Exosomal miR-133a-3p promotes the growth and metastasis of lung cancer cells following incomplete microwave ablation.

PURPOSE: Exosomal miRNAs play key roles in various biological processes such as cell proliferation, angiogenesis, migration and invasion. We explored whether exosomal miRNAs can promote local recurrence (LR) of lung tumors following incomplete microwave ablation (MWA) therapy. METHODS: Exosomal miRNA profiles before and after incomplete MWA in lung cancer (LC) patients with LR (n = 3) were sequenced and compared. The differentially expressed miRNAs of interest were validated in clinical samples (n = 10) and MWA-treated cells using RT-qPCR analysis. Target genes of the miRNAs were predicted and validated. The biological functions of miRNAs in proliferation, angiogenesis and metastasis of A549 cells were evaluated in vitro and in vivo. RESULTS: A total of 270 miRNAs (243 upregulated and 27 downregulated) were differentially expressed after incomplete MWA in patients with local recurrence. Upregulation of miR-133a-3p after MWA was validated in the cells and clinical samples. Cell functional experiments suggested that miR-133a-3p overexpression derived from serum exosomes increased cell viability, migration and invasion ability, tube formation activity and proliferation of A549 cells. Sirtuin 1 (SIRT1) was identified as a target gene for miR-133a-3p. Moreover, miR-133a-3p delivered by exosomes significantly promoted tumor growth, paralleled by reduced SIRT1 expression in a subcutaneous tumorigenesis animal model and increased the number of lung nodules by tail vein metastasis in vivo. CONCLUSION: Exosomal miR-133a-3p overexpression promoted tumor growth and metastasis following MWA and could be a promising biomarker for LC recurrence after incomplete MWA.

Facilitating combined biopsy and percutaneous microwave ablation of pulmonary ground-glass opacities using lipiodol localisation.

OBJECTIVES: Whether preoperative localisation is necessary and valuable for the microwave ablation (MWA) of small pulmonary lesions with ground-glass opacity (GGO) remains unclear. This study aimed to explore the role of the Chiba needle and lipiodol localisation techniques in facilitating MWA and biopsy. METHODS: This retrospective before-after study included patients with GGOs who underwent conventional MWA and biopsy treatment in our hospital between January 2018 and December 2019 (group A) or who underwent the Chiba needle and lipiodol localisation treatment before MWA and biopsy between January 2020 and December 2020 (group B). The characteristics of each patient and GGO lesion were collected and analysed to evaluate the safety and effectiveness of the localisation technique. RESULTS: A total of 122 patients with 152 GGOs and 131 patients with 156 GGOs underwent MWA and biopsy in groups A and B, respectively. The primary technique efficacy rate of MWA differed significantly between the two groups (A vs. B: 94.1% vs. 99.4%; p = 0.009). The positive biopsy rate in the two groups was determined by the difference (A vs. B: 93.4% vs. 98.1%; p = 0.042). The incidence of complications did not increase in group B. CONCLUSIONS: Compared with the unmarked group, the Chiba needle and lipiodol localisation technique improved the positive rate of biopsy and the initial effective rate of MWA, without significantly increasing the complication rate. KEY POINTS: • The localisation of the Chiba needle and lipiodol could improve the positive biopsy rate and the initial effective rate of MWA. • The localisation of the Chiba needle and lipiodol does not affect the subsequent MWA and biopsy and does not increase the incidence of pneumothorax and haemorrhage.

Synchronous Microwave Ablation Combined With Cisplatin Intratumoral Chemotherapy for Large Non-Small Cell Lung Cancer.

Background: Microwave ablation (MWA) and intratumoral chemotherapy (ITC) are useful for treating tumors in animal models; however, their clinical use in patients with large non-small cell lung cancer (NSCLC) remains unknown. This retrospective study aimed to evaluate preliminary outcomes of MWA + ITC for large NSCLC. Methods: From November 2015 to April 2020, a total of 44 NSCLC patients with a mean lesion diameter of 6.1 ± 1.5 cm were enrolled and underwent synchronous MWA + ITC procedures. The primary endpoint was local progression-free survival (LPFS); secondary endpoints were progression-free survival (PFS), complications, overall survival (OS), and associated prognostic factors. Results: The median follow-up time was 19.0 months. At the 1-month CT scan, complete tumor ablation was observed in 47.7% of cases. Median LPFS was 12.1 months; 1-, 2-, and 3-year LPFS rates were 51.2%, 27.9%, and 13.6%, respectively. A shorter LPFS was significantly associated with large lesions (HR 1.23, 95% CI 1.02-1.49; p = 0.032). Median PFS was 8.1 months; 1-, 2-, and 3-year PFS rates were 29.5%, 18.2%, and 9.1%, respectively. LPFS was significantly superior to PFS (p = 0.046). Median OS was 18.8 months. The 1-, 2-, 3-, and 5-year OS rates were 65.9%, 43.2%, 26.4%, and 10.0%, respectively. In univariate comparisons, high performance status (PS) score, smoking, and larger lesions were significantly correlated with poor survival. In multivariate analysis, advanced age, higher PS score, higher stage, larger lesion, and prior systematic treatment were independent prognostic factors for shorter OS. Adverse events were well tolerated and all patients recovered after appropriate intervention. Conclusions: MWA + ITC is a safe and effective new modality of local treatment for large NSCLC and can significantly prolong LPFS.

A study of microwave ablation for small cell lung cancer.

Purpose: To reveal the survival and safety of percutaneous microwave ablation (MWA) combined with chemoradiotherapy (CRT) in treating small cell lung cancer (SCLC). Materials and Methods: Clinical data of 48 SCLC patients who underwent MWA were retrospectively collected; survival and incidence of major complications were analyzed. Results: Totally, 48 SCLC patients underwent 51 MWA procedures. The median overall survival (OS) for all SCLC was 27.0 months (95% confidence interval 22.4-31.6 months). The OS of limited-stage (LS-SCLC) was longer than the extensive-stage (ES-SCLC) (median 48.0 months vs. 25.0 months, P = 0.022). The OS of SCLC with tumor diameter ≤3.0 cm was longer than that of tumor diameter >3.0 cm (median 48.0 months vs. 27.0 months, P = 0.041). For LS-SCLC, the 1-, 2-, 3-, and 5-year survival rate was 91.67%, 72.22%, 66.67%, and 61.11%, respectively. For ES-SCLC, the 1-, 2-, and 3-year survival rates were 83.33%, 50.0%, and 8.33%. Major complications included pneumothorax needing tube placement (29.4%), rarely arrhythmia (2.0%), empyema (2.0%), pulmonary fungal infection (2.0%), and shingles (2.0%). Conclusion: For SCLC patients, who received MWA combined with CRT, OS of LS-SCLC and tumor diameter ≤3.0 cm was better than that of the ES-SCLC and tumor diameter >3.0 cm. For inoperable SCLC, MWA was safe.

Microwave ablation treatment for medically inoperable stage I non-small cell lung cancers: long-term results.

OBJECTIVES: In the present study, we aim to show the results of microwave ablation (MWA) for medically inoperable stage I non-small cell lung cancers (NSCLCs) with long-term follow-up. METHODS: From Feb 2011 to Mar 2016, patients with histologically proven clinical stage I NSCLC were treated with CT-guided MWA and retrospectively analyzed. The primary end point was overall survival (OS). Secondary end points included disease-free survival (DFS), cancer-specific survival (CSS), and complications. RESULTS: A total of 105 patients with 105 lesions underwent MWA. The mean age was 70.7 years (range: 40-86 years), and the mean diameter of all lesions was 2.40 cm (range: 0.9-4.0 cm). Adenocarcinoma was the most common histological type (77, 73.3%), followed by squamous cell carcinomas (21, 20%) and undefined NSCLC (7, 6.7%). With a median follow-up of 54.8 months, the median DFS was 36.0 months, and 1-, 3-, and 5-year DFS rates were 89.5%, 49.4%, and 42.7%, respectively. The median CSS and OS were 89.8 and 64.2 months, respectively. The OS rate was 99% at 1 year, 75.6% at 3 years, and 54.1% at 5 years, while the CSS rates were 99%, 78.9%, and 60.9%, respectively. Patients with stage IB lesions had significant shorter DFS (22.3 months vs. undefined, HR: 11.5, 95%CI: 5.85-22.40) and OS (37.3 vs. 89.8 months, HR: 8.64, 95% CI: 4.49-16.60) than IA disease. CONCLUSION: MWA is a safe, effective, and potentially curative therapy for medically inoperable stage I NSCLC patients. KEY POINTS: • In this multicenter retrospective study which included 105 patients, we found the median overall survival (OS) was 64.2 months. The OS rate was 99% at 1 year, 75.6% at 3 years, and 54.1% at 5 years. • Procedures were technically successful and well tolerated in all patients. Most MWA complications were mild or moderate.

CT-guided microwave ablation in patients with lung metastases from breast cancer.

BACKGROUND: Computed tomography (CT)-guided percutaneous microwave ablation (MWA) is a very common ablation method that shows a good local tumor control rate in primary and secondary lung tumors. At present, few reports have explored the safety and efficacy of MWA for lung metastases from breast cancer. METHODS: From January 2012 to January 2018, 32 breast cancer patients with 46 pulmonary metastases received CT-guided percutaneous MWA. The study was approved by the local institutional review board. The clinical efficacy and complications of MWA were investigated. RESULTS: The median follow-up time was 32 months and the main effective rate was 97.8% (45/46). Five of 46 lesions had local progression (10.9%), with a median progression time of 10 months. The 1-, 3-, and 5-year overall survival (OS) rates were 96.9%, 53.3%, and 17.8%, respectively. The median OS time was 36 months. Among 46 MWA treatments, 11 (23.9%) had massive pneumothorax, two (4.3%) had massive pleural effusion, and two (4.3%) had a pulmonary infection. CONCLUSION: CT-guided percutaneous MWA may be safe and effective for treating lung metastases from breast cancer.

Aspirin enhances the therapeutic efficacy of cisplatin in oesophageal squamous cell carcinoma by inhibition of putative cancer stem cells.

BACKGROUND: Cancer stem cells (CSCs) are related to the patient's prognosis, recurrence and therapy resistance in oesophageal squamous cell carcinoma (ESCC). Although increasing evidence suggests that aspirin (acetylsalicylic acid, ASA) could lower the incidence and improve the prognosis of ESCC, the mechanism(s) remains to be fully understood. METHODS: We investigated the role of ASA in chemotherapy/chemoprevention in human ESCC cell lines and an N-nitrosomethylbenzylamine-induced rat ESCC carcinogenesis model. The effects of combined treatment with ASA/cisplatin on ESCC cell lines were examined in vitro and in vivo. Sphere-forming cells enriched with putative CSCs (pCSCs) were used to investigate the effect of ASA in CSCs. Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) was performed to determine the alterations in chromatin accessibility caused by ASA in ESCC cells. RESULTS: ASA inhibits the CSC properties and enhances cisplatin treatment in human ESCC cells. ATAC-seq indicates that ASA treatment results in remarkable epigenetic alterations on chromatin in ESCC cells, especially their pCSCs, through the modification of histone acetylation levels. The epigenetic changes activate Bim expression and promote cell death in CSCs of ESCC. Furthermore, ASA prevents the carcinogenesis of NMBzA-induced ESCC in the rat model. CONCLUSIONS: ASA could be a potential chemotherapeutic adjuvant and chemopreventive drug for ESCC treatment.

Thymus­expressed chemokine secreted by breast cancer cells promotes metastasis and inhibits apoptosis.

The aim of the present study was to investigate the underlying mechanisms of thymus­expressed chemokine (TECK) autocrine signaling, and its effect on carcinogenesis and the development of breast cancer. The present study also assessed epithelial­mensenchymal transition (EMT) and cell migration, invasion, proliferation and apoptosis. Breast cancer cell lines MCF­7 and MDA­MB­231 were used in the present study, and TECK basic expression in cancer cells was investigated using western blotting (WB). EMT markers, Akt pathway molecules and apoptosis indicators were detected by reverse transcription­quantitative PCR or WB. In order to assess migration and invasion, wound healing and Matrigel invasion assays were performed. Moreover, flow cytometry was used to assess the rate of proliferation and apoptosis. In vivo experiments were conducted in nude mice to assess cancer growth. It was revealed that breast cancer cells could secrete TECK in an autocrine manner. Furthermore, TECK could increase cell migration and invasion by promoting EMT and inhibit apoptosis via the Akt signaling pathway.

A feasibility and safety study of computed tomography-guided percutaneous microwave ablation: a novel therapy for multiple synchronous ground-glass opacities of the lung.

Purpose: The present study retrospectively evaluated the feasibility, safety, and short-term efficacy of computed tomography (CT)-guided percutaneous microwave ablation (MWA) to treat multiple synchronous ground-glass opacities (GGOs) of the lung.Materials and Methods: From October 2016 to May 2019, 33 patients (9 males and 24 females, mean age: 59.6 ± 10.0 years) with multiple GGOs (103 GGOs with mean size 12.3 ± 6.3 mm) were enrolled in this study. Patients underwent 66 procedures of CT-guided percutaneous MWA. The feasibility, safety, local progression-free survival, and overall survival were evaluated.Results: The technical success and technique efficacy rate were 100% and no MWA procedure-related deaths were reported. The median follow-up period was 18.1 (range: 6.8-37.7) months. Major complications included pneumothorax (11/66, 16.7%), pleural effusion (2/66, 3.0%), pneumonia (3/66, 4.5%), and nerve injury (1/66, 1.5%), which were well controlled by appropriate treatment. Minor complications included pneumothorax (38/66, 57.6%), pleural effusion (43/66, 65.2%), hemoptysis (13/66, 19.7%), subcutaneous emphysema (4/66, 6.1%), and hemothorax (2/66, 3.0%). Currently, all patients are alive without local progression or tumor recurrence, despite the relatively insufficient follow-up time.Conclusion: CT-guided percutaneous MWA for the treatment of multiple synchronous lung GGOs is feasible, safe, and efficacious over short-term follow-up. It may also be employed as an alternative approach for nonsurgical candidates. A longer follow-up is warranted to evaluate the oncologic outcomes.

Microwave ablation for non-small cell lung cancer with synchronous solitary extracranial metastasis.

AIMS: Local therapy including surgery or radiotherapy has been reported for the treatment of non-small cell lung cancer (NSCLC) with synchronous solitary metastasis, while studies with other local ablative treatment are rare. Here, we summarized our single-center experience of microwave ablation (MWA) for both primary and metastatic lesions in NSCLC patients with synchronous solitary extracranial metastases. PATIENTS AND METHODS: We retrospectively screened our institute database from January 2014 to Jun 2019. NSCLC patients with synchronous extracranial solitary metastasis with primary and metastatic lesions that were treated with MWA were identified and analyzed. RESULTS: Of the 1472 stage IV NSCLC patients found, 38 were diagnosed with synchronous extracranial solitary metastasis and 29 of them received MWA for primary and metastatic lesions. The most common distant metastases were contralateral lung metastases (14 cases), followed by bone (6), liver (4), adrenal gland (3) and pleura metastases (1). Median OS and PFS was 21.5 and 12.5 months, respectively. Patients with N0 had significantly longer PFS (median 18.5 vs. 8.0 months) and OS (median 42.7 vs. 19.0 months). In addition, systemic therapy was showed to be a prognostic factor for better PFS (12.9 vs. 7.5 months). Clinical pathological factors including age, histology, T stage, PS score, and metastasis locations are not significantly associated with survival. CONCLUSIONS: MWA may serve as an alternative treatment for NSCLCs with synchronous solitary extracranial metastases.

Microwave ablation plus chemotherapy versus chemotherapy in advanced non-small cell lung cancer: a multicenter, randomized, controlled, phase III clinical trial.

OBJECTIVES: This prospective trial was performed to verify whether microwave ablation (MWA) in combination with chemotherapy could provide superior survival benefit compared with chemotherapy alone. MATERIALS AND METHODS: From March 1, 2015, to June 20, 2017, treatment-naïve patients with pathologically verified advanced or recurrent non-small cell lung cancer (NSCLC) were randomly assigned to MWA plus chemotherapy group or chemotherapy group. The primary endpoint was progression-free survival (PFS), while the secondary endpoints included overall survival (OS), time to local progression (TTLP), and objective response rate (ORR). The complications and adverse events were also reported. RESULTS: A total of 293 patients were randomly assigned into the two groups. One hundred forty-eight patients with 117 stage IV tumors were included in the MWA plus chemotherapy group. One hundred forty-five patients with 113 stage IV tumors were included in the chemotherapy group. The median follow-up period was 13.1 months and 12.4 months, respectively. Median PFS was 10.3 months (95% CI 8.0-13.0) in the MWA plus chemotherapy group and 4.9 months (95% CI 4.2-5.7) in the chemotherapy group (HR = 0.44, 95% CI 0.28-0.53; p < 0.0001). Median OS was not reached in the MWA plus chemotherapy group and 12.6 months (95% CI 10.6-14.6) in the chemotherapy group (HR = 0.38, 95% CI 0.27-0.53; p < 0.0001) using Kaplan-Meier analyses with log-rank test. The median TTLP was 24.5 months, and the ORR was 32% in both groups. The adverse event rate was not significantly different in the two groups. CONCLUSIONS: In patients with advanced NSCLC, longer PFS and OS can be achieved with the treatment of combined MWA and chemotherapy than chemotherapy alone. KEY POINTS: • Patients treated with MWA plus chemotherapy had superior PFS and OS over those treated with chemotherapy alone. • The ORR of patients treated with MWA plus chemotherapy was similar to that of those treated with chemotherapy alone. • Complications associated with MWA were common but tolerable and manageable.

Metformin suppresses the esophageal carcinogenesis in rats treated with NMBzA through inhibiting AMPK/mTOR signaling pathway.

Metformin is a widely used antidiabetic drug for the management of type 2 diabetes mellitus. Recently, epidemiological studies demonstrate that metformin has anticancer effects on esophageal squamous cell carcinoma (ESCC) and other cancers. However, the effects and potential mechanisms of metformin on ESCC remain elusive. In this study, we used N-nitroso-N-methylbenzylamine (NMBzA), a special carcinogen for esophagi, to develop a rat ESCC model, in which the carcinogenesis progression of ESCC in rat was induced and promoted. We investigated the effects of metformin on carcinogenesis of ESCC in this model. Our results revealed that metformin significantly decreased the incidence and precancerous lesions of ESCC and inhibited proliferation and promoted apoptosis of esophageal epithelial cells in rat treated with NMBzA. Moreover, metformin also increased apoptosis and inhibited migration, colony formation and tumor sphere formation of human ESCC cells in vitro. Immunohistochemistry and western blotting showed that without interfering the metabolism of NMBzA, metformin inhibited the inflammation of esophagi via reducing the expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6). Treatment of metformin led to activation of AMP-activated protein kinase (AMPK) and attenuated signaling of the downstream molecules such as p-mTOR, p-p70S6K and cyclin D1 expression both in vivo and in vitro. Taken together, our study demonstrated that metformin suppressed the carcinogenesis of ESCC through inhibiting AMPK/mammalian target of the rapamycin (mTOR) signaling pathway, resulting in its chemopreventive effects on the carcinogenesis of ESCC.

Salvage therapy of reactive capillary hemangiomas: Apatinib alleviates the unique adverse events induced by camrelizumab in non-small cell lung cancer.

BACKGROUND: Camrelizumab is a promising anti-programmed cell death-1 agent for non-small cell lung cancer (NSCLC) and induces reactive capillary hemangiomas (RCHs). Routine clinical management of this unique and prevalent toxicity has been summarized in previous studies. The objective of this study was to provide evidence of apatinib as a salvage therapy for RCHs. MATERIALS AND METHODS: In this single-center, observational study, patients with NSCLC who were over 18 years of age and treated with camrelizumab were enrolled. The incidence of RCHs, onset and duration time, severity, evolution, and clinical practices, especially with apatinib, for their management and impact on quality of life, were recorded during a 6-month follow-up. RESULTS: A total of 28 patients were included. The incidence of RCHs was 28.6% (8/28). The median onset and duration time were 6 weeks and 8 weeks, respectively. Six (21.4%) patients had mild and moderate RCHs and four (9.3%) patients achieved a rapid regression of RCHs with the application of apatinib. The impact of the RCHs on quality of life was limited and assessed with Dermatology Life Quality Index scores. No treatment-associated termination was observed. CONCLUSION: The combination of camrelizumab and apatinib in the treatment of NSCLC reduced the incidence of RCHs. Apatinib appeared to be a salvage therapy of RCHs, which leads to rapid regression of RCHs with no impairment on the quality of life.

Camrelizumab combined with microwave ablation improves the objective response rate in advanced non-small cell lung cancer.

AIM: The present study evaluated the safety and efficacy of camrelizumab (a programmed death-1 antibody) in combination with microwave ablation (MWA) in advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A total of 21 patients were prospectively enrolled. MWA was performed in 25 pulmonary lesions during 21 sessions. Camrelizumab was administered 5-7 days after MWA as a dose of 200 mg, which was repeated every 2 weeks until disease progression or intolerable toxicities. The primary endpoints were safety and the objective response rate (ORR). Other endpoints included progression-free survival (PFS) and overall survival (OS). RESULTS: The technical success rate was 100%. No treatment-associated deaths were identified. Major complications, minor complications, and side effects of MWA were observed in 9, 8, and 14 patients, respectively. The main major complications included pneumothorax, pneumonia, hemorrhage, and pleural effusion. The adverse events of camrelizumab included reactive skin capillary hyperplasia (n = 9), hypothyroidism (n = 5), pneumonia (n = 4), fatigue (n = 2), leukopenia (n = 1), and neutropenia (n = 1). Grade 2 and 3 camrelizumab adverse events were identified in eight and three patients, respectively. The ORR was 33.3%, with two patients achieving complete response and five patients achieving partial response. The median PFS was 5.1 months and OS was not reached. CONCLUSIONS: Camrelizumab administration combined with MWA was safe in the treatment of advanced NSCLC, and the combination improved the ORR of camrelizumab alone compared to previous reports.

Chemokine (C­C motif) ligand 21/C­C chemokine receptor type 7 triggers migration and invasion of human lung cancer cells by epithelial­mesenchymal transition via the extracellular signal­regulated kinase signaling pathway.

C-C chemokine receptor type 7 (CCR7) has been implicated in lymph node metastasis of various cancers. Previous studies have revealed that epithelial­mesenchymal transition (EMT) is involved in the chemotactic process mediated by CCR7 and its ligands in various types of carcinoma. However, the underlying mechanism of this process remains to be fully elucidated. The present study investigated whether chemokine (C­C motif) ligand 21 (CCL21)/CCR7 may activate EMT of lung cancer cells and their associated signaling pathways. A549 and H520 lung cancer cell lines were examined in vitro in the present study. The results indicated that A549 and H520 expressed CCR7, but reduced levels of CCL21. Following stimulation of lung cancer cell lines with CCL21, the expression of the epithelial marker E­cadherin was downregulated, and the mesenchymal markers Vimentin/Slug and extracellular signal­regulated kinase (ERK) were upregulated. In addition, the ERK inhibitor PD98059 may inhibit EMT caused by CCL21, and decreased cell migration and invasion initiated by CCL21. Furthermore, lung adenocarcinoma tissues from 50 patients who underwent lung cancer operations were investigated by immunohistochemistry. The findings revealed that CCR7, Slug and Vimentin were highly expressed in lung carcinoma tissues, and were significantly associated with lymph node metastasis and clinical pathological stages, respectively. CCR7 expression was correlated positively with expression levels of Slug and Vimentin. CCL21 was expressed positively in the endothelium of lymphatic vessels adjacent to cancer cells, and weakly in lung cancer cells. Collectively, these results demonstrated that CCL21/CCR7 may activate EMT in lung cancer cells via the ERK1/2 signaling pathway. The current study provides evidence that a close interaction exists between CCL21/CCR7chemotaxis and EMT procedures in lung cancer metastasis, providing a basis for the development of therapeutic targets.

The impact of statins therapy on disease activity and inflammatory factor in patients with rheumatoid arthritis: a meta-analysis.

OBJECTIVES: Statin is the most widely used as HMG-CoA reductase inhibitor, and contributes to clinically significant vascular risk reduction. However, the role of statins in the rheumatoid arthritis (RA) immunomodulation is debatable. This meta-analysis aimed to determine the efficacy of statins therapy in RA patients. METHODS: A structured literature search was undertaken to identify randomised controlled trials (RCTs) conducted in RA patients receiving either statins or control. A meta-analysis on standardised mean difference (SMD) with a 95% confidence interval (95%CI) was conducted. RESULTS: We included 15 studies with a total of 992 patients (487 patients allocated to statins therapy). Our data revealed statins can attenuate disease activity markedly. Overall, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) declined significantly during the treatment (n=12, SMD: -2.222, 95%CI: -2.404, -2.040, p=0.000; n=14, SMD: -3.014, 95%CI: -3.207, -2.821, p=0.000), among which ESR and CRP decreased obviously at 12 months (n=5, SMD: -2.874, 95%CI: -3.224, -2.523, p=0.000; n=7, SMD: -3.970, 95%CI: -4.300, -3.641, p=0.000; respectively). As expected, the tender joint count (TJC) and swollen joint count (SJC) also fell (n=9, SMD: -2.005, 95% CI: -2.216, -1.794; p=0.000; n=10, SMD: -1.76, 95%CI: -1.948, -1.577; p=0.000; respectively). Besides, morning stiffness was attenuated (n=5, SMD: -1.242, 95%CI: -1.474, -1.011, p=0.000), and showed no significant differences between 12 months and 24 months (p=0.205). Notably, statins indeed potently down-regulate inflammatory factors TNF-α (n=7, SMD: -4.290, 95%CI: -4.659, -3.922; p=0.000), IL-1 (n=4, SMD: -1.324, 95%CI: -1.646, -1.003; p=0.000), and IL-6 (n=10, SMD: -1.652, 95%CI: -1.822, -1.482; p=0.000). No publication bias was observed across all studies based on the Begg and Egger test. CONCLUSIONS: This meta-analysis demonstrates the pleiotropic effects of statins on ameliorating RA activity and mediating clinically apparent anti-inflammatory effects in the context of RA autoimmune inflammation, which make it recommended as a potent treatment for RA patients.

CCL21/CCR7 axis activating chemotaxis accompanied with epithelial-mesenchymal transition in human breast carcinoma.

Secondary lymphoid tissue chemokine (SLC/CCL21) and its receptor CCR7 have been implicated in lymph node metastasis, whereas the mechanism of which remains unclear. Epithelial-mesenchymal transition (EMT) plays an important role in invasion and migration of cancer cells. We presumed that CCL21/CCR7 axis activates EMT process to induce cancer cell invasion and metastasis. Firstly, the expressions of CCR7 and EMT markers were examined by immunohistochemical staining in the primary breast carcinoma tissues from 60 patients who underwent radical mastectomy. Then, we investigated whether CCL21/CCR7 induces EMT process during mediating cancer cell invasion or migration in vitro. By immunohistolochemistry, high expressions of CCR7, Slug and N-cadherin were seen in 60, 65, and 76.67 % of tumors, respectively, and significantly associated with lymph node metastases as well as clinical pathological stage. Furthermore, the CCR7 expression was significantly correlated to Slug and N-cadherin. In vitro, stimulating breast cancer cell lines 1428, MCF-7 and MDA-MB-231 with CCL21, the invasion and migration of tumor cells were promoted, and simultaneously, EMT phenotype of tumor cells was enhanced, including down-regulation of E-cadherin, up-regulation of Slug, Vimentin and N-cadherin at both protein and mRNA levels. Inversely, knockdown of CCR7 by shRNA suppressed tumor cell invasion, migration and EMT phenotype induced by CCL21. These results indicated that CCL21/CCR7 axis could activate EMT process during chemotaxis of breast carcinoma cells.

TNF-α increases bone marrow mesenchymal stem cell migration to ischemic tissues.

The objective of this study was to analyze the influence of TNF-α on rat mesenchymal stem cells (MSCs) and to assess feasibility of MSC transplantation to repair ischemic injury. In this study, adhesion molecules and cell specific surface markers on MSCs were measured after exposure to different concentrations of TNF-α. MSCs stimulated with varying concentrations of TNF-α were cultured with aortic endothelial cells, and the adhesion rate was measured. MSCs were then stimulated with an optimum concentration of TNF-α as determined in vitro, and injected intravenously into rats with ischemic hind limb injury. The number of MSCs in muscle samples from the ischemic area was counted. The results showed that (1) TNF-α induced a concentration-dependent increase in VCAM-1 expression in MSCs, whereas the expression of L-selectin, ICAM-1 and VLA-4 did not change significantly. Expression of MSC-specific antigens was unchanged. (2) MSCs pretreated with 10 ng/ml TNF-α showed significantly increased adhesion to endothelial cells in vitro, and accumulated to a greater extent in the areas of ischemic damage in rat hind limbs. We were able to conclude that TNF-α has no effect on expression of MSC-specific markers, but can increase the expression of VCAM-1 on rat MSCs. Suitable concentrations of TNF-α can promote MSC adhesion to endothelial cells and migration to damaged tissue.