9% (4 of 45; 95% CI, 2.5%-21.2%) with chemotherapy alone (odds ratio, 4.95; 95% CI, 1.35-22.37; P = .008). The MPR rates were 65.1% (95% CI, 49.1%-79.0%) with camrelizumab plus chemotherapy and 15.6% (95% CI, 6.5%-29.5%) with chemotherapy alone. The radiographic ORRs were 72.1% (95% CI, 56.3%-84.7%) with camrelizumab plus chemotherapy and 53.3% (95% CI, 37.9%-68.3%) with chemotherapy alone. With a median follow-up of 14.1 months (IQR, 9.2-20.9 months), the median EFS and DFS were not reached in either group. The most common neoadjuvant treatment-related adverse events of grade 3 or higher were decreased white blood cell count (6 of 43 [14.0%] in the camrelizumab plus chemotherapy group vs 2 of 45 [4.4%] in the chemotherapy group) and decreased neutrophil count (3 of 43 [7.0%] in the camrelizumab plus chemotherapy group vs 5 of 45 [11.1%] in the chemotherapy group). No treatment-related deaths were reported. Conclusions and Relevance: This randomized clinical trial found that among patients with resectable stage IIIA or IIIB (T3N2) NSCLC, camrelizumab plus chemotherapy, compared with chemotherapy alone, significantly improved the pCR rate with manageable toxic effects. Trial Registration: ClinicalTrials.gov Identifier: NCT04338620.

CXCL12-CXCR4/CXCR7 Axis in Cancer: from Mechanisms to Clinical Applications.

Cancer is a multi-step disease caused by the accumulation of genetic mutations and/or epigenetic changes, and is the biggest challenge around the world. Cytokines, including chemokines, exhibit expression changes and disorders in all human cancers. These cytokine abnormalities can disrupt homeostasis and immune function, and make outstanding contributions to various stages of cancer development such as invasion, metastasis, and angiogenesis. Chemokines are a superfamily of small molecule chemoattractive cytokines that mediate a variety of cellular functions. Importantly, the interactions of chemokine members CXCL12 and its receptors CXCR4 and CXCR7 have a broad impact on tumor cell proliferation, survival, angiogenesis, metastasis, and tumor microenvironment, and thus participate in the onset and development of many cancers including leukemia, breast cancer, lung cancer, prostate cancer and multiple myeloma. Therefore, this review aims to summarize the latest research progress and future challenges regarding the role of CXCL12-CXCR4/CXCR7 signaling axis in cancer, and highlights the potential of CXCL12-CXCR4/CXCR7 as a biomarker or therapeutic target for cancer, providing essential strategies for the development of novel targeted cancer therapies.

A multicenter, single-arm, open study of neoadjuvant or conversion atezolizumab in combination with chemotherapy in resectable small cell lung cancer (Cohort Study).

BACKGROUND: This study aimed to investigate the prospects of using chemotherapy in combination with atezolizumab in the neoadjuvant or conversion treatment of small cell lung cancer (SCLC). METHODS: Prior to surgery, untreated patients with limited-stage SCLC received three cycles of neoadjuvant or conversion atezolizumab combined with chemotherapy of etoposide and platinum. The primary endpoint of the trial was pathological complete response (pCR) in the per-protocol (PP) cohort. In addition, safety was assessed based on treatment-related adverse events (AEs) and postoperative complications. RESULTS: Overall, 13 of 17 patients (including 14 males and 3 females) underwent surgery. In the PP cohort, pCR and major pathological response were observed in 8 (8/13, 61.5%) and 12 (12/13, 92.3%) patients, respectively. According to the intention-to-treat (ITT) analysis, the pCR and major pathological response in the ITT cohort were 47.1% (8/17) and 70.6% (12/17), respectively. In addition, an overall response rate of 100% was recorded in the PP cohort. Moreover, 15 (15/17, 88.2%) patients and 1 (1/17, 5.9%) in the ITT cohort attained partial remission (PR), and complete remission, respectively, with an overall response rate of 94.1%. The median overall survival of the patients of pCR and the median event-free survival of the patients on surgery had not achieved. However, the median overall survival of the patients of non-pCR was 18.2 months and the median event-free survival of the nonsurgical patients was 9.5 months. During the neoadjuvant treatment, the incidence of grade 3 or higher AEs was 58.8% (10/17). Additionally, three patients (17.6%) developed immune-related adverse event (grades 1-2). CONCLUSION: In patients with SCLC, neoadjuvant or conversion atezolizumab combined with chemotherapy significantly improved pCR with manageable AEs. Therefore, this regimen may be considered a safe and effective treatment for SCLC.

Systematic review of the perioperative immunotherapy in patients with non-small cell lung cancer: evidence mapping and synthesis.

Objectives: This study aimed to use evidence mapping to provide an overview of immune checkpoint inhibitors (ICIs) as perioperative treatments for non-small cell lung cancer (NSCLC) and to identify areas of this field where future research is most urgently needed. Methods: Multiple databases (PubMed, EMBASE, Cochrane Library, and Web of Science) were searched to identify clinical trials published up to November 2021 that examined the effect of perioperative ICIs for perioperative treatment of NSCLC. Study design, sample size, patient characteristics, therapeutic regimens, clinical stages, short-term and long-term therapeutic outcomes, surgery associated parameters, and therapeutic safety were examined. Results: We included 66 trials (3564 patients) and used evidence mapping to characterize the available data. For surgery associated outcomes, sixty-two studies (2480 patients) provided complete information regarding the use of surgery after neoadjuvant immunotherapy and data on R0 resection were available in 42 studies (1680 patients); for short-term clinical outcomes, 57 studies (1842 patients) evaluated pathologic complete response (pCR) after neoadjuvant immunotherapy and most of included studies achieved pCR in the range of 30 to 40%; for long-term clinical outcomes, 15 studies (1932 patients) reported DFS, with a median range of 17.9-53.6 months; and only a few studies reported the safety profiles of perioperative immunotherapies. Conclusion: Our evidence mapping systematically summarized the results of all clinical trials and studies that examined ICIs as perioperative treatments for NSCLC. The results indicated more studies that evaluate long-term patient outcomes are needed to provide a stronger foundation for the use of these treatments.

Regulation of CD18 stability by SIGIRR-modulated ubiquitination: new insights into the relationship between innate immune response and acute lung injury.

Inappropriate accumulation of alveolar macrophages (AMs) and subsequent excessive production of immune responses play critical roles in the pathogenesis of acute lung injury (ALI), but the core negative regulators governing innate signalling in AMs are ill defined. We have previously shown that single immunoglobin IL-1 receptor-related protein (SIGIRR), a negative regulator of IL-1 receptor and Toll-like receptor signalling, inhibits lipopolysaccharide (LPS)-induced inflammatory responses in AMs. To address the biological relevance of SIGIRR in vivo, we generated a murine ALI model via intratracheal instillation of LPS. Intriguingly, SIGIRR expression was observed to be decreased in resident and recruited macrophages during ALI. This decrease was associated with parallel induction in CD18 protein levels in LPS-challenged lung tissues. Through intranasal injection of SIGIRR lentiviral particles studies, we showed that the overexpression of SIGIRR attenuated recruitment of macrophages and neutrophils, decreased production of inflammatory cytokines and ameliorated pathological changes in lungs. Whilst exploring the basis for this phenotype, SIGIRR was found to be coexpressed with CD18 in AMs, and SIGIRR potentiated the instability of CD18 protein via enhancement of its ubiquitination and proteasome degradation. Conversely, by using CD18-/- mice, we further observed that CD18 deletion completely abolished the therapeutic effects of overexpression of SIGIRR on LPS-induced ALI. Mover, overexpression of CD18 in AMs promoted adhesion to ECM components, enhanced TLR4-mediated inflammasome activation and thereby potentiated IL-1ß production. These data collectively identify SIGIRR/CD18 as a key negative regulatory circuit maintaining innate immune homeostasis in AMs along the pathogenesis of ALI.

Predicting checkpoint inhibitors pneumonitis in non-small cell lung cancer using a dynamic online hypertension nomogram.

OBJECTIVES: Checkpoint inhibitors pneumonitis (CIP) is one of the most lethal adverse events in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs). Currently, there is no recognized and effective predictive model to predict CIP in NSCLC. MATERIALS AND METHODS: This study retrospectively analyzed 460 NSCLC patients who were first treated with ICIs. Patients were divided into three cohorts based on the occurrence of CIP: any grade CIP cohort, grade ≥ 2 CIP cohort and grade ≥ 3 CIP cohort. RESULTS: A dynamic hypertension nomogram was constructed with elements including hypertension, interstitial lung disease (ILD), emphysema at baseline, and higher baseline platelet/lymphocyte ratio (PLR). The C indices of the training cohort and the internal and external validation cohort in any grade CIP cohort were 0.872, 0.833 and 0.840, respectively. The constructed hypertension nomogram was applied to grade ≥ 2 cohort and grade ≥ 3 cohort, and their C indices were 0.844 and 0.866, respectively. Compared with the non-hypertension nomogram, the hypertension nomogram presented better predictive power. CONCLUSIONS: After validated by internal and external validation cohorts, the dynamic online hypertension has the potential to become a convenient, intuitive, and personalized clinical tool for assessing the risk of CIP in NSCLC patients.

Tislelizumab combined with chemotherapy as neoadjuvant therapy for surgically resectable esophageal cancer: A prospective, single-arm, phase II study (TD-NICE).

BACKGROUND: Clinical benefit of neoadjuvant immunotherapy in resectable esophageal squamous cell carcinoma (ESCC). remains unclear. This study evaluated the efficacy and safety of the programmed death 1 (PD-1) inhibitor tislelizumab combined with chemotherapy as neoadjuvant therapy in patients with resectable ESCC. METHODS: Treatment-naïve patients were enrolled and eligible patients received 3 cycles of neoadjuvant therapy with tislelizumab, carboplatin, and nab-paclitaxel. The primary endpoint was surgery patients major pathological response (MPR). Subgroup analysis was stratified by tumor downstaging, circumferential resection margin (CRM), PD-ligand 1 (PD-L1) expression, and tumor mutation burden (TMB). Safety was assessed by adverse events (AEs) and postoperative complications. RESULTS: Between September 2020 and March 2021, 45 patients were enrolled. Thirty-six (80.0%) of 45 patients underwent surgery, and 29 (80.5%) underwent successful R0 resection. MPR and pathological complete response (pCR) for surgery patients were 72.0% and 50.0%, respectively. Intention to treatment (ITT) patients MPR and PCR were 57.5% and 40%. Downgrading occurred in 75% of 36 patients. MPR and pCR were identified to be associated with tumor downstaging and CRM but not PD-L1 expression or TMB. TPS levels in MPR and pCR group were significantly higher than that in Non-MPR and Non-pCR group, respectively. Treatment-related AEs of grade 3-4 and immune-related AEs occurred in 42.2% and 22.2% of 45 patients, respectively, and postoperative complications occurred in 77.8% of 36 patients. No treatment-related surgical delay or death occurred. No associations between gene mutation and pathological efficacy were observed. CONCLUSIONS: Tislelizumab plus chemotherapy as neoadjuvant therapy demonstrates promising antitumor activity for resectable ESCC with high rates of MPR, pCR, and R0 resection, as well as acceptable tolerability.

QKI-6 Suppresses Cell Proliferation, Migration, and EMT in Non-Small Cell Lung Cancer.

The RNA-binding protein quaking homolog 6 (QKI-6) is a tumor-suppressor gene in several cancers. However, its role in non-small cell lung cancer (NSCLC) is unclear. In this study, we aimed to determine the association between QKI-6 expression and survival and clinicopathological features in patients with NSCLC and identify the related mechanisms. Western blot and immunohistochemistry (IHC) were used to detect QKI-6 expression in NSCLC. The effect of QKI-6 on NSCLC cells was determined by overexpression and knockdown assays, and label-free quantitative proteomics and Western blot were used to identify the underlying mechanisms. Low QKI-6 expression level was positively correlated with poor overall survival in patients with NSCLC. Furthermore, QKI-6 overexpression inhibited NSCLC cell proliferation and migration and induced a block in the G0/G1 phase, and QKI-6 downregulation increased proliferation and migration. QKI-6 inhibited EMT processes via EGFR/SRC/STAT3 signaling by upregulating AGR2. In conclusion, QKI-6 could be used to develop novel strategies for the treatment of NSCLC.

Surgical treatment of primary tracheobronchial tumors: 16-year experience in a single center.

Background: Primary tracheobronchial tumor (TBT) is a rare disease, and the prognostic factors of surgical treatment have not been well identified. Methods: Patients with primary TBT and accepted surgical treatment between January 2004 and January 2020 at our institution were retrospectively analyzed. The univariate analysis and multivariate analysis were conducted on the malignant cases. The overall survival (OS) was analyzed using Kaplan-Meier method, and potential prognostic factors were analyzed using Cox regression analysis. Results: A total of 69 patients (29 males and 40 females) were included. The median follow-up duration was 75.7 months (1.2-177.4 months). The most common histology was adenoid cystic carcinoma (ACC) (37.7%) followed by squamous cell carcinoma (SCC) (23.2%). For patients with malignant tumors, the estimated 5-year OS of the overall population was 77.2% and the estimated 5-year OS of SCC patients was 73.8% especially. The univariate Cox regression analysis identified that age and tumor size had significant effects on OS. The multivariate analysis showed that age (≤50 or >50 years) was independent prognostic factor for OS (P<0.05). Conclusions: Age is independent factor affecting the OS of primary TBT treated by surgery. And patients of TBT with younger age should be much more referred for surgery.

CircRIP2 promotes NSCLC progression by sponging for miR-671-5p to regulate FOXM1 expression.

Lot of attention had been paid to the role of circular RNAs (circRNAs) in carcinogenesis recently. However, knowledge about circRNAs in NSCLC development is far from satisfactory. In this study, we aimed to provide a novel insight into the circRIP2 in NSCLC development. We used NSCLC tissues, as well as cell lines to elucidate the expression and location of circRIP2 in NSCLC. We also established the circRIP2 overexpression cells A549-circRIP2 and repression cells HCC827-shcircRIP2 for further functional and mechanism studies. The pro-tumorigenic role of circRIP2 was tested by using CCK-8, BrdU and transwell assays. The interaction between circRIP2 and miR-671-5p were validated by luciferase reporter assay, RIP assay, as well as RNA pull down assay. We showed circRIP2 is differentially expressed NSCLC, and acted as a predictor for overall survival (OS) and disease-free survival (DFS). CircRIP2 promoted NSCLC progression by acting as a miRNA sponge for miR-671-5p, thus facilitating its target gene FOXM1 expression. Targeting circRIP2 could be potentially beneficial for NSCLC patients in the future.

[A Nomogram for Prediction of Complications Based on TM&M System of VATS Major Lung Surgery for Lung Cancer].

BACKGROUND: Postoperative complications are an important cause of death after lung resection. At present, the adoption of video assisted thoracoscopic surgery (VATS) for lung cancer in China is increasing every year, but the prediction model of postoperative complications of VATS for lung cancer is still lack of evidence based on large sample database. In this study, Thoracic Mortality and Morbidity (TM&M) classification system was used to comprehensively describe the postoperative complications of VATS major lung resection in our center, and the prediction model of complications was established and verified. The model can provide basis for the prevention and intervention of postoperative complications in such patients, and accelerate the recovery of patients. METHODS: The clinical data of patients underwent VATS major lung resection in our center from January 2007 to December 2018 were collected retrospectively. Only patients with stage I-III lung cancer were included. The postoperative complications were registered strictly by TM&M classification system. The patients were divided into two groups according to the operation period: the early phase group (From 2007 to 2012) and the late phase group (From 2013 to 2018). The baseline data of the two groups were matched by propensity score matching. After matching, binary logistic regression analysis was used to establish the prediction model of complications, and bootstrap internal sampling was used for internal verification. RESULTS: A total of 2,881 patients with lung cancer were included in the study, with an average age of (61.0±10.1) years, including 180 major complications (6.2%). Binary Logistic regression analysis of 1,268 matched patients showed: age (OR=1.04, 95%CI: 1.02-1.06, P<0.001), other period (OR=0.62, 95%CI: 0.49-0.79, P<0.001), pathological type (OR=1.73, 95%CI: 1.24-2.41, P=0.001), blood loss (OR=1.001, 95%CI: 1.000-1.003, P=0.03), dissected lymph nodes (OR=1.022, 95%CI: 1.00-1.04, P=0.005) were independent risk factors for postoperative complications. The ROC curve indicates that the model has good discrimination (C-index=0.699), and the C-index is 0.680 verified by bootstrap internal sampling for 1,000 times. The calibration curve shows a good calibration of the prediction model. CONCLUSIONS: TM&M system can comprehensively and accurately report the postoperative complications of thoracoscopic lung cancer surgery. Age, operative period, pathological type, intraoperative bleeding and dissected lymph nodes were independent risk factors for postoperative complications of VATS major lung resection for lung cancer. The established complication prediction model has good discrimination and calibration.

Dynamin 3 Inhibits the Proliferation of Non-small-Cell Lung Cancer Cells by Suppressing c-MET-GBR2-STAT3 Complex Formation.

Dynamin 3 (DNM3) has gained increased attention ever since its potential as a tumor suppressor was reported. However, its action in lung cancer (LC) is undefined. In this study, the role of DNM3 in LC development was investigated. DNM3 expression was found to be downregulated in tumors of patients with LC, especially those with metastasis. The DNM3 downregulation enhanced the proliferative and metastatic ability of LC cells, whereas its upregulation had the opposite effects. In vivo xenograft experiments confirmed that lung tumors with lower DNM3 expression had higher growth and metastatic abilities. Mechanistic studies revealed that DNM3 interacts with growth factor receptor-bound protein 2 (GBR2), thereby interrupting tyrosine-protein kinase Met (c-MET)-GBR2-signal transducer and activator of transcription 3 (STAT3) complex formation, which suppressed STAT3 activation. Therefore, the absence of DNM3 frees GBR2 to activate STAT3, which regulates the expression of genes related to LC proliferation and metastasis (e.g., cyclin D1 and Snail family transcriptional repressor 1). Additionally, the c-MET inhibitor crizotinib effectively suppressed LC cell proliferation and migration in vitro and in vivo, even with DNM3 depleted. Therefore, our study has demonstrated the antitumor effect of DNM3 in LC and suggests that the inhibition of c-MET might be a promising strategy for treating those LC patients with low DNM3 expression.

Di-methylation of CD147-K234 Promotes the Progression of NSCLC by Enhancing Lactate Export.

CD147 is a tumor-associated glycoprotein that regulates cell metabolism. However, CD147 methylation and its subsequent role in cancer cell metabolism remain unclear. Here, we detect CD147 di-methylation in 16 non-small-cell lung cancer (NSCLC) tissues using liquid chromatography-tandem mass spectrometry. CD147 is di-methylated to CD147-K234me2 by lysine methyltransferase 5A (KMT5A). The increase in KMT5A expression boosts the levels of CD147-K234me2, further promoting the interaction between CD147 and monocarboxylate transporter 4 (MCT4), which enhances the translocation of MCT4 from the cytoplasm to the membrane. Overexpression of CD147-K234me2 and KMT5A enhances glycolysis and lactate export in NSCLC cells. Clinical analysis shows that high CD147-K234me2 expression is significantly related to cancer progression and overall survival, and has prognostic significance in individuals with NSCLC, especially for those in the early stages. Our findings indicate that CD147-K234me2 plays a critical role in cancer metabolism, and it can be a highly promising therapeutic target for NSCLC.

Restoration of the Antibiotic Susceptibility of Methicillin-Resistant Staphylococcus aureus and Extended-Spectrum ß-Lactamases Escherichia coli Through Combination with Chelerythrine.

Multidrug resistance poses a severe threat to public health and urgently requires new solutions. The natural product chelerythrine (CHE) is a benzophenanthridine alkaloid with antimicrobial potential. In this study, CHE was effective against seven gram-positive bacterial strains, and the minimum inhibitory concentrations (MICs) ranged from 2 to 4 µg/mL. By contrast, CHE showed inferior antibacterial activities against 11 gram-negative strains, and the MICs varied from 16 to 256 µg/mL. We also determined the synergistic/additive effects of combining CHE with nine currently used antibiotics. CHE restored the antibacterial efficacy of the antibiotics against methicillin-resistant Staphylococcus aureus and extended-spectrum ß-lactamases producing Escherichia coli. This study suggests that the combination of CHE with conventional antibiotics may be a promising strategy to combat infections caused by multidrug-resistant organisms.

Negative Effects of SIGIRR on TRAF6 Ubiquitination in Acute Lung Injury In Vitro.

In this study, the effects of single immunoglobin IL-1 receptor-related protein (SIGIRR) on tumor necrosis factor- (TNF-) receptor-associated factor 6 (TRAF6) ubiquitination in acute lung injury (ALI) were evaluated in both alveolar epithelial cells and alveolar macrophage cells in vitro. Our results found that SIGIRR negatively regulated TRAF6 ubiquitination and such SIGIRR inhibition could enhance the TRAF6 expression in both alveolar epithelial cells (AECs) and alveolar macrophage cells (AMCs). SIGIRR knockdown may increase NF-κB activity via TRAF6 regulation by the classical but not the nonclassical NF-κB signaling pathway. Such modulation between TRAF6 and SIGIRR could affect cytokine secretion and exacerbate the immune response; the IL-8, NFKB1, and NFKBIA mRNA levels were reduced after SIGIRR overexpression. The current study reveals the molecular mechanisms of the negative regulatory roles of SIGIRR on the innate immune response related to the LPS/TLR-4 signaling pathway and provides evidence for strategies to clinically treat inflammatory diseases.