The effects of a biodegradable Mg-based alloy on the function of VSMCs via immunoregulation of macrophages through Mg-induced responses.

BACKGROUND: Restenosis is one of the worst side effects of percutaneous coronary intervention (PCI) due to neointima formation resulting from the excessive proliferation and migration of vascular smooth muscle cells (VSMCs) and continuous inflammation. Biodegradable Mg-based alloy is a promising candidate material because of its good mechanical properties and biocompatibility, and biodegradation of cardiovascular stents. Although studies have shown reduced neointima formation after Mg-based CVS implantation in vivo, these findings were inconsistent with in vitro studies, demonstrating magnesium-mediated promotion of the proliferation and migration of VSMCs. Given the vital role of activated macrophage-driven inflammation in neointima formation, along with the well-demonstrated crosstalk between macrophages and VSMCs, we investigated the interactions of a biodegradable Mg-Nd-Zn-Zr alloy (denoted JDBM), which is especially important for cardiovascular stents, with VSMCs via macrophages. METHODS: JDBM extracts and MgCl2 solutions were prepared to study their effect on macrophages. To study the effects of the JDBM extracts and MgCl2 solutions on the function of VSMCs via immunoregulation of macrophages, conditioned media (CM) obtained from macrophages was used to establish a VSMC-macrophage indirect coculture system. RESULTS: Our results showed that both JDBM extracts and MgCl2 solutions significantly attenuated the inflammatory response stimulated by lipopolysaccharide (LPS)-activated macrophages and converted macrophages into M2-type cells. In addition, JDBM extracts and MgCl2 solutions significantly decreased the expression of genes related to VSMC phenotypic switching, migration, and proliferation in macrophages. Furthermore, the proliferation, migration, and proinflammatory phenotypic switching of VSMCs were significantly inhibited when the cells were incubated with CMs from macrophages treated with LPS + extracts or LPS + MgCl2 solutions. CONCLUSIONS: Taken together, our results suggested that the magnesium in the JDBM extract could affect the functions of VSMCs through macrophage-mediated immunoregulation, inhibiting smooth muscle hyperproliferation to suppress restenosis after implantation of a biodegradable Mg-based stent.

The Optimal Second-Line Systemic Treatment Model for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: A Bayesian Network Meta-Analysis.

Background: The optimal second-line systemic treatment model for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains controversial. A Bayesian network meta-analysis (NMA) was performed to address this issue with regard to efficacy and toxicity. Methods: By searching MEDLINE (via PubMed), Embase, the Cochrane Central Register of Controlled Trials and Web of Science, we extracted eligible studies. Efficacy, represented as overall survival (OS) and progression-free survival (PFS), and overall toxicity, represented as ≥ grade 3 severe acute events (sAE), were assessed to compare the following 7 treatment models through an NMA: standard-of-care therapy (SoC), single targeted therapy different from SoC (ST), double targeted therapy (DT), targeted therapy combined with chemotherapy (T+C), single immune checkpoint inhibitor therapy (SI), double immune checkpoint inhibitor therapy (DI) and single chemotherapy different from SoC (SC). Rank probabilities according to the values of the surface under the cumulative ranking curve (SUCRA) were separately determined for efficacy and toxicity. Results: In total, 5285 patients from 24 eligible studies were ultimately screened, with 5184, 4532 and 4026 involved in the NMA of OS, PFS and sAE, respectively. All qualifying studies were absent from first-line immune checkpoint inhibitor therapy. In terms of OS, SI was superior to the other treatments, followed by DI, ST, T+C, SoC, DT and SC. Other than SI and SC, all treatments tended to be consistent, with hazard ratios (HRs) close to 1 between groups. For PFS, ST ranked first, while DT ranked last. For the toxicity profiles, compared with the other models, SI resulted in the lowest incidences of sAE, with statistical significance over SoC (odds ratio [OR] 0.31, 95% credible interval [CrI] 0.11 to 0.90), ST (OR 0.23, 95% CrI 0.06 to 0.86) and DT (OR 0.11, 95% CrI 0.02 to 0.53), while DT was the worst. When the SUCRA values of OS and sAE were combined, a cluster plot illustrated the superiority of SI, which demonstrated the best OS and tolerability toward sAE. Conclusion: For R/M HNSCC patients without immune checkpoint inhibitors in the first-line setting, SI may serve as the optimal second-line systemic treatment model, demonstrating the best OS and least sAE.

Effect of white matter changes on risk score for peri-procedural complications after carotid artery stenting.

OBJECTIVES: The presence of more severe white matter changes (WMC) may be associated with a higher risk of peri-procedural strokes in patients undergoing carotid artery stenting (CAS). However, to what extent WMC affects peri-procedural risk of CAS is unclear. We aimed to evaluate the effect of WMC on peri-procedural complications by modifying a CAS peri-procedural risk scale through adding the assessment of WMC. PATIENTS AND METHODS: A database of patients undergoing CAS was sampled from 2007 to 2014 in a single Chinese medical center. Risk factors were evaluated for peri-interventional cerebral and cardiac events and mortality. A risk score including contralateral stenosis ≥ 50%, diabetes with HbA1c > 7%, age ≥ 80 years old, symptomatic stenosis or with an ulcer lesion was applied to predict peri-interventional risk. Age-related white matter change (ARWMC) score was calculated and added to this risk scale. The predictive power of the new scale was evaluated. RESULTS: 151 patients were enrolled in the study. 14 peri-interventional events were recorded. Patients with peri-procedural complications had higher rates of diabetes (57.1% vs 18.2%, P = 0.001), contralateral stenosis (64.29% vs 32.85%, P = 0.019), coronary heart disease (42.9% vs 14.6%, P = 0.008) and ARWMC ≥ 7 (64.3% vs 25.5%, P = 0.002) compared with patients without peri-procedural complications. ARWMC ≥ 7 was an independent risk factor for peri-procedural complications from factors of the CAS scale after adjusting other confounders including contralateral stenosis ≥ 50%, HbA1c > 7%, age ≥ 80 years old and symptomatic stenosis or with an ulcer lesion. After the ARWMC score was added to the original scale, the AUC value of the new scale to predict the risk of peri-procedural complications after CAS was elevated (0.808 vs 0.730, p = 0.068). CONCLUSION: More severe WMC was a risk factor for peri-procedural complications after CAS in patients with carotid artery stenosis. ARWMC score may help to improve the predictive power of the risk scale for peri-procedural complications after CAS.

Rab5a­mediated autophagy regulates the phenotype and behavior of vascular smooth muscle cells.

Rab5a, a key member of the Rab family of GTPases, was determined to be a regulator of vascular smooth muscle cell (VSMC) proliferation and migration. However, the exact regulatory mechanism remains unclear. As Rab5a has been shown to be associated with autophagy, which is essential for the conversion of VSMCs from a contractile to a synthetic phenotype in order to prevent cell death due to oxidative stress. The present study hypothesized that autophagy may be responsible for the proliferation and migration of VSMCs via the Rab5a protein. The aim of the present study was to evaluate the effect of Rab5a on autophagy in VSMCs. The human aorta vascular smooth muscle cell line, T/G HA­VSMCs, was treated with small interfering (si)RNA against Rab5a and/or platelet­derived growth factor (PDGF). Following treatment, the phenotype transition of the VSMCs was evaluated by detecting the mRNA and protien expression levels of VSMC molecular markers using reverse transcription­quantitative polymerase chain reaction and western blotting, respectively. In addition, autophagy in VSMCs was evaluated by western blotting for autophagy­associated proteins, flow cytometry of acidic vesicular organelles, punctate fluorescence of microtubule associated protein light chain 3 and transmission electron microscopy of typical scattered double­membrane vacuolar structures. Additionally, the proliferation, migration, cell cycle and apoptotic response of VSMCs were detected by sulforhodamine B assay, transwell assay and flow cytometry, respectively. The results revealed that transfection with siRNA against Rab5a led to a significant decrease in Rab5a protein expression, while the reduced expression trend of Rab5a was rescued by intervention with PDGF. Furthermore, cells transfected with siRNA against Rab5a inhibited the autophagy of VSMCs. Downregulated Rab5a inhibited the phenotype transition of VSMCs. Additionally, downregulated Rab5a led to slowed cell growth, decreased numbers of migrated cells, decreased numbers of cells at the G0­G1 phase and a higher apoptosis rate. However, PDGF significantly rescued these phenomena caused by siRNA against Rab5a. These results indicated that Rab5a­mediated autophagy may regulate the phenotype transition and cell behavior of VSMCs through the activation of the extracellular­regulated kinase 1/2 signaling pathway.

Effect of microtopographic structures of silk fibroin on endothelial cell behavior.

Stent implantation has become the preferred revascularization treatment for occlusive blood vessel disease; however, there are occasionally complications resulting in re-narrowing of the treated artery. One approach to overcoming this problem is to establish a confluent monolayer of endothelial cells (ECs) on the stent, and a coating would facilitate the attachment of ECs. Silk fibroin was reported to be used as an ideal coating applied to stent for the culture of human ECs. The aim of the present study is to gain more insight into the influence of the internal microtopographical structure of silk fibroin on cell behavior, such as attachment and growth, and to further investigate its molecular mechanism using human umbilical vein ECs (HUVECs). Our results evaluated the effect of different microtopographical structures on cell behavior. In addition, we analyzed the cell cycle and investigated relevant molecules involved. The results indicated that the microtopographic structure of silk fibroin was associated with EC morphology, attachment and proliferation.

[Clinical research of carotid artery stenting under the protection of proximal embolic protection device].

OBJECTIVES: To study the efficacy of proximal embolic protection device in preventing intracranial artery embolization during carotid artery stenting (CAS) and to evaluate its security and maneuverability. METHODS: From October 2007 to July 2008, 23 patients with carotid artery stenosis who were suitable for surgical therapy according to the standards of NASCET or ACAS were enrolled in this clinical research. Among them 19 patients (82.6%) were symptomatic, 6 patients (26.1%) with 50%-70% stenosis and 17 cases (73.9%) with > 70% stenosis. All the patients received carotid angioplasty and stenting under the protection of MO. MA system (one kind of proximal embolic protection device). We recorded the cerebral ischemic time during the procedure and observed neurologic events within 30 days. RESULTS: All the procedures were performed successfully, the mean carotid artery blocking time was (5.3 +/- 1.2) min. No death or stroke occurred during perioperative period. Two cases of patients developed transient loss of consciousness combined with contralateral limb convulsion, while the common carotid artery was occluded by balloon. Two cases of patients developed bradycardia, sustained 6 hours and 1 week. Plaque debris in the withdrawal blood from carotid artery were found in 9 cases. At 30-day follow-up after CAS, TIA occurred in 1 case, new contralateral stroke occurred in 1 case, the incidence of 30-day stroke and death rate was 4.3%. CONCLUSION: The application of proximal embolic protection device in CAS procedure for preventing neurologic complications is safe and effective, especially for severe stenosis and unstable plaque in carotid artery stenting.

[A clinical trial of using antiplatelet therapy to prevent restenosis following peripheral artery angioplasty and stenting].

OBJECTIVE: To evaluate the clinical effect and restenosis rate of antiplatelet therapy following peripheral artery angioplasty and stenting. METHODS: After successful placement of peripheral artery stents to 103 patients with peripheral arterial occlusive disease (PAOD) in were randomized assigned to 2 groups: antiplatelet therapy group receiving clopidogrel 75 mg plus aspirin 100 mg (n = 56) and control group (n = 47) receiving anticoagulation therapy low molecular weight heparin (LWMH) for 7 d plus long-term warfarin. The patients were followed up 1 day, and 1, 6, 12, and 18 months after the operation to undergo color Doppler ultrasonography, and examinations of blood routine, bleeding time, coagulation time, and ankle-brachial Index. The primary endpoint events included major bleeding rate, and composite rate of restenosis and reocclusion. The secondary endpoint events included cardiovascular events, death, and adverse drug reaction. RESULTS: There were no significant differences in the baseline data between these two groups. The thrombotic occlusion rate was 1.8% in the antiplatelet group and 0% in control group, and the restenosis rate was 14.3% in the antiplatelet group and 25.5% in control group (both P > 0.05). The bleeding complication rate of the antiplatelet group was 1.8%, significantly lower than that of the anticoagulation group (19.1%, P < 0.01). There were not significant differences in cardiovascular event rate and mortality 18 months after operation between these two groups. CONCLUSION: Antiplatelet therapy combined with clopidogrel plus aspirin is effective and safe in preventing restenosis following peripheral artery angioplasty and stenting.