Lactate-induced IGF1R protein lactylation promotes proliferation and metabolic reprogramming of lung cancer cells.

Lung cancer (LC) is regarded as a fatal cancer, and insulin-like growth factor 1 (IGF1) and its receptor (IGF1R) have been found to play a key role in regulating tumor glycolytic metabolism. The aim of this study is to investigate LC proliferation regulated by metabolite-mediated IGF1R lactylation. IGF1R was highly expressed in LC tissues and cells, and the effects of IGF1R on protein stability were inhibited by Lactate dehydrogenase A (LDHA) inhibition. Moreover, the tightness of IGF1R binding to IGF1 was also enhanced by exogenous lactic acid but suppressed by LDHA silencing, while cell viability and proliferation were promoted by over-expression of IGF1R. Exogenous lactic acid further exacerbated the effects of the IGF1R gene, while LDHA knocking down reduced the IGF1R-induced malignant behaviors. The IGF1R and exogenous lactic acid were also found to increase extracellular acidification rate (ECAR) and decrease oxygen consumption rate to regulate glycolysis, which was inhibited by LDHA deficiency in LC cells. The study concluded that IGF1R-mediated aggressive behaviors of LC cells were associated with higher levels of IGF1R lactylation. Moreover, lactic acid can improve the protein stability of the IGF1R oncogene, thus promoting glycolysis and generating lactic acid, forming a closed loop. Therefore, targeting IGF1R is envisaged to provide a novel strategy for developing therapeutic agents against LC.

Prognostic significance of programmed cell death ligand 1 blood markers in non-small cell lung cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis.

Background: Immune checkpoint inhibitors (ICIs) are effective for non-small cell lung cancer (NSCLC) treatment, but the response rate remains low. Programmed cell death ligand 1 (PD-L1) in peripheral blood, including soluble form (sPD-L1), expression on circulating tumor cells (CTCs PD-L1) and exosomes (exoPD-L1), are minimally invasive and promising markers for patient selection and management, but their prognostic significance remains inconclusive. Here, we performed a meta-analysis for the prognostic value of PD-L1 blood markers in NSCLC patients treated with ICIs. Methods: Eligible studies were obtained by searching PubMed, EMBAS, Web of Science, and Cochrane Library prior to November 30, 2023. The associations between pre-treatment, post-treatment and dynamic changes of blood PD-L1 levels and progression-free survival (PFS)/over survival (OS) were analyzed by estimating hazard ratio (HR) and 95% confidence interval (CI). Results: A total of 26 studies comprising 1606 patients were included. High pre- or post-treatment sPD-L1 levels were significantly associated with worse PFS (pre-treatment: HR=1.49, 95%CI 1.13-1.95; post-treatment: HR=2.09, 95%CI 1.40-3.12) and OS (pre-treatment: HR=1.83, 95%CI 1.25-2.67; post-treatment: HR=2.60, 95%CI 1.09-6.20, P=0.032). High pre-treatment exoPD-L1 levels predicted a worse PFS (HR=4.24, 95%CI 2.82-6.38, P<0.001). Pre-treatment PD-L1+ CTCs tended to be correlated with prolonged PFS (HR=0.63, 95%CI 0.39-1.02) and OS (HR=0.58, 95%CI 0.36-0.93). Patients with up-regulated exoPD-L1 levels, but not sPD-L1, after ICIs treatment had significantly favorable PFS (HR=0.36, 95%CI 0.23-0.55) and OS (HR=0.24, 95%CI 0.08-0.68). Conclusion: PD-L1 blood markers, including sPD-L1, CTCs PD-L1 and exoPD-L1, can effectively predict prognosis, and may be potentially utilized for patient selection and treatment management for NSCLC patients receiving ICIs.

Hetrombopag for the management of chemotherapy-induced thrombocytopenia in patients with advanced solid tumors: a multicenter, randomized, double-blind, placebo-controlled, phase II study.

Background: Chemotherapy-induced thrombocytopenia (CIT) increases the risk of bleeding, necessitates chemotherapy dose reductions and delays, and negatively impacts prognosis. Objectives: This study aimed to evaluate the efficacy and safety of hetrombopag for the management of CIT in patients with advanced solid tumors. Design: A multicenter, randomized, double-blind, placebo-controlled, phase II study. Methods: Patients with advanced solid tumors who experienced a chemotherapy delay of ⩾7 days due to thrombocytopenia (platelet count <75 × 109/L) were randomly assigned (1:1) to receive oral hetrombopag at an initial dose of 7.5 mg once daily or a matching placebo. The primary endpoint was the proportion of treatment responders, defined as patients resuming chemotherapy within 14 days (platelet count ⩾100 × 109/L) and not requiring a chemotherapy dose reduction of ⩾15% or a delay of ⩾4 days or rescue therapy for two consecutive cycles. Results: Between 9 October 2021 and 5 May 2022, 60 patients were randomized, with 59 receiving ⩾1 dose of assigned treatment (hetrombopag/placebo arm, n = 28/31). The proportion of treatment responders was significantly higher in the hetrombopag arm than in the placebo arm [60.7% (17/28) versus 12.9% (4/31); difference of proportion: 47.6% (95% confidence interval (CI): 26.0-69.3); odds ratio = 10.44 (95% CI: 2.82-38.65); p value (nominal) based on the Cochran-Mantel-Haenszel: <0.001)]. During the double-blind treatment period, grade 3 or higher adverse events (AEs) occurred in 35.7% (10/28) of patients with hetrombopag and 38.7% (12/31) of patients on placebo. The most common grade 3 or higher AEs were decreased neutrophil count [35.7% (10/28) versus 35.5% (11/31)] and decreased white blood cell count [17.9% (5/28) versus 19.4% (6/31)]. Serious AEs were reported in 3.6% (1/28) of patients with hetrombopag and 9.7% (3/31) of patients with placebo. Conclusion: Hetrombopag is an effective and well-tolerated alternative for managing CIT in patients with solid tumors. Trial registration: ClinicalTrials.gov identifier: NCT03976882.

A cross-sectional study of factors influencing left ventricular myocardial work in peritoneal dialysis patients.

Objectives: To evaluate myocardial work in peritoneal dialysis patients by pressure-strain loop. To analyze the factors influencing myocardial work in peritoneal dialysis patients with preserved ejection fraction. Methods: We collected clinical data on possible effects on myocardial work in 105 maintenance peritoneal dialysis patients with preserved ejection fraction and applied ultrasonic pressure-strain loops to obtain the left ventricular global constructive work (GCW), Global work index (GWI), global work waste (GWW), and global work efficiency (GWE) of the patients. Then, the clinical data and myocardial work indices were statistically described and correlated. Results: Left ventricular hypertrophy was observed in 78 % of peritoneal dialysis patients with left ventricular ejection fraction preservation. There is a correlation between the left ventricular mass index and myocardial work indices (P < 0.05). On multiple linear regression analysis, systolic blood pressure (SBP), IL-6, and hemoglobin correlated with GCW(P < 0.05); SBP and IL-6 correlated with GWI(P < 0.05); homocysteine, SBP, TNF-α, and hemoglobin correlated with GWW(P < 0.05); homocysteine, TNF-α and hemoglobin correlated with GWE (P < 0.05). Conclusions: Using noninvasive pressure-strain loops to assess left ventricular myocardial work can provide information on cardiac function more consistent with pathophysiological changes than conventional ejection fraction. Hypertension, anemia, hyperhomocysteinemia, and inflammation influence left ventricular myocardial work in peritoneal dialysis patients, and they selectively affect one or more myocardial work indices.

Pucotenlimab in patients with advanced mismatch repair-deficient or microsatellite instability-high solid tumors: A multicenter phase 2 study.

We report a multicenter, phase 2 study evaluating the efficacy of pucotenlimab, an anti-PD-1 antibody, in patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, and potential biomarkers for response. Overall, 100 patients with previously treated, advanced solid tumors centrally confirmed as dMMR or MSI-H received pucotenlimab at 200 mg every 3 weeks. The most common cancer type is colorectal cancer (n = 71). With a median follow-up of 22.5 months, the objective response rate is 49.0% (95% confidence interval 38.86%-59.20%) as assessed by the independent review committee, while the median progression-free survival and overall survival have not been reached. Grade ≥3 treatment-related adverse events were observed in 18 patients. For the biomarker analysis, responders are enriched in patients with mutations in the KMT2D gene. Pucotenlimab is an effective treatment option for previously treated advanced dMMR/MSI-H solid tumors, and the predictive value of KMT2D mutation warrants further research. This study is registered with ClinicalTrials.gov: NCT03704246.

Safety and effectiveness of apatinib in elderly patients with metastatic gastric cancer: a sub-analysis from the large-scale, prospective observational study of apatinib for gastric cancer treatment in a real-world clinical setting (AHEAD-G202).

Background: Apatinib was shown to improve the survival of Chinese patients with refractory metastatic gastric cancer (mGC). As an orally administered drug, it has been widely used in elderly patients because the dosing schedule can be adjusted flexibly. However, data on the efficacy and safety of apatinib in elderly patients is scarce. The aim of this study was to evaluate the toxicity and effectiveness of apatinib for elderly patients with mGC in a real-world setting. Methods: Data from the sub-population of patients who were ≥65 years enrolled in the AHEAD-G202 trial were analyzed. Patients with mGC were prospectively registered and initially received ≤850 mg oral apatinib daily combined or not combined with chemotherapy, at the investigator's discretion. The primary endpoint was safety. The secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results: A total of 117 patients were included. There were 51 (43.59%) patients in the low-dose (250 mg) group, 60 (51.28%) patients in the mid-dose (425 to 500 mg) group, and 6 (5.13%) patients in the high-dose (850 mg) group according to the initial daily doses. Hypertension (6.84%) was the only grade 3-4 adverse event (AE) with a prevalence of more than 5% and across the low-dose (11.76%), mid-dose (3.33%) and high-dose group (0%). The median OS and PFS were 7.13 months (95% CI: 5.04 to 9.22 months) and 4.27 months (95% CI: 3.24 to 5.29 months), respectively. The OS and PFS were similar among the 65-74 and ≥75 years groups (χ2=1.406, P=0.306; χ2=0.378, P=0.066, respectively). The OS and PFS were also comparable among the 3 dose groups. Conclusions: Elderly patients with mGC can tolerate and benefit from apatinib therapy. A lower initial daily dosing strategy may be a suitable choice for elderly patients in clinical practice.

On-treatment blood TMB as predictors for camrelizumab plus chemotherapy in advanced lung squamous cell carcinoma: biomarker analysis of a phase III trial.

BACKGROUND: Camrelizumab plus chemotherapy significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone as first-line treatment in advanced lung squamous cell carcinoma (LUSC) in the phase III trial (CameL-sq), which has become an option of standard-of-cares for Chinese patients with advanced LUSC. However, the predictive biomarkers remain unknown. METHODS: Tumor tissue samples at baseline, and peripheral blood samples at baseline (pretreatment) and after two cycles of treatment (on-treatment) were prospectively collected from 270 LUSC patients from the CameL-sq study. Blood tumor mutation burden (bTMB) and its dynamics were analyzed to explore their predictive values. RESULTS: Pretreatment bTMB was not associated with objective response, PFS and OS in camrelizumab or placebo plus chemotherapy groups. Low on-treatment bTMB was associated with significantly better objective response (73.8% vs 27.8%, P < 0.001), PFS (median, 9.1 vs 4.1 months; P < 0.001) and OS (median, not reached vs 8.0 months; P < 0.001) in camrelizumab plus chemotherapy group whereas it did not correlate with objective response and PFS in chemotherapy alone group. Importantly, on-treatment bTMB level could discriminate patients of initially radiological stable disease who would long-term benefit from camrelizumab plus chemotherapy (low vs high, median OS, 18.2 vs 7.8 months; P = 0.001). Combing on-treatment bTMB and its dynamics improved the ability for predicting the efficacy of camrelizumab plus chemotherapy. CONCLUSION: On-treatment bTMB together with its dynamics could serve as a predictive biomarker for camrelizumab plus chemotherapy in patients with advanced LUSC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03668496.

Camrelizumab Plus Carboplatin and Paclitaxel as First-Line Treatment for Advanced Squamous NSCLC (CameL-Sq): A Phase 3 Trial.

INTRODUCTION: Camrelizumab, a humanized immunoglobulin G4-κ monoclonal antibody against programmed cell death protein 1, has exhibited antitumor activity and tolerability across various tumors, including lung cancers. We conducted this double-blind, randomized phase 3 trial to investigate the efficacy and safety of camrelizumab or placebo plus chemotherapy as first-line treatment for patients with advanced squamous NSCLC. The predictive value of circulating tumor DNA (ctDNA) dynamics was also analyzed. METHODS: CameL-sq, a double-blind, randomized phase 3 trial (NCT03668496), was conducted in 53 centers in the People's Republic of China. A total of 389 patients with stage IIIB-IV squamous NSCLC were randomized (1:1) to receive 4 to 6 cycles of carboplatin plus paclitaxel with camrelizumab or placebo (every 3 wk), followed by maintenance therapy with camrelizumab or placebo. Peripheral blood ctDNA samples were collected at baseline and the time after two cycles of treatment. RESULTS: Of 389 eligible patients, 193 patients allocated camrelizumab plus chemotherapy and 196 patients allocated placebo plus chemotherapy were included in the efficacy and safety analysis. The results revealed significantly prolonged progression-free survival (median, 8.5 vs. 4.9 mo; p <0.0001) and overall survival (median, not reached vs. 14.5 mo; p <0.0001) with camrelizumab-chemotherapy versus placebo-chemotherapy. No unexpected treatment immune-related adverse events were observed in both groups. Biomarker analysis revealed that ctDNA clearance after two cycles of treatment was independently associated with dramatically longer progression-free survival (p <0.0001) and overall survival (p <0.0001) in camrelizumab plus chemotherapy group. CONCLUSIONS: Our findings support camrelizumab plus chemotherapy as a first-line treatment option in advanced squamous NSCLC. On-treatment ctDNA dynamics exhibited the potency to predict the efficacy of camrelizumab plus chemotherapy.

MicroRNA-429 acts as a tumor suppressor in colorectal cancer by targeting high mobility group box 3.

Colorectal cancer (CRC) is one of the most common solid tumors worldwide and has an extremely poor prognosis. MicroRNA-429 (miR-429) has been reported to participate in the progression of CRC. However, the pathological mechanisms require further investigation. The aim of the present study was to investigate the association between miR-429 and high mobility group box 3 (HMGB3) in CRC and the associated mechanism. The mRNA expression levels of miR-429 and HMGB3 in 65 paired CRC and adjacent tissues were examined by reverse transcription-quantitative PCR. Furthermore, a dual-luciferase reporter assay was performed to identify the association between miR-429 and HMGB3. Finally, the effects of miR-429 and HMGB3 on the proliferation and apoptosis of CRC cells were detected. As a result, it was identified that miR-429 expression was downregulated and HMGB3 expression was upregulated in CRC tissues compared with in adjacent non-cancer tissues, and the expression levels of miR-429 were negatively associated with those of HMGB3. Notably, HMGB3 was demonstrated to be a direct target of miR-429 by dual-luciferase reporter assay. Furthermore, transfection with a miR-429 mimic significantly inhibited HMGB3 expression and led to decreased proliferation and increased apoptosis of CRC cells. On the other hand, transient overexpression of HMGB3 partially inhibited the antitumor effects of miR-429. To the best of our knowledge, the present study demonstrated for the first time that miR-429 regulated the proliferation and apoptosis of CRC cells via HMGB3, suggesting a specific tumor suppressive function of the miR-429/HMGB3 signaling pathway in CRC.

Pharmacogenetic Association between XRCC1 Polymorphisms and Response to Platinum-Based Chemotherapy in Asian Patients with NSCLC: A Meta-Analysis.

BACKGROUND: Platinum-based chemotherapy plays an antitumor role by damaging DNA. X-ray repair crosscomplementing protein 1 (XRCC1) participates in DNA repair and thus affects the sensitivity to platinum drugs. Two polymorphisms of XRCC1, rs25487 (Arg399Gln) and rs1799782 (Arg194Trp), have been widely studied for the association with clinical outcomes of platinum-based chemotherapy in Asian patients with non-small-cell lung cancer (NSCLC), but the results remain inconclusive. Thus, we performed the present meta-analysis. METHODS: Literature search was performed in PubMed, Web of Science, and EMBASE up to June 2019. Odds ratios (ORs) for objective response ratio (ORR), Cox proportional hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS), and the corresponding 95% confidence intervals (95% CIs) were calculated to assess the association strengths between XRCC1 polymorphisms and clinical outcomes. Comparisons were performed in homozygous, heterozygous, dominant, and recessive models. RESULTS: Finally, a total of 23 studies involving 5567 patients were included in the meta-analysis. Compared to ArgArg of rs25487, GlnGln (OR = 1.71, 95% CI: 1.16-2.52, p = .007, I 2 = 56.8%) and GlnArg (OR = 1.23, 95% CI: 1.07-1.40, p = .003, I 2 = 29.0%) were associated with higher ORR. Meanwhile, GlnGln indicated a favorable OS (HR = 0.60, 95% CI: 0.40-0.88) and PFS (HR = 0.64, 95% CI: 0.46-0.90). We also found positive associations between rs1799782 and ORR in all comparison models with low between-study heterogeneity. The association strength increased with the number of variant alleles (TrpTrp vs. ArgArg: OR = 1.73, 95% CI:1.31-2.27; TrpArg vs. ArgArg: OR = 1.28, 95% CI: 1.06-1.55), suggesting a gene dosage effect. In addition, TrpTrp predicted a longer OS. CONCLUSION: Our results showed that rs25487 and rs1799782 of XRCC1 are potential markers to predict clinical outcomes of platinum-based chemotherapy in Asian patients with NSCLC.

Safety and effectiveness of apatinib in patients with previously treated metastatic gastric cancer: a sub-analysis from the real-world study of apatinib for gastric cancer treatment (AHEAD-G202).

Apatinib, a VEGFR2 receptor tyrosine kinase inhibitor, showed survival benefits in Asian patients with heavily pretreated advanced gastric cancer. However, the adverse event (AEs) profile of apatinib has limited its use. Dosing schedules are used to alleviate toxicities despite no supportive evidence. This study aimed to analyze the toxicity and effectiveness of apatinib alone, especially with different dosing strategies in advanced gastric cancer patients under a real-world setting. Data from the subpopulation of patients who failed ≥2 chemotherapy regimens enrolled in the AHEAD-G202 trial were analyzed. The primary endpoint was safety. The secondary endpoints were overall survival (OS) and progression-free survival (PFS). Totally 120 patients were included into three groups by the initial daily doses: 43 (35.8%) patients in the low-dose (250 mg) group, 67 (55.8%) patients in the mid-dose (425 mg to 500 mg) group, and 10 (8.3%) patients in the high-dose (675 to 850 mg) group. Grade 3/4 treatment-emergent AEs were infrequent (<5%), with the most commonly reported grade 3/4 AEs being hand-foot syndrome (4.2%), hypertension (4.2%,), fatigue (4.2%), and difficulty in swallowing (4.2%) which gradually decreased among the high-, mid-, and low-dose groups. The median OS and PFS were 6.33 months (95% CI, 4.57-7.73) and 3.83 months (95% CI: 1.40-4.20), respectively and were comparable among the three doses groups. We found heavily pretreated advanced gastric cancer patients can tolerate and benefit from lower-doses of apatinib therapy. The lower initial daily dosing strategy represents an alternative approach for optimizing apatinib dosing in clinical practice.

An open label, multicenter, noninterventional study of apatinib in advanced gastric cancer patients (AHEAD-G202).

BACKGROUND: Apatinib has been proved to be effective and well tolerated among patients in phase II and III studies. Here, we evaluated the safety and effectiveness of apatinib in advanced gastric cancer patients in a real-world setting. METHODS: This study enrolled advanced gastric cancer patients who had progressed or relapsed despite systemic chemotherapy. The primary outcome was safety and the secondary outcomes included overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 337 patients were included. In total, 62 (18.4%), 102 (30.3%), and 173 (51.3%) patients received first, second, and third or higher line apatinib therapy, respectively. Grade 3/4 treatment-emergent adverse events (AEs) were infrequent (<5%), with hypertension (6.8%) being the only grade 3/4 AE occurring in more than 5% of the patients and across the low-dose (250 mg, 7.3%), mid-dose (425-500 mg, 6.1%), and high-dose group (675-850 mg, 2/15, 13.3%). The median OS and PFS were 7.13 months (95% CI, 6.17-7.93) and 4.20 months (95% CI, 4.60-4.77), respectively, and were comparable among the low-, mid-, and high-dose groups. CONCLUSION: Lower daily doses of apatinib achieved comparable OS and PFS versus higher daily doses of apatinib while maintaining a more benign safety profile in advanced gastric cancer patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02668380.

Clinical efficacy and safety of apatinib combined with S-1 in advanced esophageal squamous cell carcinoma.

Background Esophageal cancer is a very common malignant tumor in China, especially esophageal squamous cell carcinoma (ESCC), but there is currently no effective treatment for patients after first-line chemotherapy failure. Apatinib has shown promising outcomes in treatment with various solid tumors. Objectives To evaluate the clinical efficacy and safety of apatinib combined with S-1 in the treatment of advanced ESCC patients after first-line chemotherapy failure. Methods In this prospective study, fifteen patients with advanced ESCC who failed first-line chemotherapy were enrolled from Nov 2016 to Apr 2019. Patients received the combination therapy with apatinib (250-500 mg, once daily) plus S-1 (40-60 mg based on body surface area, twice daily). Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), disease control rate (DCR) and objective response rate (ORR). Adverse events (AEs) were recorded to evaluate the safety. Results A total of 12 patients were included in the efficacy analysis. The median PFS was 6.23 months, and the median OS was 8.83 months. Two (16.67%) patients achieved partial remission, 9 patients (75.00%) achieved stable disease and 1 (8.33%) patient achieved progressive disease. DCR and ORR was 91.67%and 16.67%, respectively. Most frequent AEs were hypertension, myelosuppression, weakness, hemorrhage, hand-foot syndrome, total bilirubin elevation, sick, proteinuria, oral ulcer, loss of appetite, and transaminase elevation. The most AEs were in grade I~II. Conclusion The combination therapy of apatinib plus S-1 was effective and well tolerated in the treatment of advanced ESCC patients after first-line chemotherapy failure. The combination therapy has the potential to be a potent therapeutic option for advanced ESCC patients after first-line chemotherapy failure.

The RNA helicase DHX33 is required for cancer cell proliferation in human glioblastoma and confers resistance to PI3K/mTOR inhibition.

Human Glioblastoma is one deadly disease; the median survival time is reported to be 13.9 months after treatment. In the present study, we discovered that DHX33 is highly expressed in 84% of all Glioblastoma multiforme (GBM). Knockdown of DHX33 led to significant reduced proliferation and migration in glioblastoma cells in vitro and in vivo. Mechanistically, DHX33 regulated a set of critical genes involved in cell cycle and cell migration to promote glioblastoma development. Additionally, DHX33 was found to be induced by inhibitors of PI3K and mTOR whose activation has been detected in 50% of glioblastoma. Overexpression of wild type DHX33 protein, but not the helicase dead mutant, confers resistance to mTOR inhibitors in glioblastoma cells. DHX33 probably functions as a critical regulator to promote GBM development. Our results highlight its therapeutic potential in treating GBM.

The effect of downregulation of Stathmin gene on biological behaviors of U373 and U87-MG glioblastoma cells.

BACKGROUND: Stathmin as a critical protein involved in microtubule polymerization, is necessary for survival of cancer cells. However, extremely little is known about Stathmin in glioblastoma. So, this study was designed to elucidate the function of Stathmin gene in the tumorigenesis and progression of glioblastoma cells. METHOD: The lentiviral interference vector pLV3-si-Stathmin targeting Stathmin gene and the control vector pLV3-NC were established for the co-transfection of 293T cells together with the helper plasmids. Viral titer was determined via limiting dilution assay. Then pLV3-si-Stathmin and pLV3-NC were stably co-transfected into U373 and U87-MG glioblastoma cells. Expression levels of Stathmin protein in each group were determined by using Western Blot, and the proliferation and migration ability of the cells with downregulated Stathmin were evaluated through CCK8 assay and transwell invasion assay, respectively. Cell cycles and cell apoptosis were detected with flow cytometry. Finally, the effect of Stathmin in tumor formation was determined in nude mice. RESULT: DNA sequencing and viral titer assay indicated that the lentiviral interference vector was successfully established with a viral titer of 4 × 108 TU/ml. According to the results from Western Blotting, Stathmin protein expression level decreased significantly in the U373 and U87-MG cells after transfected with pLV3-si-Stathmin, respectively, compared with those transfected with pLV3-NC. In glioblastoma cells, the cell proliferation and migration were greatly inhibited after the downregulation of Stathmin protein. Flow cytometry showed that much more cells were arrested in G2/M phasein Stathmin downregulated group, compared with the non-transfection group and NC group. But Stathmin downregulation did not induce significant cell apoptosis. Tumor formation assay in nude mice showed that tumor formation was delayed after Stathmin downregulation, with a reduction in both tumor formation rate and tumor growth velocity. CONCLUSION: Stathmin downregulation affected the biological behaviors of U373 and U87-MG glioblastoma cells, inhibiting the proliferation and migration of tumor cells. Stathmin gene may serve as a potential target in gene therapy for glioblastoma.

Scaled Group Consensus in Multiagent Systems With First/Second-Order Continuous Dynamics.

We investigate scaled group consensus problems of multiagent systems with first/second-order linear continuous dynamics. For a complex network consisting of two subnetworks with different physical quantities or task distributions, it is concerned with this case that the agents' states in one subnetwork converge to a consistent value asymptotically, while the states in the other subnetwork approach another value with a ratio of the former. For the case of the information exchange being directed, novel consensus protocols are designed for both first-order and second-order dynamics to solve the scaled group consensus problems. By utilizing algebra theory, graph theory, and Lyapunov stability theory, several necessary and sufficient conditions are established to guarantee the agents' states reaching the scaled group consensus asymptotically. Finally, several simulation results are presented to demonstrate the effectiveness of the theoretical results.

The effect of downregulation of Stathmin gene on biological behaviors of U373 and U87-MG glioblastoma cells

BACKGROUND: Stathmin as a critical protein involved in microtubule polymerization, is necessary for survival of cancer cells. However, extremely little is known about Stathmin in glioblastoma. So, this study was designed to elucidate the function of Stathmin gene in the tumorigenesis and progression of glioblastoma cells. METHOD: The lentiviral interference vector pLV3-si-Stathmin targeting Stathmin gene and the control vector pLV3-NC were established for the co-transfection of 293T cells together with the helper plasmids. Viral titer was determined via limiting dilution assay. Then pLV3-si-Stathmin and pLV3-NC were stably co-transfected into U373 and U87-MG glioblastoma cells. Expression levels of Stathmin protein in each group were determined by using Western Blot, and the proliferation and migration ability of the cells with downregulated Stathmin were evaluated through CCK8 assay and transwell invasion assay, respectively. Cell cycles and cell apoptosis were detected with flow cytometry. Finally, the effect of Stathmin in tumor formation was determined in nude mice. RESULT: DNA sequencing and viral titer assay indicated that the lentiviral interference vector was successfully established with a viral titer of 4 × 108 TU/ml. According to the results from Western Blotting, Stathmin protein expression level decreased significantly in the U373 and U87-MG cells after transfected with pLV3-si-Stathmin, respectively, compared with those transfected with pLV3-NC. In glioblastoma cells, the cell proliferation and migration were greatly inhibited after the downregulation of Stathmin protein. Flow cytometry showed that much more cells were arrested in G2/M phasein Stathmin downregulated group, compared with the non-transfection group and NC group. But Stathmin downregulation did not induce significant cell apoptosis. Tumor formation assay in nude mice showed that tumor formation was delayed after Stathmin downregulation, with a reduction in both tumor formation rate and tumor growth velocity. CONCLUSION: Stathmin downregulation affected the biological behaviors of U373 and U87-MG glioblastoma cells, inhibiting the proliferation and migration of tumor cells. Stathmin gene may serve as a potential target in gene therapy for glioblastoma.

RUNX3 inhibits the proliferation and metastasis of gastric cancer through regulating miR-182/HOXA9.

OBJECTIVE: This study intended to explore the molecular mechanism of RUNX3 in inhibiting the process of migration and proliferation of gastric cancer (GC) cells. METHODS: The overexpressed plasmids of RUNX3 and the interfering siRNA of RUNX3 were transfected into GC cells. Then, qRT-PCR and western blot were performed to identify the expression level of RUNX3 and miR-182 in tumors and adjacent tissues respectively. ChIP and luciferase assay were performed to detect the relationship between RUNX3 and miR-182 as well as miR-182 and HOXA9. Furthermore, EdU assay were used to investigate the proliferation of GC cells, Transwell assay and wound healing assay were utilized to assess cell metastasis. Xenograft mouse model was set to evaluate the proliferation in vivo. RESULTS: The results of qRT-PCR and western blot indicated that RUNX3 could regulate the expression of miR-182. RUNX3 can be straightly interacted with the promoter region of miR-182 in accordance with the results of ChIP. Luciferase assay revealed that HOXA9 was the direct target gene of miR-182. In addition, EdU proliferation, wound healing assay and transwell assay showed that miR-182 mimics and HOXA9 siRNA could inhibit the ability of cells proliferation, migration and invasion. The findings of in vivo experiments strongly supported the view that miR-182/HOXA9 was involved in the process of RUNX3-mediated GC tumor growth. CONCLUSIONS: RUNX3 could impede the ability of GC cells proliferation, migration and invasion by modulating miR-182/HOXA9 pathway.

Silver nanoparticles well-dispersed in amine-functionalized, one-pot made vesicles as an effective antibacterial agent.

We report a simple route to prepare silver nanoparticle (Ag NP) loaded amine functionalized poly-oligomeric (ethylene glycol) methyl ether methacrylate block poly-glycidyl methacrylate (POEGMA-b-PGMA) vesicles as an effective antibacterial agent. Self-assemblies of POEGMA-b-PGMA were prepared from reversible addition-fragmentation chain transfer (RAFT) dispersion polymerization mediated by a POEGMA macro-chain transfer agent (macro-CTA) in ethanol. Amine-functionalized self-assemblies were applied for Ag NP loading by using amine and hydroxyl groups as both the coordination agent and reductant under hydrothermal condition in high-pressure steam sterilization. 12.7 wt.% content of fine Ag NP well-dispersed in vesicles showed excellent antibacterial activities with the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) below 5.0 and 10.0 mg/L against Escherichia coli and 2.5 and 80 mg/L against Staphylococcus aureus respectively.

Genetic association between CD95 rs2234767 polymorphism and cervical cancer risk: a meta analysis.

BACKGROUND: CD95 rs2234767 polymorphism in the promotor region of CD95 gene has been implicated in several studies of cervical cancer. However, the results have not been conclusively established. OBJECTIVE: The main aim of this study was to deal with the controversy with respect to the correlation between CD95 rs2234767 polymorphism and risk of cervical cancer through a meta-analysis. METHODS: Association studies that pertain to CD95 rs2234767 polymorphism and risk of cervical cancer were identified up to May 26, 2014. ORs and 95% CIs were calculated assuming AA versus GG, AA + AG versus GG, AA versus AG + GG, A versus G and AG versus GG genetic models. RESULTS: A total of 5 case-control studies were included in this meta-analysis. Overall, no significant effect modification of cervical cancer risk was revealed either at the genotypic or the allelic level for CD95 rs2234767 polymorphism. This null association persisted in the stratified analysis of Asian population. CONCLUSIONS: These findings revealed that CD95 rs2234767 polymorphism may not act as a causative agent of cervical cancer. Further evidence is needed to confirm our findings.