Endovascular treatment of symptomatic severe intracranial atherosclerotic stenosis with a novel intracranial dedicated drug-eluting stent: a more effective treatment approach.

Background: Endovascular treatment of severe intracranial atherosclerotic stenosis (ICAS) using coronary drug-eluting stents (DESs) significantly reduces the risk of in-stent restenosis (ISR) and stroke recurrence. However, there are few reports regarding the treatment of ICAS with intracranial dedicated DES. Herein, we present our experience with the feasibility, safety, and medium-term follow-up outcomes of a novel intracranial DES, named NOVA stent, in patients with symptomatic severe ICAS (≥70%). Methods: From December 2021 to May 2022, patients with symptomatic severe ICAS who underwent implantation of the NOVA stent in our institution were retrospectively analyzed for procedural results, perioperative complications, imaging and clinical follow-up outcomes. Results: Twenty-four patients, 16 (66.7%) with anterior circulation lesions and 8 (33.3%) with posterior circulation lesions, were enrolled. All patients with intracranial ICA (n = 6), middle cerebral artery (n = 10), basilar artery (n = 3), intracranial vertebral artery (n = 3), and the vertebrobasilar junction (n = 2) stenosis were treated successfully using NOVA stents. The severity of stenosis ranged from 75 to 96% (mean 85.9%) before treatment and this was reduced to 0 to 20% (mean 8.6%) immediately after stent placement. Symptomatic distal embolism occurred in one case; however, there were no other perioperative complications. The mean follow-up duration was 12.2 ± 1.06 months. No symptomatic ischemic events occurred during follow-up. Follow-up cerebral angiography was performed in 22 of 24 patients (91.7%), and significant ISR occurred in one patient (4.2%). Conclusion: Our results demonstrate that implantation of the novel intracranial DES NOVA in severe ICAS is feasible, safe, and effective in selected cases, reducing the incidence of ISR, and showing excellent midterm clinical outcomes, providing a promising option for ICAS treatment.

Predictors of successful endovascular recanalization in patients with symptomatic nonacute intracranial large artery occlusion.

BACKGROUND: Endovascular recanalization in patients with symptomatic nonacute intracranial large artery occlusion (ILAO) has been reported to be feasible, but technically challenging. This study aimed to determine the predictors of successful endovascular recanalization in patients with symptomatic nonacute ILAO. METHODS: The outcomes of endovascular recanalization attempts performed in 70 consecutive patients showing symptomatic nonacute ILAO with hemodynamic cerebral ischemia between January 2016 to December 2022 were reviewed. Potential variables, including clinical and radiological characteristics related to technical success, were collected. Univariate analysis and multivariate logistic regression were performed to identify predictors of successful recanalization for nonacute ILAO. RESULTS: Technically successful recanalization was achieved in 57 patients (81.4%). The periprocedural complication rate was 21.4% (15 of 70), and the overall 30-day morbidity and mortality rates were 7.1% (5 of 70) and 2.9% (2 of 70), respectively. Univariate analysis showed that successful recanalization was associated with occlusion duration, stump morphology, occlusion length, slow distal antegrade flow sign, and the presence of bridging collateral vessels. Multivariate analysis showed that occlusion duration ≤ 3 months (odds ratio [OR]: 22.529; 95% confidence interval [CI]: 1.636-310.141), tapered stump (OR: 7.498; 95% CI: 1.533-36.671), and occlusion length < 10 mm (OR: 7.049; 95% CI: 1.402-35.441) were independent predictive factors for technical success of recanalization. CONCLUSIONS: Occlusion duration ≤ 3 months, tapered stump, and occlusion length < 10 mm were independent positive predictors of technical success of endovascular recanalization for symptomatic nonacute ILAO. These findings may help predict the likelihood of successful recanalization in patients with symptomatic nonacute ILAO and also provide a reference for the selection of appropriate patients. Further prospective and multicenter studies are required to validate our findings.

Circ-ATL1 silencing reverses the activation effects of SIRT5 on smooth muscle cellular proliferation, migration and contractility in intracranial aneurysm by adsorbing miR-455.

BACKGROUND: Alterations in vascular smooth muscle cells (VSMCs) contribute to the pathogenesis of intracranial aneurysms (IAs). However, molecular mechanisms underlying these changes remain unknown. The present study aimed to characterize the molecular mechanisms underlying VSMC-mediated IAs. METHODS: Expression of the circular RNA circ-ATL1 and microRNA miR-455 was detected in IAs by RT-qPCR. Interactions between circ-ATL1, miR-455 and SIRT5 were examined by luciferase reporter analysis and RT-qPCR. The regulatory roles of circ-ATL1, miR-455 and SIRT5 in VSMC migration, proliferation and phenotypic modulation were also examined by CCK8, Transwell® migration and western blot assays. RESULTS: Biochemical and bioinformatic techniques were used to demonstrate that circ-ATL1 and miR-455 participated in disparate biological processes relevant to aneurysm formation. Clinically, increased expression of circ-ATL1 and downregulated miR-455 expression were observed in IA patients compared with healthy subjects. Silencing of circ-ATL1 led to suppression of VSMC migration, proliferation and phenotypic modulation. Both SIRT5 and miR-455 were found to be downstream targets of circ-ATL1. SIRT5 upregulation or miR-455 inhibition reversed the inhibitory effects induced by circ-ATL1 silencing on VSMC proliferation, migration and phenotypic modulation. We found that VSMC phenotypic modulation by circ-ATL1 upregulation and miR-455 downregulation had a critical role in the development and formation of AIs. Specifically, circ-ATL1 downregulation reversed IA formation. CONCLUSION: Our data provide the theoretical basis for future studies on potential clinical treatment and prevention of IAs.

Drug-eluting bead transarterial chemoembolization (TACE) exhibits superior efficacy and equal tolerance to conventional TACE in hepatocellular carcinoma patients with conventional TACE history.

OBJECTIVE: Multiple conventional transarterial chemoembolization (cTACE) procedures would cause treatment resistance in hepatocellular carcinoma (HCC) patients, whether drug-eluting bead transarterial chemoembolization (DEB-TACE) would resolve this issue is a necessary topic. Thus, this study aimed to compare the efficacy and safety between DEB-TACE and cTACE in HCC patients with cTACE treatment history. METHODS: Totally, 134 HCC patients with cTACE treatment history were retrospectively reviewed. They were categorized into DEB-TACE group (N = 70) and cTACE group (N = 64) based on the current treatment they received. RESULTS: After 1-month treatment, DEB-TACE group exhibited an elevated objective response rate (ORR) (71.9% vs. 47.3%, P = 0.008) while similar disease control rate (DCR) (93.0% vs. 81.8%, P = 0.074) compared to cTACE group. Besides, after 3-month treatment, DEB-TACE group also displayed higher ORR (68.4% vs. 44.1%, P = 0.038) and DCR (81.6% vs. 58.8%, P = 0.034) compared to cTACE group. Furthermore, the median progression-free survival (PFS) (11.5 months vs. 6.5 months P = 0.014) and overall survival (OS) (18.5 months vs. 13.0 months, P = 0.025) were longer in DEB-TACE group compared to cTACE group. Moreover, DEB-TACE (vs. cTACE) independently correlated with prolonged PFS (P = 0.021) and OS (P = 0.017) after adjustment by multivariate Cox's regression. Besides, most of liver function indexes were similar before and after treatment between these two groups. Also, the commonly observed adverse events were pain, fever, nausea/vomiting and blood pressure elevation with similar incidence between these two groups (all P > 0.050). CONCLUSION: DEB-TACE exhibits superiority over cTACE in HCC patients with cTACE treatment history.

Bakkenolide­IIIa ameliorates lipopolysaccharide­induced inflammatory injury in human umbilical vein endothelial cells by upregulating LINC00294.

Inflammation, which causes injury to vascular endothelial cells, is one of the major factors associated with atherosclerosis (AS); therefore, inhibition of endothelial inflammation is a key step toward preventing AS. The present study aimed to investigate the effects of bakkenolide­IIIa (Bak­IIIa), an important active component of bakkenolides, on endothelial inflammation, as well as the mechanisms underlying such effects. Lipopolysaccharide (LPS)­damaged human umbilical vein endothelial cells (HUVECs) were treated with Bak­IIIa. The results of the MTT assay and enzyme­linked immunosorbent assay indicated that Bak­IIIa significantly alleviated survival inhibition, and decreased the levels of LPS­induced TNF­α, interleukin (IL)­1ß, IL­8, and IL­6. Furthermore, long noncoding RNA (lncRNA) microarray analyses revealed 70 differentially expressed lncRNAs (DELs) in LPS­damaged HUVECs treated with Bak­IIIa. lncRNA target prediction results revealed that 44 DELs had 52 cis­targets, whereas 12 DELs covered 386 trans­targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses of the trans­targets indicated that three GO terms were associated with inflammation. Therefore, 17 targets involved in these GO terms and six relevant DELs were screened out. Validation via reverse transcription­quantitative PCR indicated that the fold change of NR_015451 (LINC00294) was the highest among the six candidates and that overexpression of LINC00294 significantly alleviated LPS­induced survival inhibition and inflammatory damage in HUVECs. In conclusion, Bak­IIIa ameliorated LPS­induced inflammatory damage in HUVECs by upregulating LINC00294. Thus, Bak­IIIa exhibited potential for preventing vascular inflammation.

Long non-coding RNA BCAR4 aggravated proliferation and migration in esophageal squamous cell carcinoma by negatively regulating p53/p21 signaling pathway.

Long non-coding RNA breast cancer antiestrogen resistance 4 (lncRNA BCAR4) is an independent factor on the survival prognosis of patients with multiple cancers. However, the role of lncRNA BCAR4 in esophageal squamous cell cancer (ESCC) remains unknown. Here, we unraveled that lncRNA BCAR4 was upregulated in ESCC and predicted poor prognosis. Functionally, lncRNA BCAR4 knockdown induced cell apoptosis and G1/S arrest, while inhibited cell proliferation and migration in vitro; conversely, overexpressing lncRNA BCAR4 promoted proliferation and metastasis. Mechanistically, lncRNA BCAR4 sponged miR-139-3p to upregulate ELAVL1, thereby inhibiting p53/p21 pathway in ESCC cells. In conclusion, lncRNA BCAR4 promotes ESCC tumorigenesis via regulating p53/p21 signaling pathway and develops a brand-new biomarker and medicine target for ESCC.

Endoleak management and postoperative surveillance following endovascular repair of internal carotid artery vascular diseases using Willis covered stent.

To report the clinical results and experiences of endoleak management and postoperative surveillance following endovascular repair of internal carotid artery vascular diseases (ICAVDs) using Willis covered stents. METHODS: Seventy-three patients with ICAVD who received Willis covered stent implantation between November 2013 and September 2018 were retrospectively reviewed. The clinical data of endoleak management and postoperative surveillance were analyzed. RESULTS: Seventy-three cases with ICAVD, including 57 aneurysms, 11 carotid-cavernous sinus fistulas (CCF), and 5 surgical injuries, were all successfully installed with covered stents. Total isolation of ICAVDs was achieved in 59 patients (80.8%), and endoleaks were observed in 14 patients (19.2%). Of the 14 patients with endoleaks, 12 had type I endoleaks and 2 had type II; 13 had aneurysms and one had CCF. 10 patients with type I endoleaks received balloon dilatation, and 7 of them underwent a second stent-graft implantation after then. One patient with type II endoleak received embolization of the branch artery, and another one received follow-up observation. Endoleaks resolved in 6 patients and were minimal in 5 patients after balloon dilatation or the second stent implantation. During the follow-up period, minor endoleaks spontaneously resolved in 4 patients and minimal endoleaks were still demonstrated in 4 patients without enlargement of residual lumen and rupture. CONCLUSIONS: Endoleaks are the major complication after endovascular repair of ICAVDs and represent one of the limitations of this procedure. Improving the understanding and management of endoleaks can be beneficial in the clinical setting, including the popularization and application of this technique.

Integrative bioinformatics analysis identifies LINC01614 as a potential prognostic signature in esophageal cancer.

BACKGROUND: Esophageal cancer (EC) is one of the most common gastrointestinal cancers and the incidence is on the increase in recent years. The aim of the present study was to assess novel long non-coding RNA (lncRNA) biomarkers for the prognosis of EC through the analysis of gene expression microarrays. METHODS: Three datasets (GSE53622, GSE53624, and GSE53625) were downloaded from the Gene Expression Omnibus (GEO) database and EC patients' clinical information were from The Cancer Genome Atlas (TCGA) databases. Differentially expressed genes (DEGs) were screened by comparing tumor tissues with normal tissues using limma R package. The Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database was used to obtain the novel lncRNAs and their co-expression genes in EC and these were visualized with the Cytoscape software. The Kyoto Encyclopedia of Genes and Genomes (KEGG) Orthology Based Annotation System (KOBAS) database was used to analyze the functions enrichment of selected DEGs. Cell Counting Kit-8 (CCK8) and Transwell assays were used to further confirm the function of target lncRNAs. RESULTS: We identified 24 differentially expressed (DE) lncRNAs and 659 DE mRNAs from the intersection of GEO and TCGA databases. And we found that only LINC01614 was concerned with a candidate prognostic signature in EC. "Extracellular matrix (ECM)-receptor interaction" and "PI3K-Akt signaling pathway" were observed, and we constructed a lncRNA-mRNA co-expression network for EC that includes LINC01614 and 64 mRNAs. The results of CCK8 and Transwell assays showed that suppression of LINC01614 inhibited EC cell proliferation and migration. CONCLUSIONS: Our study might provide LINC01614 as a novel lncRNA biomarker for diagnosis and prognosis in EC.

Endovascular Treatment of Complex Vascular Diseases of the Internal Carotid Artery Using the Willis Covered Stent: Preliminary Experience and Technical Considerations.

Purpose: The Willis covered stent (WCS) is used to treat complex vascular diseases of the internal carotid artery; however, its performance requires further investigation. This study aimed to present our single-center clinical results and experience of endovascular repair of complex vascular diseases of the internal carotid artery using the WCS. Methods: Patients who presented with complex vascular diseases of the internal carotid artery and who were treated with the WCS from December 2013 to September 2018 were retrospectively reviewed. Procedural results, perioperative complications, incidence of endoleak, and follow-up outcomes were analyzed. Results: Sixty-five patients were enrolled. A total of 25 large aneurysms, 10 pseudoaneurysms, 14 blood blister-like aneurysms, 11 carotid-cavernous fistulas, and 5 surgical injuries were assessed. WCS placement was successful in all patients. Immediate angiography showed that complete repair of the target artery was achieved in 56 patients (86.2%). Endoleak was observed in nine patients, including seven type I endoleaks and two type II endoleaks. Occlusion of a side-branch vessel occurred in four patients. Acute in-stent thrombosis occurred in one patient. No ischemic or hemorrhagic events or other complications developed during the perioperative and follow-up periods. Angiographic follow-up (mean duration, 12 ± 3.29 months) was performed in 60 patients and showed complete target artery repair in 58 patients, and asymptomatic mild to moderate in-stent stenosis was observed in four patients. Slight endoleak persisted in two patients without enlargement or rupture of the residual lumen. Conclusion: WCS implantation is safe, feasible, and efficacious for endovascular repair in patients with complex vascular diseases of the internal carotid artery, showing excellent short-term target artery patency and clinical outcomes.

Endovascular recanalization for symptomatic subacute and chronic intracranial large artery occlusion of the anterior circulation: initial experience and technical considerations.

PURPOSE: This study aimed to report the clinical findings and initial clinical experience of endovascular recanalization for symptomatic subacute/chronic intracranial large artery occlusion (ILAO) of the anterior circulation. METHODS: From October 2015 to December 2017, 13 patients with symptomatic subacute/chronic ILAO of the anterior circulation were enrolled in this study and underwent endovascular recanalization. We collected the initial procedural results, including the rate of successful recanalization and periprocedural complications, and data pertaining to angiographic and clinical follow-up. RESULTS: Recanalization was successful in 11 of 13 patients (84.6%). Intraoperative complications occurred in four cases, including symptomatic distal embolism in three cases; one of which was simultaneously complicated with artery dissection. Intracerebral hemorrhage occurred in one case. Eleven patients underwent angiographic follow-up, and 12 patients underwent clinical follow-up. The results of the angiography follow-up (mean 6 ± 3.29 months) showed that in-stent restenosis occurred in one of the 11 successfully recanalized patients. However, the artery was occluded again in the patient who achieved thrombolysis in cerebral infarction (TICI) grade of 2a after treatment. Clinical follow-up (mean 5.8 ± 2.25 months) showed no recurrence of transient ischemic attack (TIA) or stroke in ten successfully recanalized cases. However, the patient who developed in-stent stenosis suffered TIA. CONCLUSIONS: Endovascular recanalization for symptomatic subacute/chronic ILAO of anterior circulation is feasible, relatively safe, and efficacious in highly selected cases, improving patients' symptoms in the short-term. However, further larger scale pilot studies are needed to determine the efficacy and long-term outcome associated with this treatment.

LncRNA CACS15 contributes to oxaliplatin resistance in colorectal cancer by positively regulating ABCC1 through sponging miR-145.

Increasing evidence suggests that long non-coding RNAs (lncRNAs) are implicated with chemoresistance of cancers. However, their functional role and molecular mechanisms in colorectal cancer (CRC) chemoresistance are still largely unclear. In this work, we aimed to investigate the functional role of lncRNA cancer susceptibility candidate 15 (CASC15) in oxaliplatin (OXA) resistance of CRC and reveal the underlying molecular mechanism. Our results discovered that CASC15 was up-regulated in OXA-resistant CRC tissues and cells. Patients with high CASC15 expression level had a poor prognosis. CASC15 knockdown re-sensitized HT29/OXA and HCT116/OXA cells to OXA. Moreover, CASC15 could act as a competing endogenous RNA (ceRNA) to de-repress ABCC1 expression through sponging miR-145. miR-145 overexpression or ABCC1 knockdown could mimic the functional role of down-regulated CACS15 in OXA resistance, which was counteracted by CASC15 overexpression. Furthermore, CASC15 knockdown facilitated OXA sensitivity of OXA-resistant CRC cells in vivo. In summary, CASC15 silencing overcame OXA resistance of CRC by regulating miR-145/ABCC1 axis, providing a potential therapeutic target for CRC chemoresistance.

The miR-143/145 cluster reverses the regulation effect of KLF5 in smooth muscle cells with proliferation and contractility in intracranial aneurysm.

Alterations in vascular smooth muscle cells (VSMCs) contribute to the pathogenesis of intracranial aneurysms (IAs), but the molecular mechanisms of these alterations are unclear. The aim of this study was therefore to identify the molecular mechanism of VSMC-mediated IAs at clinical and cellular levels. We used bioinformatic and biochemical analyses to show that the microRNA (miR)-143/145 cluster was involved in various biological processes related to aneurysm formation. Clinical studies showed that the miR-143/145 cluster was downregulated in IA patients when compared with healthy subjects. However, KLF5 expression was upregulated in IA patients. In vitro experiments showed that overexpression of the miR-143/145 cluster inhibited proliferation and migration of VSMCs, but increased contractile protein expression and decreased matrix metalloproteinase-2 and -3. KLF5 overexpression had the opposite effect, even reversing the protective effect of the miR-143/145 cluster on IAs. Bifluorescein report experiments further confirmed that both miR-143 and miR-145 interacted with the 3'-UTR of KLF5 and inhibited post-transcriptional expression of KLF5. Taken together, the results showed that VSMC phenotypic modulation with upregulation of KLF5 by downregulation of the miR-143/145 cluster played an important role in formation and growth of IAs. The process of IA formation was reversed by overexpression of the miR-143/145 cluster. Together, the results provided a theoretical basis for further investigation of the potential clinical prevention and treatment of IAs.

A single-center experience in the endovascular treatment of carotid siphon aneurysms using the Willis covered stent: a retrospective analysis.

OBJECTIVE: To report the clinical results and initial clinical experience of endovascular isolation with the Willis covered stent for carotid siphon aneurysms. METHODS: Between November 2013 and December 2016, a total of 57 patients who presented with carotid siphon aneurysms were treated with the Willis covered stent. Results of the procedures, technical events, and complications were recorded. Clinical and imaging follow-ups were performed at 3 months following the endovascular procedures. RESULTS: Placement of the Willis covered stent was successful in all patients. Immediate angiography revealed complete exclusion of aneurysms in 48 patients (84%), while endoleak occurred in nine patients (16%). Procedure-related complications occurred in three cases, including displacement of the covered stent in one patient, acute in-stent thrombosis in one patient, and microwire-related intracranial hemorrhage in one patient. Angiographic follow-ups were done in 49 patients, with complete exclusion of aneurysms in 47 patients. Endoleak was present in two patients. No aneurysm recurrence occurred. Forty-four patients showed good parent artery patency, while the other five patients showed mild to moderate asymptomatic in-stent stenosis. During the follow-up period, no ischemic or hemorrhagic event occurred. The modified Rankin Scale scores at follow-up were 0-2 in 56 patients and >2 in one patient. CONCLUSIONS: The treatment of siphon aneurysms with Willis covered stent implantation resulted in satisfactory clinical outcomes. The Willis covered stent seems safe and feasible for the treatment of siphon aneurysms, which still needs to be confirmed by longer follow-up periods and controlled studies with larger samples.

Endovascular isolation of intracranial blood blister-like aneurysms with Willis covered stent.

OBJECTIVE: Intracranial blood blister-like aneurysm (BBA) is a rare type of aneurysm that lacks all layers of the arterial wall. These fragile aneurysms have the propensity to rupture with minimal manipulation, which makes them hazardous and difficult to treat. The present study evaluated the safety and feasibility of endovascular treatment of BBAs with the Willis covered stent. MATERIALS: Thirteen patients (7 men and 6 women, age range 28-68 years) who presented with ruptured BBAs and were treated with the Willis covered stent were retrospectively reviewed. Results of the procedures and treatment-related complications were recorded. Angiographic and clinical follow-ups were performed 4-6 months after the procedure. RESULTS: Placement of the covered stent was successful in all patients. Immediate angiography showed complete aneurysm occlusion in 12 patients while one patient showed a mild endoleak. This high rate of aneurysm exclusion ensured the security of postoperative antiplatelet treatment. Occlusion of the ophthalmic artery occurred in two patients and occlusion of the anterior choroidal artery occurred in one patient; however, none of them showed acute or delayed clinical symptoms. Thrombosis, aneurysm rupture, and other complications did not develop in any case. Angiographic follow-up showed complete aneurysm exclusion without aneurysm recurrence in any patients. Only two patients showed asymptomatic mild to moderate in-stent stenosis. All patients had satisfactory clinical outcomes (modified Rankin Scale score ≤1). CONCLUSIONS: Willis covered stent implementation may be safe and feasible for BBAs. This strategy might be a promising option for this high-risk type of aneurysm.

Transcatheter Arterial Infusion of Autologous CD133(+) Cells for Diabetic Peripheral Artery Disease.

Microvascular lesion in diabetic peripheral arterial disease (PAD) still cannot be resolved by current surgical and interventional technique. Endothelial cells have the therapeutic potential to cure microvascular lesion. To evaluate the efficacy and immune-regulatory impact of intra-arterial infusion of autologous CD133(+) cells, we recruited 53 patients with diabetic PAD (27 of CD133(+) group and 26 of control group). CD133(+) cells enriched from patients' PB-MNCs were reinfused intra-arterially. The ulcer healing followed up till 18 months was 100% (3/3) in CD133(+) group and 60% (3/5) in control group. The amputation rate was 0 (0/27) in CD133(+) group and 11.54% (3/26) in control group. Compared with the control group, TcPO2 and ABI showed obvious improvement at 18 months and significant increasing VEGF and decreasing IL-6 level in the CD133(+) group within 4 weeks. A reducing trend of proangiogenesis and anti-inflammatory regulation function at 4 weeks after the cells infusion was also found. These results indicated that autologous CD133(+) cell treatment can effectively improve the perfusion of morbid limb and exert proangiogenesis and anti-inflammatory immune-regulatory impacts by paracrine on tissue microenvironment. The CD133(+) progenitor cell therapy may be repeated at a fixed interval according to cell life span and immune-regulatory function.

Tripterine treatment improves endothelial progenitor cell function via integrin-linked kinase.

BACKGROUND/AIMS: Atherosclerosis is associated with dysfunction of endothelial progenitor cells (EPCs). Tripterine, a chemical compound derived from the Chinese medicinal plant Tripterygium wilfordii Hook, displays anti-inflammatory properties in several animal models. We hypothesized that tripterine can improve EPC function and thus the efficiency of EPC transplantation. METHODS AND RESULTS: Tripterine preconditioning (2.5 µM, 4 h) improved EPC proliferation, tube formation, migration, and adhesion, and reduced apoptosis in cells cultured in ox-LDL (200 µg/ml). Tripterine restored integrin-linked kinase (ILK) levels downregulated by ox-LDL in EPCs, suggesting the involvement of the ILK/Akt pathway. Small interfering RNA-mediated depletion of ILK and dominant-negative ILK transduction inhibited the phosphorylation of the ILK downstream signaling targets protein kinase B/Akt and glycogen synthase kinase 3-beta (GSK-3ß), and reduced ß-catenin and cyclin D1 expression. In atherosclerotic mice injected with green fluorescent protein-labeled EPCs to evaluate EPC function, tripterine decreased aortic lesions and plaque deposition, and injection of tripterine-treated EPCs restored ILK levels. CONCLUSION: The present results suggest that tripterine improves vascular function in atherosclerosis by enhancing EPC function through a mechanism involving the ILK signaling pathway.

ROBO3 promotes growth and metastasis of pancreatic carcinoma.

Pancreatic carcinoma is a highly lethal malignancy with an extremely poor prognosis. Recent genome-wide studies have implicated axon guidance pathways, including the SLIT/ROBO pathway, in pancreatic tumor development and progression. Here we showed that ROBO3 expression is up-regulated in pancreatic cancer tissue samples and cell lines. Over-expression of ROBO3 promotes pancreatic cancer cell growth, invasion and metastasis in vitro and in mouse xenograft tumor models. We identified miR-383 as a suppressor of ROBO3, and revealed its expression to be inversely correlated with ROBO3. Over-expression of ROBO3 activates Wnt pathway components, ß-catenin and GSK-3, and the expression of markers indicating an EMT. By means of immunoprecipitation, we revealed an interaction between Wnt inhibitor SFRP and ROBO3 in pancreatic cancer cell lines. Our work suggests that ROBO3 may contribute to the progression of pancreatic cancer by sequestering Wnt inhibitor SFRP, which in turn leads to increased Wnt/ß-catenin pathway activity. We also confirmed that ROBO3 increases with clinical grade and miR-383 expression is inversely correlated to that of ROBO3.

Genotype-Guided Dosing of Coumarin Anticoagulants: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Coumarin anticoagulants (acenocoumarol, phenprocoumon, and warfarin) are generally used for the prevention of stroke in patients with atrial fibrillation or for the therapy and prevention of venous thromboembolism. However, the safe use of coumarin anticoagulants is restricted by a narrow therapeutic window and large interindividual dosing variations. Some studies found that the effectiveness and safety of coumarin anticoagulants therapy were increased by pharmacogenetic-guided dosing algorithms, while others found no significant effect of genotype-guided therapy. METHODS: Four electronic databases were searched from January 1, 2000, to March 1, 2014, for randomized controlled trials of patients who received coumarin anticoagulants according to genotype-guided dosing algorithms. The primary outcome was the percentage of time that the international normalized ratio (INR) was within the normal range (2.0-3.0). Secondary outcomes included major bleeding events, thromboembolic events, and INR ≥4 events. RESULTS: Eight studies satisfied the inclusion and exclusion criteria. Genotype-guided dosing of coumarin anticoagulants improved the percentage of time within the therapeutic INR range (95% confidence interval [CI], 0.02-0.28; P = .02; I(2) = 70%). Subgroup analysis was performed after dividing the nongenotype-guided group into a standard-dose group (95% CI, 0.14-0.49; P = .0004; I(2) = 50%) and a clinical variables-guided dosing algorithm group (95% CI, -0.07-0.15; P = .48; I(2) = 34%). There is a statistically significant reduction in numbers of secondary outcomes (INR ≥4 events, major bleeding events, and thromboembolic events; 95% CI, 0.79-1.00; P = .04). Subgroup analysis of secondary outcomes showed no significant difference between genotype-guided dosing and clinical variables-guided dosing (95% CI, 0.84-1.10; P = .57; I(2) = 11%), but genotype-guided dosing reduced secondary outcomes compared with standard dosing (95% CI, 0.62-0.92; P = .006; I(2) = 0%). CONCLUSIONS: This meta-analysis showed that genotype-guided dosing increased the effectiveness and safety of coumarin therapy compared with standard dosing but did not have advantages compared with clinical variables-guided dosing.

Short time tripterine treatment enhances endothelial progenitor cell function via heat shock protein 32.

The dysfunction of endothelial progenitor cells (EPCs) limits their potential for the treatment of ischemia and atherosclerosis. Therefore, we investigated the effect of tripterine on EPC function and examined the underlying mechanisms. The effect of tripterine, an active component of Tripterygium wilfordii Hook, on the enhancement of EPC function and the efficiency of EPC transplantation was investigated in vitro and in vivo. Treatment of EPCs with tripterine at 2.5 µM for 4 h inhibited oxidized low-density lipoprotein (ox-LDL) induced ROS production, cell apoptosis, and cell senescence and improved the migration and tube formation capacities of EPCs treated with ox-LDL (200 µg/ml). In vivo studies showed that tripterine conditioning of EPCs administered to ischemic foci improved blood perfusion and microvascular density in a mouse hindlimb ischemia model. Examination of the underlying mechanisms indicated that the effect of tripterine is mediated by the induction of heat shock protein 32 expression and the inhibition of JNK activation. The present results are of clinical significance because they suggest the potential of tripterine as a therapeutic agent to improve the efficacy of EPC transplantation for the treatment of ischemic diseases.

Effects of lipids and lipoproteins on diabetic foot in people with type 2 diabetes mellitus: a meta-analysis.

BACKGROUND: To conduct a meta-analysis of case-control studies to determine the effects of lipids and lipoproteins on morbidity of diabetic foot in adults with type 2 diabetes. METHODS: We searched the PubMed and EMBASE to identify eligible studies. The Newcastle-Ottawa Quality Assessment Scale was used to determine the quality of selected studies. We assessed the strength of associations using standardized mean differences with 95% confidence intervals. RESULTS: A total of 4 articles were found. Decreased HDL-cholesterol had a significant association with diabetic foot susceptibility in fixed-effects model, but no significant associations were found between diabetic foot and LDL-cholesterol, TC or TG levels. CONCLUSIONS: Our results suggested that decreased HDL-cholesterol was associated with diabetic foot, so possible measures to prevent diabetic foot should include targeting increases in HDL-cholesterol.