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Hypoxia is a hallmark of the tumor microenvironment, which promotes the proliferation, metastasis and invasion of tumors and stimulates the resistance of cancer treatments, leading to the serious consequence of tumor recurrence. Many nanotechnology-based studies have been conducted to improve the efficacy of cancer treatments using a hypoxia strategy. This is usually achieved by (i) activating bioreductive prodrugs in the tumor hypoxic/exacerbated hypoxic microenvironment, or (ii) delivering therapeutic agents to hypoxic tumor tissue using targeting molecules. Normally, a good therapeutic effect can be expected upon modulating the hypoxic microenvironment for tumor treatments. To achieve this, various nanotechnology strategies based on overcoming hypoxia have been exploited to alleviate tumor hypoxia and enhance the therapeutic efficacy of tumor therapy, including (i) reducing oxygen consumption by inhibiting cell respiration, (ii) normalizing tumor vessels to promote blood flow in the tumor, (iii) carrying exogenous oxygen into the tumor, and (iv) generating oxygen in situ. The strategy of in situ oxygen production is refined, and the scope of this strategy is further expanded. Finally, the inspiration of using advanced nanotechnology in hypoxia-associated antitumor therapy guides the study of tumor hypoxia for clinical use.

As a metallic orthopedic implant, 316 L stainless steel (316 L SS) is used extensively for its good resistance to corrosion and mechanical properties. However, it takes a long time to achieve osseointegration between 316 L SS and adjacent tissues due to its bio-inert characteristic. Hence, the aim is to improve the bio-adaption of 316 L SS. A good approach is to add elements to materials to improve their osteogenic capabilities by the appropriate release of ions. Hence copper-containing 316 L stainless steel (316L-Cu SS) was investigated in this work, where Cu is an essential trace element that can stimulates osteogenesis. It was found that 316L-Cu SS was bio-safe and did not affect the proliferation of co-cultured osteoblasts in comparison with 316 L SS. It increased cell apoptosis on day 1 but inhibited it on day 3, which cooperates with new bone formation processes. Osteoblasts extend themselves more quickly and in a better manner on the surface of 316L-Cu SS, wheneven more pseudopodia are present. Furthermore, the gene expression of alkaline phosphatase, collagen I and runt-related transcription factor 2 (Runx2) in osteoblasts cultured with 316L-Cu SS was significantly enhanced. Runx2 protein expression increased, and osteogenesis was stimulated by 316L-Cu SS via an Akt cell signaling pathway. In conclusion, 316L-Cu SS stimulates osteogenesis through activation of the Akt cell signaling pathway and the upregulation of Runx2. Thus, 316L-Cu SS is a promising material that may be used in surgical implants to stimulate osteogenesis.

Purpose: CADM1-AS1 (cell adhesion molecule 1 antisense RNA 1, long non-coding RNA), was firstly characterized in renal clear cell carcinoma, and exhibits a tumor suppressor role. However, its clinical relevance and exact effects in hepatocellular carcinoma (HCC) remain unknown. Therefore, in this study, we aimed to assess the clinical significance and function of CADM1-AS1 in HCC. Methods: We detected CADM1-AS1 expression in liver cancer tissue samples and cell lines, and analyzed the association between CADM1-AS1 expression and clinical parameters in 90 liver cancer patients. Moreover, we conducted gain-of-function and loss-of-function studies in liver cancer cell to explore the biological function and molecular mechanism of CADM1-AS1. Results: CADM1-AS1 expression was reduced in HCC. Clinical data showed that this downregulation was associated with advanced tumor stage, high TNM stage and reduced survival in HCC patients. CADM1-AS1 overexpression inhibited HCC cells proliferation, migration and invasion, while inducing G0/G1 phase arrest. Meanwhile, we revealed that CADM1-AS1 inhibited the phosphorylation of AKT and GSK-3β. Furthermore, our study showed that CADM1-AS1 decreased the cell cycle associated proteins expression of cyclinD, cyclinE, CDK2 CDK4, CDK6, and enhanced the levels of p15, p21 and p27. More importantly, SC79, a specific activator for AKT;, apparently attenuated the effects of CADM1-AS1 on above cell-cycle associated proteins, confirming that CADM1-AS1 inhibited cell cycles through the AKT signaling pathway. And we also found the CADM1-AS1 has antitumor effect in vivo by a xenograft HCC mouse model. In conclusion, the present findings show that the CADM1-AS1 inhibits proliferation of HCC by inhibiting AKT/GSK-3β signaling pathway, then upregulate p15, p21, p27 expression and downregulate cyclin, CDK expression to inhibit the G0/G1 to S phase transition both in vitro and in vivo. Conclusion: CADM1-AS1 functions as a tumor-suppressive lncRNA. This study reveals a molecular pathway involving PTEN/AKT/GSK-3β which regulates HCC cell-cycle progression.

A 55-year-old man developed deep venous thrombosis and inferior vena cava (IVC) thrombosis 7 years earlier and was treated by placement of a permanent IVC filter. One week ago, he was admitted with bilateral lower limb swelling and pain. Digital subtraction angiography showed a filling defect above the original filter. A retrievable Tulip filter was placed and catheter-directed thrombolysis was performed. Six days later, the patient experienced sudden, persistent upper right abdominal pain, and a computed tomography scan revealed the formation of retroperitoneal hematoma. Symptomatic treatments were administered, and the hematoma gradually resolved during follow-up.

Vessel embolization is recommended as the first line treatment for unresectable hepatocellular carcinoma (HCC). However, owing to the imprecise vessel embolization and heterogeneous response performance among patients, its survival benefits are often compromised. Herein, we reported an innovative strategy to extensively embolize the tumor by triggering the coagulation cascade, and predict the embolization effect with vessel density assessment. We synthesized manganese dioxide (MnO2)/verteporfin (BPD) nanocomposites, in which BPD bound to the tumor vessel endothelial cells (TVECs) and MnO2 nanosheets served as the carrier. MnO2 was reduced to Mn2+ ions and self-assembled with BPD to produce nanoBPD, resulting in enhanced TVECs apoptosis and coagulation cascade compared to that with free BPD. Furthermore, multimodal imaging was used to visualize tumor vessel density, which can be used as a predictor to identify the patients who would benefit from embolization. Our findings describe a promising strategy for both tumor eradication and effect prediction to improve survival benefits in unresectable HCC patients.

Background:Mitogen-inducible gene 6 (Mig-6) is a tumor suppressor gene that plays an important role in many types of cancers by interacting with EGFR. Thus far, little is known about the molecular mechanism of Mig-6 in hepatocellular carcinoma (HCC). Also, the relationship between Mig-6 and miRNAs needs to be elucidated. Therefore, this study first aimed to find whether Mig-6 could promote apoptosis and inhibition of the flux of autophagy by its downstream miRNA in HCC cell lines. Methods: Two cell lines, HepG2and HLE, were used in this study. Mig-6 overexpression and knockdown models , miR-193a mimics and inhibitors models,were established. MiRNA microarray profiling were used to verified Mig-6 regulated- miRNA. Real-time PCR, Western blot analysis were carried out to detect RNA and protein expression.Evaluation of fluorescent LC3 puncta and cell fow cytometer assay were used to test the autophagy and apoptosis respectively. Results: Mig-6 induced the apoptosis and reduced the autophagy of HCC cell lines. MiR-193a-3p is a Mig-6-regulated miRNA in Mig-6 overexpression model, and miR-193a-3p affected the apoptosis and autophagy of HCC cells by regulating the expression of TGF-β2. Additionally, the relationship between Mig-6 and transforming growth factor TGF-β2 was explored in depth for the first time.Conclusion:These findings revealed an important regulatory axis Mig-6/miR-193a-3p/TGF-β2 in the apoptosis and autophagy of HCC cells, providing a novel insight into the therapeutic target in HCC.

Iron oxide based magnetic nanoparticles (MNPs) as typical theranostic nanoagents have been popularly used in various biomedical applications. Conventional core–shell MNPs are usually synthesized from inside to outside. This method has strict requirements on the interface properties of magnetic cores and the precursors of the coating shell. The shape and size of MNPs are significantly influenced by that of the pre-synthesized magnetic cores. Most core–shell MNPs have only single T2W MRI imaging ability. Herein, we propose a new synthetic strategy for core-mesoporous shell structural MNPs, where hollow mesoporous nanospheres which exhibit an intrinsic property for both CT imaging and drug loading were used as the shell and the magnetic cores were produced in the cavity of the shell. A new type of MNPs, Fe3O4@ZrO2 nanoparticles (M-MZNs), were developed using this facile outside-to-inside way, where multiple Fe3O4 nanoparticles grew inside the cavity of the mesoporous hollow ZrO2 nanospheres through chemical coprecipitation. The obtained MNPs not only exhibited superior magnetic properties and CT/MR imaging ability but also high drug loading capacity. In vitro experiment results revealed that M-MZNs-PEG loaded with doxorubicin (DOX) presented selective growth inhibition against cancer cells due to pH-sensitive DOX release and enhanced endocytosis by cancer cells under a magnetic field. Furthermore, the proposed MNPs exhibited CT/MRI dual modal imaging ability and effective physical targeting to tumor sites in vivo. More importantly, experiments of magnetic targeting chemotherapy on tumor bearing mice demonstrated that the nanocomposites significantly suppressed tumor growth without obvious pathological damage to major organs. Henceforth, this study provides a new strategy for CT/MRI dual-modal imaging guided and magnetic targeting cancer therapy.

There are acknowledged risks of metastasis of cancer cells and obstructing cancer treatment from hypoxia. In this work, we design a multifunctional nanocomposite for treating hypoxia based on the oxygen release capability of CuO triggered by microwave (MW). Core–shell CuO@ZrO2 nanocomposites are prepared by confining CuO nanoparticles within the cavities of mesoporous ZrO2 hollow nanospheres. 1-Butyl-3-methylimidazolium hexafluorophosphate (IL) is loaded to the CuO@ZrO2 nanocomposites for improving microwave thermal therapy (MWTT). 1-Tetradecanol (PCM) is introduced to regulate the release of chemotherapeutic drugs of doxorubicin (DOX). Thus, the IL-DOX-PCM-CuO@ZrO2 multifunctional (IDPC@Zr) nanocomposites are obtained. Finally, IDPC@Zr nanocomposites are modified by monomethoxy polyethylene glycol sulfhydryl (mPEG-SH, 5 kDa) (IDPC@Zr-PEG nanocomposites). IDPC@Zr-PEG nanocomposites can produce oxygen in the tumor microenvironment during the course of tumor treatment, thereby alleviating the hypoxic state ...

Background Several studies have reported that hepatitis B virus (HBV) infection affects the risk of coronary heart disease. However, its association is controversial. Thus, we conducted a systematic review and meta-analysis to better understand it. Methods Relevant studies published before October 2017 were identified by searching PubMed, EMBASE, and ISI Web of Science. The relationships between HBV and the risk of coronary heart disease were assessed using Relative risk (RR) values and the corresponding 95% confidence intervals (CIs). We used the random effects model proposed by DerSimonian and Laird to quantify the relationship. Results Nine articles, including 65,058 HBV-infected patients and 534,998 uninfected controls, were included in the meta-analysis. The present study does not support that HBV infection is associated with the risk of coronary heart disease (RR = 0.99, CI = 0.76–1.22; I 2 = 68.9%). Sensitivity analysis and ‘trim and fill' method yielded similar results. No evidence of publication bias was observed. Conclusions HBV infection does not increase the risk of coronary heart disease. The associations were not significant both in cohort studies and in case-control studies.

Objectives The aim was to evaluate the feasibility and safety of a new unibody branched stent graft for the reconstruction of the canine aortic arch. Methods The unibody branched stent grafts included single branched stent grafts and double branched stent grafts. The main stent graft and branched limbs were sutured together. The branched stent grafts were folded into the introducer system, which consisted of a double channel catheter, a detachable sleeve, and an introducer sheath. The branched stent grafts were introduced and deployed into the aortic arch by the delivery system. Twenty adult mongrel dogs were used for the experiments. Ten dogs were implanted with single branched stent grafts; the other 10 were implanted with double branched stent grafts. The surviving animals were followed up for 3 months. Computed tomography angiography (CTA) was performed to observe the status of the branched stent grafts. Results All the unibody branched stent grafts were successfully implanted into the canine aortic arches. The technical success rate was 100%. There was no cerebral infarction, paraplegia or incision infection. CTA showed that all the branched stent grafts were patent; there was no endoleak or stent migration. Conclusions The unibody branched stent graft system could be used to reconstruct the aortic arch. The animal experimental procedures demonstrated the safety and feasibility of the unibody branched stent graft system.

The present study investigated the role of tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) in regulating the proliferation, migration, apoptosis and activity of matrix metalloproteinase (MMP)-2 and −9, during the development of an atherosclerotic abdominal artery aneurysm (AAA). Experiments were conducted using rabbit AAA neck (NA) smooth muscle cells (SMCs), to investigate the potential for TIMP-3 to be used as a novel stent coating in preventing aortic dilation adjacent to the AAA. The atherosclerotic AAA model was induced in New Zealand white rabbits via a 6-week high-cholesterol diet, followed by incubation of the targeted aortic region with elastase. SMCs were isolated from the aorta adjacent to the aneurysm 30 days after AAA model induction, and stimulated with 3, 10, 30 or 100 ng/ml TIMP-3. Cell proliferation was investigated using Cell Counting Kit-8 reagent, migration was examined using a Boyden chamber assay and apoptotic rate was analyzed using the Annexin V-fluorescein isothiocyanate Apoptosis Detection kit. Gelatin zymography and ELISA were used to measure the activity of MMP-2 and MMP-9, and the expression of tumor necrosis factor-α (TNF-α), respectively. Analysis of cell proliferation indicated that 10, 30 and 100 ng/ml TIMP-3 reduced cell viability. Cell migration was decreased by 10, 30 and 100 ng/ml TIMP-3. MMP-2 activity was inhibited by 10, 30 and 100 ng/ml TIMP-3, and MMP-9 activity was suppressed by 30 and 100 ng/ml TIMP-3. The protein levels of secreted TNF-α were reduced by 10, 30 and 100 ng/ml TIMP-3. The present study demonstrated the ability of 30 and 100 ng/ml TIMP-3 to attenuate migration and proliferation, and to inhibit the activity of MMP-2, MMP-9 and TNF-α secretion of NA SMCs. In conclusion, TIMP-3 may be considered a potential therapeutic drug for use in a novel drug-eluting stent, to attenuate the progressive dilation of the aortic NA.

Background With the development of nanomaterials, nanoparticle-based therapeutics have found increasing application in various fields, including clinical and basic medicine. Real-time monitoring of nanoparticle-based therapeutics is considered critical to both pharmacology and pharmacokinetics. Methods In this review, we discuss the different methods of real-time monitoring of nanoparticle-based therapeutics comprising different types of nanoparticle carriers, such as metal nanoparticles, inorganic nonmetallic nanoparticles, biodegradable polymer nanoparticles, and biological nanoparticles. Results In the light of examples and analyses, we conclude that the methods of analysis of the four types of nanoparticle carriers are commonly used methods and mostly not necessary. Under most circumstances, real-time monitoring differs according to nanoparticle type, drugs, diseases, and surroundings. Conclusion With technology development and advanced researches, there have been increasing measures to track the real-time changes in nanoparticles, and this has led to great progress in pharmacology and therapeutics. However, future studies are warranted to determine the accuracy, applicability, and practicability of different technologies.

AIM To investigate 30-year treatment outcomes associated with Budd-Chiari syndrome (BCS) at a tertiary hospital in China. METHODS A total of 256 patients diagnosed with primary BCS at our tertiary hospital between November 1983 and September 2013 were followed and retrospectively studied. Cumulative survival rates and cumulative mortality rates of major causes were calculated by Kaplan-Meier analysis, and the independent predictors of survival were identified using a Cox regression model. RESULTS Thirty-four patients were untreated; however, 222 patients were treated by medicine, surgery, or interventional radiology. Forty-four patients were lost to follow-up; however, 212 patients were followed, 67 of whom died. The symptom remission rates of treated and untreated patients were 81.1% (107/132) and 46.2% (6/13), respectively (P = 0.009). The cumulative 1-, 5-, 10-, 20-, and 30-year survival rates of the treated patients were 93.5%, 81.6%, 75.2%, 64.7%, and 58.2%, respectively; however, the 1-, 5-, 10-, 20-, and 30-year survival rates of the untreated patients were 70.8%, 70.8%, 53.1%, 0%, and unavailable, respectively (P = 0.007). Independent predictors of survival for treated patients were gastroesophageal variceal bleeding (HR = 3.043, 95%CI: 1.363-6.791, P = 0.007) and restenosis (HR = 4.610, 95%CI: 1.916-11.091, P = 0.001). The cumulative 1-, 5-, 10-, 20-, and 30-year mortality rates for hepatocellular carcinoma were 0%, 2.6%, 3.5%, 8%, and 17.4%, respectively. CONCLUSION Long-term survival is satisfactory for treated Chinese patients with BCS. Hepatocellular carcinoma is a chronic complication and should be monitored with long-term follow-up.

Endothelialization is an important process after stenting in coronary artery. Recovery of the injured site timely can reduce the neointima formation and platelet absorbance, leading to a lower risk of in-stent restenosis. Copper is known to be critical in vascular construction. Thus a combination of copper with stent materials is a meaningful attempt. A copper bearing L605-Cu cobalt alloy was prepared and its effect on human umbilical vein endothelial cells (HUVECs) was evaluated in vitro in this study. It was found that HUVECs attached and stretched better on the surface of L605-Cu compared with L605, and the apoptosis of cells was decreased simultaneously. The migration and tube formation of HUVECs were also enhanced by the extract of L605-Cu. Furthermore, L605-Cu increased the mRNA expression of VEGF in HUVECs significantly. However it had no effect on the secretion of NO or mRNA expression of eNOS. The result of blood clotting test indicated that L605-Cu had better blood compatibility. These results above have demonstrated that the L605-Cu alloy is promising to be a new stent material with function of accelerating endothelialization. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 561-569, 2018.

Aim The aim of this study was to evaluate transauricular digital subtraction angiography (DSA) as an alternative to conventional intra-arterial DSA for rabbit abdominal aortic aneurysm (AAA). Materials and methods AAA models were created in 8 New Zealand white rabbits by sewing vein patch. The diameters of aortic arteries were measured by DSA via ear vein and ear central artery. The common carotid artery (CCA) was exposed and cannulated for DSA as conventional angiography. Diameter size was measured and compared. Results Aortic diameters, tested by DSA via ear vein, ear central artery and CCA were 7.9 ± 1.2 mm, 7.8 ± 1.0 mm and 7.9 ± 1.1 mm respectively, with no significant differences. Angiography via CCA as standard procedure, correlation in aneurysm neck diameter was r = 0.93 for IVDSA and r = 0.96 for angiography via central artery (P, Highlights • Correlations of DSA via ear vein and ear central artery to conventional DSA were good. • Transauricular DSA shows good correlation to conventional DSA. • Transauricular DSA can be used repeatedly with less invasiveness, and suitable for rabbit AAA follow-up study.

Combined thermo-chemotherapy displays outstanding synergically therapeutic efficiency when compared with standalone thermotherapy and chemotherapy. Herein, we developed a smart tri-stimuli-responsive drug delivery system involving X@BB-ZrO2 NPs (X represents loaded IL, DOX, keratin and tetradecanol) based on novel ball-in-ball-structured ZrO2 nanoparticles (BB-ZrO2 NPs). The microwave energy conversion efficiency of BB-ZrO2 NPs was 41.2% higher than that of traditional single-layer NPs due to the cooperative action of self-reflection and spatial confinement effect of the special two-layer hollow nanostructure. The tri-stimuli-responsive controlled release strategy indicate that integrated pH, redox and microwaves in single NPs based on keratin and tetradecanol could effectively enhance the specific controlled release of DOX. The release of DOX was only 8.1% in PBS with pH = 7.2 and GSH = 20 μM. However, the release could reach about 50% at the tumor site (pH = 5.5, GSH = 13 mM) under microwave ablation. The as-made X@BB-ZrO2 NPs exhibited perfect synergic therapy effect of chemotherapy and microwave ablation both in subcutaneous tumors (H22 tumor-bearing mice) and deep tumors (liver transplantation VX2 tumor-bearing rabbit model). There was no recurrence and death in the X@BB-ZrO2 + MW group during the therapy of subcutaneous tumors even on the 42nd day. The growth rates in the deep tumor of the control, MW and X@BB-ZrO2 + MW groups were 290.1%, 14.1% and -42% 6 days after ablation, respectively. Dual-source CT was used to monitor the metabolism behavior of the as-made BB-ZrO2 NPs and traditional CT was utilized to monitor the tumor growth in rabbits. Frozen section examination and ICP results indicated the precise control of drug delivery and enhanced cytotoxicity by the tri-stimuli-responsive controlled release strategy. The ball-in-ball ZrO2 NPs with high microwave energy conversion efficiency were first developed for synergic microwave ablation and tri-stimuli-responsive chemotherapy, which may have potential applications in clinic.

There are acknowledged risks of metastasis of cancer cells and obstructing cancer treatment from hypoxia. In this work, we design a multifunctional nanocomposite for treating hypoxia based on the oxygen release capability of CuO triggered by microwave (MW). Core-shell CuO@ZrO

To evaluate the effect of transarterial infusion of iRGD-modified and doxorubicin-loaded zirconia-composite nanoparticles (R-DZCNs) with lipiodol in the improvement of the distribution of doxorubicin (DOX) in liver tumors and its antitumor efficacy.The effect of R-DZCNs was evaluated in vitro by tumor cellular uptake and cytotoxicity assays. For the in vivo study, DOX distribution and antitumor efficiency were assessed. In the DOX distribution study, VX2 tumor-bearing rabbits received transarterial infusion of lipiodol with DOX, doxorubicin-loaded zirconia-composite nanoparticles (DZCNs), or R-DZCNs, respectively. DOX distribution was assessed by immunofluorescence. In the antitumor study, tumor-bearing rabbits received transarterial infusions of lipiodol with DOX, DZCNs, R-DZCNs, or saline respectively. Tumor volume was measured using magnetic resonance imaging, and the expression of apoptosis-related factors (caspase-3, Bax, Bcl-2) was analyzed by immunohistochemistry and Western blotting.R-DZCNs increased cellular uptake and caused stronger cytotoxicity. Compared with the DOX + lipiodol or DZCNs + lipiodol group, the R-DZCNs + lipiodol group showed more DOX fluorescence spots (2,449.15 ± 444.14 vs. 3,464.73 ± 632.75 or 5,062.25 ± 585.62, respectively; P.001) and longer penetration distance (117.58 ± 19.36 vs 52.64 ± 8.53 or 83.37 ± 13.76 μm, respectively; P.001). In the antitumor study, the R-DZCNs + lipiodol group showed smaller tumor volumes than the DOX + lipiodol or DZCNs + lipiodol group (1,223.87 ± 223.58 vs. 3,695.26 ± 666.25 or 2281.06 ± 457.21 mmTransarterial infusion of R-DZCNs with lipiodol improved the distribution of DOX and enhanced its antitumor efficacy.

The characterization of high recurrence rate of HCC after TAE provides insights into persistent issues surrounding the role of adjunct therapies administered with TAE. As a regulator of the HER family, Mig-6 is down-regulated in HCC and predicts the prognosis of HCC. In this study, we found up-regulation the expression of Mig-6 enhances autophagy in HCC cells. This function of Mig-6 is related to the activation of the JNK pathway. Next AAV-9 encoding Mitogen inducible gene 6 (Mig-6) was delivered into VX2 liver transplant tumor of rabbits by using hepatic artery catheter. Wild-type AAV is not associated with any human or animal disease and has very low immunogenicity. There are over 100 different AAV serotypes that vary in the amino acid sequence of their capsid protein. We also describe a novel combination therapy coupling AAV-Mig-6 and TAE in a rabbit model resulted in a growth rate decrease in tumor compared with TAE alone. Furthermore, we show that the changes of LC3b and p62, as well as the p-JNK were consistent with changes in vitro experiments. These results suggest that Mig-6 efficiently inhibits tumor progression in vivo. Our findings suggest that Mig-6 induced autophagy inhibition may become a necessary target for adjunct therapy in TAE.

Drug eluting stents (DES) have been extensively applied nowadays and reduce the incidence of in-stent restenosis (ISR) greatly as compared with bare metal stents (BMS). However, the development of DES is hindered by the risk of late stent thrombosis (LST) due to delayed re-endothelialization, while endothelialization is an important process related to ISR and LST after implantation. 316L is a traditional stent material without bioactivity and have a high risk of ISR. Cu is recognized for angiogenesis stimulation in these years. Hence a copper bearing 316L stainless steel (316L-Cu) was prepared and evaluated about its effect on endothelialization in this paper. Compared with traditional 316L, it was proved that 316L-Cu increased the proliferation of co-cultured human umbilical vein endothelial cells (HUVECs) at first day. Moreover, HUVECs stretched better on the surface of 316L-Cu. It also improved the expression of angiogenesis related genes and tube formation ability in vitro. 316L-Cu-BMS, DES and 316L-BMS were implanted in swine to evaluate the re-endothelialization ability in vivo. And 316L-Cu-BMS showed the best effect on endothelialization with good biosafety. Consequently, 316L-Cu is a kind of promising BMS material for coronary field.

Zeolitic imidazolate frameworks (ZIFs) have attracted great interest as pH-sensitive drug carrier because of high drug loading and intrinsic biodegradability. In this work, a biocompatible NIR and pH-responsive drug delivery nanoplatform based on ZIFs (PDA-PCM@ZIF-8/DOX) is synthesized for in vivo cancer therapy. The biocompatibility of ZIFs is greatly improved by polydopamine (PDA) modifying and proved by cytotoxicity and in vivo acute toxicity evaluation. The degradability is also regulated in an appropriate rate. Due to mild reaction condition of ZIFs, the synthesis and drug loading is achieved in one pot with high loading (37.86%) and encapsulation rate (78.76%). Meanwhile, PDA acts as a photothermal transfer agent to trigger thermal response switch of phase change materials for NIR controlled drug release. Under the dual stimulus of NIR and acid environment, the drug release is as high as 78%, while only 21% is released without stimulus, showing a remarkable effect of control release. In vivo anti-tumor experiments demonstrate the high tumor inhibition rate of photothermal-chemotherapy group with a significant synergistic effect. The biocompatible and biodegradable drug delivery platform based on ZIFs has shown great promise for future clinic cancer therapy.

Combined thermo-chemotherapy displays outstanding synergically therapeutic efficiency when compared with standalone thermotherapy and chemotherapy. Herein, we developed a smart tri-stimuli-responsive drug delivery system involving X@BB-ZrO

Endothelialization is an important process after stenting in coronary artery. Recovery of the injured site timely can reduce the neointima formation and platelet absorbance, leading to a lower risk of in-stent restenosis. Copper is known to be critical in vascular construction. Thus a combination of copper with stent materials is a meaningful attempt. A copper bearing L605-Cu cobalt alloy was prepared and its effect on human umbilical vein endothelial cells (HUVECs) was evaluated in vitro in this study. It was found that HUVECs attached and stretched better on the surface of L605-Cu compared with L605, and the apoptosis of cells was decreased simultaneously. The migration and tube formation of HUVECs were also enhanced by the extract of L605-Cu. Furthermore, L605-Cu increased the mRNA expression of VEGF in HUVECs significantly. However it had no effect on the secretion of NO or mRNA expression of eNOS. The result of blood clotting test indicated that L605-Cu had better blood compatibility. These results above have demonstrated that the L605-Cu alloy is promising to be a new stent material with function of accelerating endothelialization. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 561-569, 2018.

Purpose To evaluate the effect of transarterial infusion of iRGD-modified and doxorubicin-loaded zirconia-composite nanoparticles (R-DZCNs) with lipiodol in the improvement of the distribution of doxorubicin (DOX) in liver tumors and its antitumor efficacy. Materials and Methods The effect of R-DZCNs was evaluated in vitro by tumor cellular uptake and cytotoxicity assays. For the in vivo study, DOX distribution and antitumor efficiency were assessed. In the DOX distribution study, VX2 tumor-bearing rabbits received transarterial infusion of lipiodol with DOX, doxorubicin-loaded zirconia-composite nanoparticles (DZCNs), or R-DZCNs, respectively. DOX distribution was assessed by immunofluorescence. In the antitumor study, tumor-bearing rabbits received transarterial infusions of lipiodol with DOX, DZCNs, R-DZCNs, or saline respectively. Tumor volume was measured using magnetic resonance imaging, and the expression of apoptosis-related factors (caspase-3, Bax, Bcl-2) was analyzed by immunohistochemistry and Western blotting. Results R-DZCNs increased cellular uptake and caused stronger cytotoxicity. Compared with the DOX + lipiodol or DZCNs + lipiodol group, the R-DZCNs + lipiodol group showed more DOX fluorescence spots (2,449.15 ± 444.14 vs. 3,464.73 ± 632.75 or 5,062.25 ± 585.62, respectively; P Conclusions Transarterial infusion of R-DZCNs with lipiodol improved the distribution of DOX and enhanced its antitumor efficacy.

Nanozymes with excellent enzyme-mimicking catalytic property are playing an increasingly significant role in tumor diagnosis and therapy. Fe-metal organic framework nanoparticles (MIL-101(Fe) NPs) are prepared as nanozymes to generate reactive oxygen species (ROS) and induce cancer cell death by catalyzing endogenous substances in tumor microenvironment. Abundant stimuli-responsive hydroxyl radicals (·OH) are accelerated to generate in the presence of microwave irradiation, realizing microwave enhancing dynamic therapy (MEDT). Moreover, MIL-101(Fe) NPs possess biodegradability and bioresponsibility, which exhibit favourable properties of metabolism and non-toxic accumulation comparing with inorganic nanozymes. Fluorescent gold nanoclusters (BSA-Au NCs) are rapidly coupled with the surface of MIL-101(Fe) NPs to obtain MIL-101(Fe)@BSA-AuNCs NPs. MIL-101(Fe)@BSA-AuNCs NPs with magnetic resonance imaging (MRI) and fluorescent imaging (FI) not only image accurately for the site of tumor, but also monitor dynamic distribution process of MIL-101(Fe) in vivo. The signal intensity of FI and MRI reaches maximum at 1 h in the liver and 5 h in the tumor. Ionic liquid (IL) is also loaded into MIL-101(Fe)@BSA-AuNCs NPs as microwave sensitive reagents for microwave thermal therapy (MTT). This work synthesizes the nanozymes that possess degradability, microwave sensitivity and dual-mode imaging to achieve the combination of MTT and MEDT against tumor. Experiment result in vivo confirms that the kill rate of tumor is up to 96.65%, showing an outstanding anti-tumor efficacy.

Mitogen-inducible gene-6 (Mig-6), an immediate early response gene, is a specific negative regulator of epidermal growth factor receptor (EGFR). Ablation of Mig-6 has been shown to induce tumor formation in various tissues, supporting the tumor suppressor function of Mig-6. However, little is known about the role of Mig-6 in non-small cell lung cancer (NSCLC) apoptosis, nor has the contribution of upregulated Mig-6 on biological behaviors of A549 and H157 cells previously been reported. The aim of the present study was to investigate the effects of exogenously transfected Mig-6 on proliferation, invasion and apoptosis of A549 and H157 cells and to identify novel underlying mechanisms of Mig-6-induced apoptosis. We used immunohistochemical staining to examine the expression of Mig-6 protein in NSCLC tissues. For evaluation of the prognostic value of Mig-6 expression to each clinicopathologic factor, Kaplan-Meier method and Cox's proportional hazards model were employed. Mig-6 low expression was correlated with a poor prognosis in patients with lung cancer. Patients with high expression of Mig-6 had a statistically significantly longer survival than those with low expression of Mig-6. Cox's regression analysis indicated that loss of Mig-6 expression was an independent, unfavorable prognostic factors. We utilized siRNA-targeting Mig-6 and Mig-6 overexpression plasmid to determine the effect of Mig-6 on lung cancer cells. Flow cytometry studies revealed Mig-6 overexpression promoted apoptosis in NSCLC cell lines. siRNA-mediated Mig-6 knockdown inhibited apoptosis of cancer cells, but this anti-apoptotic effect was abolished by inhibition of ERK. Upregulation of Mig-6 decreased the proliferation and invasive potential of transfected cells. Moreover, upregulation of Mig-6 inhibited proliferation and invasion of A549 and H157 cells. Collectively, our results showed that Mig-6 is a potential biomarker for evaluation of tumor prognosis of lung cancer. Mig-6 promotes apoptosis in lung cancer cells via the ERK pathway.

OBJECTIVES To establish an animal model of proximal descending thoracic aortic aneurysm for the study of branched stent grafts. MATERIALS AND METHODS Eleven mongrel dogs underwent the surgical procedure during which an autologous pericardial patch was sewn onto a longitudinal incision in the anterolateral wall of the thoracic aorta near the left subclavian artery to create an artificial thoracic aortic aneurysm. RESULTS All eleven animals survived the surgical procedure. One animal died from rupture at the surgical site during the first week after surgery. The distance between the artificial aneurysm and the left subclavian artery was 8.29 ± 0.91 mm. The average diameter of the artificial aneurysms did not significantly change over the 4-month follow-up period. CONCLUSION A canine model for proximal descending thoracic aortic aneurysm can be achieved using a safe and convenient method. The model can be used in the study of new branched stent graft applied to the aortic arch.

Animal models are required to explore the mechanisms of and therapy for proximal descending thoracic aortic aneurysm (TAA). This study aimed to establish a reproducible swine model of proximal descending TAA that can further explain the occurrence and progression of proximal descending TAA.Eighteen Chinese Wuzhishan miniature pigs (30.32 ± 1.34 kg) were randomized into the elastase group (n = 12) and the control group (n = 6). The elastase group received intra-adventitial injections of elastase (5 mL, 20 mg/mL), and the control group received injections of physiologic saline solution. A 4-cm descending thoracic aortic segment proximal to the left subclavian artery was isolated. The distance between the left subclavian artery and the injection starting point of the descending thoracic aorta was 0.5 cm. Elastic protease was circumferentially injected intra-adventitially into the isolated segment of the aortic wall in the elastase group by a handmade bent syringe. The length of the elastic protease injection was 2 cm. An average of 12 injection points were distributed in this 2-cm aortic segment. Each injection point used about 0.4 mL of elastic protease. The distance between two injection points was about 1.5 cm. All animals underwent digital subtraction angiography preoperatively and 3 weeks after operation. Three weeks after TAA induction, aortas were harvested for biochemical and histologic measurements.All animals in the elastase group developed TAAs. No aneurysms were observed in the control group. The distance between the left subclavian artery and the TAA was 8.00 ± 4.19 mm. Preoperative and postoperative aortic diameters of the elastase group were 15.42 ± 0.43 mm and 24.53 ± 1.41 mm, respectively (P .0001). Preoperative and postoperative aortic diameters of the control group were 15.31 ± 0.33 mm and 15.57 ± 0.40 mm, respectively (P = .5211). The changes of aortic structure and composition included reduction of smooth muscle cells and degradation of elastic fibers. Levels of matrix metalloproteinases 2 and 9 were increased in TAA tissue.This study established a reproducible large animal model of proximal descending TAA. This model has the same biochemical characteristics as human aneurysms in the aspects of aortic expansion, aortic middle-level degeneration, and changes in the levels of matrix metalloproteinases and provides a platform for further study.

The ablation of Mig-6 has been shown to induce tumor formation in various tissues. However, the relationships between Mig-6 expression, clinical pathological factors, and prognosis have not been clarified in hepatocellular carcinoma (HCC), and the mechanism by which Mig-6 regulates the proliferation of HCC cells has not been reported. In this study, we investigated the clinical significance of the loss of Mig-6 expression in HCC and the mechanism underlying the inhibition of cell proliferation by Mig-6. The down-regulation of Mig-6 correlated significantly with large tumors, a more advanced BCLC stage, and a more advanced TNM stage, and low Mig-6 expression predicted significantly reduced survival. Low Mig-6 expression and high Cyclin D1 expression were independent predictors for survival. The overexpression of Mig-6 led to significant G1 arrest and growth inhibition in HCC cells, possibly through the inhibition P-ERK and Cyclin D1. These results indicate that Mig-6 expression is low in HCC, which predicts a poor prognosis. Mig-6 may regulate cell proliferation and the cell cycle through the P-ERK/Cyclin D1 pathway.

Although mesoporous silica nanoparticles (MSNs) are widely used in food products, cosmetics and nanomedicines as vector for drug delivery, data on their potential genotoxocity are limited. The aim of this study was to investigate the cytotoxic and genotoxic potentials of MSNs of different shapes, and to establish a high-throughput screening method for nanoparticles. We used functional macrophage receptor with collagenous structure (MARCO)-expressing DNA repair deficient chicken DT40 cells, which are designed to internalize nanoparticles and to be deficient in several specific DNA repair pathways. In addition, we verified the validity of this assay by analyzing and characterizing the genotoxicity of sphere- or rod-shaped MSNs. We demonstrated that both sphere- and rod-shaped MSNs were cytotoxic, and that this effect was greater in FEN1(-/-) and REV3(-/-) cells compared with wild-type cells. Effects of rod-shaped MSNs were more severe compared with sphere-shaped MSNs. Furthermore, MSNs induced oxidative damage and a larger number of mitotic chromosomal aberrations in repair-deficient cells compared with repair-proficient cells. Taken together, this assay system using the chimeric receptor-expressing DNA repair-deficient DT40 cells provides a sensitive method to screen for genotoxicity of MSNs.

� The unibody branched stent-graft described in this paper could be used to reconstruct the aortic arch while preserving the three branch vessels. Compared to other branched stent-grafts, this version appears more versatile, while the implantation procedure appears to be simpler. abstract Objectives: To evaluate the feasibility and safety of a new unibody branched stent-graft for reconstruction of the canine aortic arch. Materials and methods: Twenty adult hybrid dogs were used for the experiments. Ten dogs were implanted with single-branched stent-grafts; the other ten dogs were implanted with double-branched stent-grafts. The stent-grafts were implanted transluminally via the abdominal aorta. The branched limbs were caught and pulled into supra-aortic vessels using gooseneck snare wires introduced via the axillary arteries. The animals were euthanized 4 months after implantation. Results: One of the ten dogs implanted with a single-branched stent-graft died from failure of the implantation procedure, and two of the ten dogs implanted with double-branched stent-grafts died from failure of the procedure and excessive blood loss. After month 4, the remaining unibody branched stent- grafts were patent and did not migrate. Conclusions: This new unibody branched stent-graft could be used to reconstruct the aortic arch. This is a total endovascular technique, and compared to other branched stent-grafts appears to be safer and easier to implant.

Purpose: To determine the efficacy of sirolimus-eluting bioabsorbable magnesium alloy stents (SEBMAS) in restenosis prevention. Methods: A balloon-expandable bioabsorbable magnesium alloy stent (BMAS) was created and coated with biodegradable poly(lactic acid-co-trimethylene carbonate) that contained the antiproliferative drug sirolimus (140 +/- 40 mu g/cm(2)). Both the uncoated BMAS and the coated SEBMAS were deployed 2 cm apart in balloon-injured infrarenal abdominal aortas of 20 New Zealand white rabbits. The stented aortic segments were removed at 30, 60, 90, and 120 days (5 rabbits per interval) after implantation. The average stent strut sectional area of each group was measured to evaluate the degree of magnesium corrosion and to forecast the biodegradation time profile of the magnesium stent. Histology and histopathology of the sectioned stented aortic segments were performed to evaluate neointima formation, endothelialization, and inflammation. Results: The SEBMAS degraded gradually after being implanted into the rabbit aorta, and total biocorrosion occurred after similar to 120 days. In all groups, the lumen area was significantly greater, but the neointimal area was significantly smaller in SEBMAS segments compared with the uncoated BMAS segments (p

A 28-year-old man underwent successful transcatheter occlusion of three huge pulmonary arteriovenous malformations (PAVMs) using homemade double-umbrella occluders and stainless steel coils. Thoracic CT with three-dimensional reconstruction and pulmonary angiography were used for treatment planning and follow-up. The diameters of the feeding vessels were 11 mm, 13 mm, and 14 mm, respectively. This report demonstrates the novel design and utility of the double-umbrella occluder, an alternative tool for treatment of large PAVMs.

Background Peripheral artery disease (PAD), which is caused by atherosclerosis, results in progressive narrowing and occlusion of the peripheral arteries and inhibits blood flow to the lower extremities. Therapeutic angiogenesis is a promising strategy for treating ischemia caused by PAD. Nitric oxide (NO) has been shown to be a key mediator of angiogenesis. It has been demonstrated that β-cyclodextrincan stimulate vessel growth in rabbit corneas. In this study, we assessed the mechanism of action and therapeutic potential of a new angiogenic molecule, (2-hydroxypropyl)-β-cyclodextrin (2HP-β-CD). Methods and Results 2HP-β-CD significantly increased vascular endothelial growth factor A (VEGF-A) and platelet-derived growth factor BB (PDGF-BB) peptides in human umbilical vein endothelial cells (HUVECs) and also increased basic fibroblast growth factor (bFGF) peptide in human aortic smooth muscle cells (HASMCs). 2HP-β-CD stimulated both proliferation and migration of HUVECs in an endothelial nitric oxide synthase (eNOS)/NO-dependent manner, whereas NO was found to be involved in proliferation, but not migration, of HASMCs. In a unilateral hindlimb ischemia model in mice, 2HP-β-CD injections not only promoted blood flow recovery and increased microvessel densities in ischemic muscle, but also promoted coverage of the vessels with smooth muscle cells, thus stabilizing the vessels. Administration of 2HP-β-CD increased the expression of several angiogenic factors, including VEGF-A, PDGF-BB and transforming growth factor beta-1 (TGF-β1) in ischemic muscle. Injections of 2HP-β-CD also stimulated protein kinase B and extracellular regulated protein kinases (ERK), leading to an increase in phosphorylation of eNOS in ischemic muscle. Treatment with the NOS inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME), showed that stimulation of blood flow induced by 2HP-β-CD was partially dependent on NO. Conclusions Therapeutic angiogenesis by 2HP-β-CD may be beneficial to patients with PAD.