RBMS3, a downstream target of AMPK, Exerts Inhibitory Effects on Invasion and Metastasis of Lung Cancer.

Background: Lung cancer is a highly malignant disease, primarily due to its propensity for metastasis. AMP-activated protein kinase (AMPK), the principal downstream effector of Liver Kinase B1 (LKB1), orchestrates a broad spectrum of molecular targets, thereby constraining tumor invasion and metastasis. In parallel, the RNA-binding protein RBMS3 (RNA-binding motif, single-stranded-interacting protein 3) plays a pivotal role in the epithelial-mesenchymal transition (EMT), a pivotal process in tumorigenesis. Therefore, our research aims to clarify the important role of RBMS3 as a mediator in the LKB1/AMPK inhibition of tumor invasion and metastasis. Methods: We investigated the expression and correlation between RBMS3 and LKB1 in lung cancer tissues utilizing immunohistochemistry and TCGA-LUAD data, respectively. The relationship between RBMS3 and clinical pathological features and prognosis of lung cancer was also analyzed. The functions of RBMS3 in lung cancer cell proliferation, invasion, and migration were investigated in real-time in vitro. Additionally, we investigated the effects of AMPK agonists and inhibitors to explore the mediating role of RBMS3 in AMPK-induced inhibition of lung cancer invasion and migration. Results: The IHC and TCGA data both revealed low expression of RBMS3 in lung cancer. Moreover, we found that low expression of RBMS3 was positively associated with lung cancer's histological grade, clinical stage, and N stage. Additionally, low RBMS3 expression was associated with poor overall survival. Cox regression analysis revealed that RBMS3 was an independent prognostic factor for lung cancer patients. In vitro experiments verified that RBMS3 inhibited lung cancer cell proliferation, invasion, and migration. Furthermore, our findings suggested that RBMS3 played an essential role in mediating AMPK's inhibitory effect on lung cancer invasion and migration. Conclusion: Our study highlights a novel mechanism by which LKB1/AMPK pathway activation inhibits lung cancer invasion and metastasis by promoting RBMS3 expression, offering insights in developing innovative lung cancer therapies.

The Binding of PD-L1 and Akt Facilitates Glioma Cell Invasion Upon Starvation via Akt/Autophagy/F-Actin Signaling.

Glioma, especially glioblastoma, is pathologically characterized by high aggressiveness, which largely contributed to the ineffectiveness of current therapies. It has been recently reported that intrinsic PD-L1 can regulate tumor malignancy, whereas underlying mechanisms remain mostly unclear. Here, we report a novel mechanism by which PD-L1 promotes glioma cell infiltration. In orthotopic glioma models, PD-L1 expression was up-regulated predominantly in glioma cells in the infiltrating front. For PD-L1-overexpressed glioma cells, PI3K/Akt and actin regulations were among the top six most altered signaling pathways as detected by RNA-sequencing. PD-L1 significantly activated Akt/F-actin signaling while suppressed autophagic signaling upon cell starvation. Mechanistically, PD-L1 preferentially bound to Akt among various PI3K/Akt signaling proteins. Serial truncation identified the interaction between the 128-237aa fragment of PD-L1 and the 112-480aa fragment of Akt, which facilitates the membrane translocation/activation of Akt, and was unaffected by Perifosin (specific p-Akt inhibitor targeting Akt PH-domain). Taken together, our data indicate that in glioma cells, PD-L1 is induced to prevent autophagic cytoskeleton collapse via Akt binding/activation, facilitating glioma cell invasion upon starvation stress.

[Correlation between Asymptomatic Bacteriuria and Surgical Site Infection in Middle-aged and Elderly Patients Undergoing Open Hysterectomy].

Objective To explore the correlation between asymptomatic bacteriuria(AB)and surgical site infection(SSI)in middle-aged and elderly women undergoing open hysterectomy.Methods The clinical data of 1469 middle-aged and elderly women undergoing open hysterectomy in the Third Affiliated Hospital of Guizhou Medical University from June 2011 to August 2018 were retrospectively analyzed.Factors associated with SSI after operation were analyzed by univariate and multivariate regression models to identify the relationship of AB with SSI after open hysterectomy.Results Of these 1469 patients,101(6.88%)had SSI and 124 had AB[including 14 patients(11.29%)with infections].In addition,1345 patients had no AB,among whom 87(6.47%)had infections.Thus,the infection rate in patients with AB was significantly higher than that in patients without AB(χ 2=4.123,P=0.042).Univariate analysis showed AB,history of diabetes mellitus,surgical procedure,length of stay(>15 d),season(summer and autumn),body mass index(≥25 kg/m 2),nature of lesions(malignant tumors),ASA grade(>grade Ⅱ),incision length(≥10 cm),and operative time(≥3 h),bleeding volume(≥1000 ml),serum albumin concentration(<30 g/L),blood glucose(≥10 mmol/L),and hemoglobin concentration(<90 g/L)were associated with SSI(all P <0.05).Multivariate analysis showed that AB,nature of lesions(malignant tumors),blood glucose(≥10 mmol/L),operative time(≥3 h),and ASA grade(>grade Ⅱ)were risk factors for SSI in these patients(all P <0.05). Conclusions AB is one of the risk factors for SSI in middle-aged and elderly women undergoing open hysterectomy.Screening and treatment of AB before surgery can reduce the risk of SSI.ASA grading shall be performed before surgery before corresponding preparation was offered.Effective control of blood glucose,improved surgical skills,and shorter operative time are helpful for lowering postoperative SSI.

Long noncoding RNA PAGBC contributes to nitric oxide (NO) production by sponging miR-511 in airway hyperresponsiveness upon intubation.

BACKGROUND AND OBJECTIVES: In this study, we aimed to study the molecular mechanisms underlying the symptoms of hyperresponsiveness during intubation. METHOD: The value of circulating long noncoding RNA (lncRNA)-prognosis-associated gallbladder cancer (PAGBC) in the prediction of hyperresponsiveness upon intubation during general anesthesia was evaluated via the receiver operating characteristic analyses of serum miR-511, serum PAGBC, and serum nitric oxide (NO). In addition, the possible association between lncRNA-PAGBC/NOS1 messenger RNA (mRNA) and miR-511 was further validated via real-time quantitative polymerase chain reaction, immunohistochemistry assay, computational analysis, and luciferase assay. Enzyme-linked immunosorbent assay and Western blot analysis were also conducted to establish the regulatory relationship among PAGBC, miR-511, and NO synthase 1 (NOS1). RESULTS: Compared with circulating miR-511 and serum NO, circulating PAGBC was associated with a higher predictive value. In addition, a negative correlation was found between serum miR-511 and serum PAGBC (multicorrelation coefficient: -0.5) as well as between serum miR-511 and serum NO (multicorrelation coefficient: -0.6). In addition, both lncRNA-PAGBC and NO were decreased in patients with hyperresponsiveness, whereas the levels of miR-511 and NOS1 in these patients were similar to those in normal patients. Furthermore, our computational analyses and luciferase assays validated the direct binding between miR-511 and lncRNA-PAGBC, whereas NOS1 mRNA was identified as a virtual target gene of miR-511. Moreover, in the presence of lncRNA-PAGBC, we also observed an evident increase in the levels of NOS1 and NO accompanied by an obvious decrease of miR-511 expression. CONCLUSION: LncRNA-PAGBC downregulated the expression of miR-511, which in turn upregulated the expression of NOS1 mRNA and led to the increase in NOS1 expression, thus leading to the inhibited responsiveness (normal-responsiveness rather than hyperresponsiveness) to intubation in patients.

PD-L1 confers glioblastoma multiforme malignancy via Ras binding and Ras/Erk/EMT activation.

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor due to the lack of effective therapeutic drugs. Cancer therapy targeting programmed cell death protein 1 (PD-1) or programmed death ligand-1 (PD-L1) is of revolutionary. However, the role of intrinsic PD-L1, which determines immune-therapy outcomes, remains largely unclear. Here we demonstrated an oncogenic role of PD-L1 via binding and activating Ras in GBM cells. RNA-sequencing transcriptome data revealed that PD-L1 significantly altered gene expression enriched in cell growth/migration/invasion pathways in human GBM cells. PD-L1 overexpression and knockout or knockdown demonstrated that PD-L1 promoted GBM cell proliferation and migration in vitro and in vivo. Mechanistically, PD-L1 prominently activated epithelial mesenchymal transition (EMT) process in a MEK/Erk- but not PI3K/Akt-dependent manner. Further, we identified intracellular interactions of PD-L1 and H-Ras, which led to Ras/Erk/EMT activation. Finally, we demonstrated that PD-L1 overexpression promoted while knockdown abolished GBM development and invasion in orthotopic GBM models of rodents. Taken together, we found that intracellular PD-L1 confers GBM cell malignancy and aggressiveness via binding Ras and activating the downstream Erk-EMT signaling. Thus, these results shed important insights in improving efficacy of immune therapy for GBM as well as other malignant tumors.

Meta-analysis of efficacy and safety of fast-track surgery in gastrectomy for gastric cancer.

BACKGROUND: Fast-track surgery (FTS) is a promising program for surgical patients and has been applied to several surgical diseases. FTS is much superior to conventional perioperative care. Our aim was to evaluate and compare the safety and efficacy of FTS and conventional perioperative care for patients undergoing gastrectomy using a systematic review. METHODS: We searched the literature in PubMed, SCOPUS, and EMBASE up to November 2013. No language restriction was applied. Weighted mean differences (WMDs) and odds ratios (ORs) with their 95 % confidence intervals (CIs) were used for analysis by a fixed or a random effects model according to the heterogeneity assumption. RESULTS: In the present meta-analysis, we included five randomized controlled trials and one controlled clinical trial from five studies. Compared with conventional care, FTS shortened the duration of flatus (WMD -21.08; 95 % CI -27.46 to -14.71, z = 6.48, p < 0.00001 in the open surgery group; WMD -8.20; 95 % CI -12.87 to -3.53, z = 3.44, p = 0.0006 in the laparoscopic surgery group), accelerated the decrease in C-reactive protein (WMD -15.56; 95 % CI 21.28 to 9.83, z = 5.33, p < 0.00001), shortened the postoperative stay (WMD -2.00; 95 % CI -2.69 to -1.30, z = 5.64, p < 0.00001), and reduced hospitalization costs (WMD -447.72; 95 % CI -615.92 to -279.51, z = 5.22, p < 0.00001). FTS made no significant difference in operation times (p = 0.93), intraoperative blood loss (p = 0.79), or postoperative complications (p = 0.07). CONCLUSIONS: Based on current evidence, the FTS protocol was feasible for gastric cancer patients who underwent gastrectomy (distal subtotal gastrectomy, proximal subtotal gastrectomy, or radical total gastrectomy) via open or laparoscopic surgery. Larger studies are needed to validate our findings.