Effect of non-recommended doses versus recommended doses of direct oral anticoagulants in atrial fibrillation patients: A meta-analysis.

BACKGROUND: Several observational studies have shown that the inappropriate dosing use of direct oral anticoagulants (DOACs) in atrial fibrillation (AF) that does not conform to recommendations is becoming a widespread phenomenon. Therefore, we performed a meta-analysis and systematic review to assess the effect of non-recommended doses versus recommended doses of DOACs on the effectiveness and safety outcomes among AF patients. METHODS: The PubMed and Ovid databases were systematically searched to identify the relevant studies until December 2020. The effect estimates were hazard ratios (HRs) and 95% confidence intervals (CIs), which were pooled using a fixed-effects model (I2 ≤ 50%) or a random-effects model (I2 > 50%). RESULTS: A total of 11 studies were included in this meta-analysis. Compared with recommended dosing of DOACs, non-recommended low dosing of DOACs was associated with increased risks of stroke or systemic embolism (SSE, HR = 1.29, 95% CI 1.12-1.49) and all-cause death (HR = 1.37, 95% CI 1.15-1.62), but not the ischemic stroke, myocardial infarction, gastrointestinal bleeding, intracranial bleeding, and major bleeding. Compared with recommended dosing of DOACs, non-recommended high dosing of DOACs was associated with increased risks of SSE (HR = 1.44, 95% CI 1.01-2.04), major bleeding (HR = 1.99, 95% CI 1.48-2.68), and all-cause death(HR = 1.38, 95% CI 1.02-1.87). CONCLUSION: Compared with recommended dosing of DOACs, non-recommended low dosing of DOACs was associated with increased risks of SSE and all-cause death. Further study should confirm the findings of non-recommended high dosing versus recommended dosing of DOACs.

The role of non-vitamin K antagonist oral anticoagulants in Asian patients with atrial fibrillation: A PRISMA-compliant article.

BACKGROUND: Given the huge burden of atrial fibrillation (AF) and AF-related stroke in Asia, stroke prevention represents an urgent issue in this region. We herein performed a network meta-analysis to examine the role of non-vitamin K antagonist oral anticoagulants (NOACs) in Asian patients with AF. METHODS: A systematic search of the publications was conducted in PubMed and Embase databases for eligible studies until July 2019. The odds ratios (ORs) and 95% confidence intervals (CIs) were regarded as the effect estimates. The surface under the cumulative ranking area (SUCRA) for the ranking probabilities was calculated. RESULTS: A total of 17 studies were included. For comparisons of NOACs vs warfarin, dabigatran (OR = 0.77, 95% CI 0.68-0.86), rivaroxaban (OR = 0.72, 95% CI 0.65-0.81), apixaban (OR = 0.56, 95% CI 0.49-0.65), but not edoxaban reduced the risk of stroke or systemic embolism, wheres dabigatran (OR = 0.56, 95% CI 0.41-0.76), rivaroxaban (OR = 0.66, 95% CI 0.50-0.86), apixaban (OR = 0.49, 95% CI 0.36-0.66), and edoxaban (OR = 0.34, 95% CI 0.24-0.49) decreased the risk of major bleeding. In reducing the risk of stroke or systemic embolism, apixaban and rivaroxaban ranked the best and second best (SUCRA 0.2% and 31.4%, respectively), followed by dabigatran (50.2%), edoxaban (75.2%), and warfarin (93.0%). In reducing the risk of major bleeding, edoxaban, and apixaban ranked the best and second best (1.5% and 30.8%, respectively), followed by dabigatran (48.4%), rivaroxaban (69.2%), and warfarin (100%). CONCLUSION: NOACs were at least as effective as warfarin, but more safer in Asians with AF. Apixaban was superior to other NOACs for reducing stroke or systemic embolism, while edoxaban showed a better safety profile than other NOACs.

Overexpression of MACC1 and Its significance in human Breast Cancer Progression.

BACKGROUND: Metastasis-associated in colon cancer-1 (MACC1) was first identified as a transcriptional activator for proto-oncogene c-MET expression, and its overexpression is frequently associated with metastatic progression for multiply tumor types. In the present study, we analyzed for the first time the expression of MACC1 in breast cancer and its correlation with clinicopathologic features, including metastasis and patient survival. RESULTS: MACC1 protein expression was analyzed in two cohorts of clinicopathologically characterized breast cancer using immunohistochemistry. Statistical analysis showed a significant correlation of MACC1 expression with the primary tumor, lymph node metastasis, distant metastasis classifications as well as the clinical staging in breast cancer patients. Moreover, overexpression of MACC1 was associated with both a reduced recurrence-free survival (RFS) and poorer patients' overall survival (OS). Multivariate analysis with a Cox proportional-hazards model suggested that MACC1 expression was an independent prognostic indicator for RFS and OS. Stratification of breast cancer patients according to the estrogen receptor (ER) status revealed that MACC1 was prognostic for both ER-negative and ER-positive patients. CONCLUSIONS: MACC1 may represent a potentially useful biomarker for the prognosis of breast cancer patients and might be involved in progression of breast cancer.

Expressions of miRNAs in papillary thyroid carcinoma and their associations with the BRAFV600E mutation.

OBJECTIVE: Alterations in microRNA (miRNA) expression have been described in thyroid tumors, suggesting a role for miRNAs in thyroid carcinogenesis. BRAF(V600E) is the most frequently identified genetic alteration in papillary thyroid carcinoma (PTC). We investigated the link between BRAF(V600E) status and the expression of miRNAs in PTC and analyzed the associations of these factors with clinicopathological characteristics. DESIGN AND METHODS: Prospective study of patients who underwent thyroid surgery between October 8, 2008 and November 1, 2010. BRAF(V600E) status was determined by mutant allele-specific amplification PCR and direct sequencing of exon 15 of the BRAF gene in 69 PTC tissues and 69 respective paracancerous normal thyroid tissues. Initially, miRNA expression was analyzed in 12 PTC tissues and three associated paracancerous tissues using a miRNA microarray. miRNAs differentially expressed between BRAF(V600E)-positive and -negative PTC tissues were then validated by real-time quantitative PCR on 69 PTC tissues and 69 paracancerous tissues. We also explored the associations between BRAF(V600E) status or differential miRNA expression and clinicopathological characteristics. RESULTS: The mutation rate of BRAF(V600E) in PTC was 47.8%. Twelve miRNAs were upregulated and six were downregulated in PTC tissues, among which miR-15a, 15a*, 34a*, 34b*, 551b, 873, 876-3p, and 1274a were first identified. miR-21* and 203 were significantly dysregulated (P<0.05) in PTC tissues with BRAF(V600E). Additionally, there were significant associations (P<0.05) between BRAF(V600E) and a higher tumor-node-metastasis staging (III/IV), and between miR-21* over-expression and lymph node metastasis. CONCLUSIONS: We identified two miRNAs that are differentially expressed in PTC tissues with BRAF(V600E) and revealed their associations with clinicopathological features. These findings may lead to the development of a potential diagnostic biomarker or prognostic indicator of PTC.

Differentially expressed microRNAs at different stages of atherosclerosis in ApoE-deficient mice.

BACKGROUND: Atherosclerosis is the primary cause of cardiovascular disease, carotid artery disease, and peripheral vascular disease. However, it is hard to obtain human arterial tissue at different stages of atherosclerosis for a systematic study. The ApoE-deficient (ApoE(-/-)) mice predictably develop spontaneous atherosclerotic plaques with numerous features similar to the human lesions and contain nearly the entire spectrum of lesions observed during atherogenesis in humans. MicroRNA expression profiles at different stages of atherosclerosis in ApoE-deficient mice were screened to find out the differentially expressed microRNAs. METHODS: ApoE-deficient mice were euthanized at 4, 8, and 20 weeks of age and divided into three groups according to the three time points, including groups A4 (fed a Western-type diet for 0 week), A8 (fed a Western-type diet for 4 weeks), and A20 (fed a Western-type diet for 16 weeks). Atherosclerotic lesions were analyzed. Fifteen aortas were collected and combined into three pools (five aortas in one pool) in each group. MicroRNA microarray analysis was replicated thrice in each group. The threshold of fold change ≥ 2.0 was used to screen up or down-regulated microRNAs. Differentially expressed microRNAs were subsequently verified with quantitative real-time polymerase chain reaction. Those increasingly up or down-regulated microRNAs during the progression of atherosclerosis were selected. RESULTS: Atherosclerotic lesions first appeared in the aortic arch in group A8. Severe atherosclerotic lesions were observed in group A20. In group A8, seven MicroRNAs were up-regulated while two were down-regulated. In group A20, 15 microRNAs were up-regulated while two were down-regulated. miR-34a-5p and miR-497-5p were increasingly up-regulated, while miR-434-3p was progressively down-regulated when atherosclerosis progressed. CONCLUSIONS: In this study, we described that microRNAs are differentially expressed at different stages of atherosclerosis in ApoE-deficient mice. Those increasingly up or down-regulated microRNAs during the progression of atherosclerosis may play an important role in the pathogenesis of atherosclerosis and provide us opportunities for investigating atherosclerosis from early to advanced stages.

Circulating tissue factor positive microparticles in patients with acute recurrent deep venous thrombosis.

INTRODUCTION: Circulating tissue factor positive microparticles (MPTF) were reported in a wide range of diseases with thrombotic tendency. Though D-dimer assay had a high negative predictive value for deep venous thrombosis (DVT) recurrence, there are currently no reliable positive predictors for recurrent DVT. We therefore quantified MPTF in patients with acute recurrent DVT to determine whether MPTF levels could be used to predict recurrent DVT. MATERIALS AND METHODS: Microparticles (MPs) were isolated from plasma of initial DVT patients (n=25), recurrent DVT patients (n=25) and sex- and age-matched healthy individuals (n=25), stained with annexin V, cell-specific monoclonal antibodies (MoAbs) and a MoAb directed against tissue factor (TF), and analyzed by flow cytometry. We also determined the plasma procoagulant activity with a Human TF Chromogenic Activity Assay Kit. RESULTS: We found total MPTF to be elevated in recurrent DVT patients versus normal individuals (P=0.001). The number of monocyte-derived MPTF in both initial and recurrent DVT was higher than in normal individuals (P<0.01, respectively). The platelet and endothelial cell derived MPTF in recurrent DVT were significantly increased relative to other MPTF (P<0.05), although there was no difference between initial DVT patients and normal individuals. We demonstrated elevated procoagulant activity of platelet-free plasma in DVT patients relative to normal individuals, and a positive correlation with MPTF. CONCLUSIONS: The elevated MPTF could be a potentially predictor for DVT recurrence. Further studies are needed to validate its sensitivity and specificity.

Abdominal aorta aneurysms in children: single-center experience of six patients.

BACKGROUND: Abdominal aortic aneurysms (AAA) are rare in children and are associated with significant morbidity and mortality as in adults. We summarize our experience in the diagnosis and management of AAAs in 6 children at a single institution. METHODS: The clinical data of 6 pediatric patients with AAAs treated at our hospital from November 2005 to November 2008 were retrospectively analyzed. RESULTS: There were 4 males and 2 females with a mean age at diagnosis of 8 years (range, 17 months to 18 years). All patients presented with pulsatile abdominal masses. Color Doppler ultrasonography and computed tomography angiography were the primary diagnostic tools. One patient has a history of tuberous sclerosis, and 1 had Takayasu's arteritis; no risk factors or identifiable causes were found in the other patients. All of the AAAs identified were infrarenal. Surgical reconstruction with aneurysm resection and prosthetic graft placement was performed successfully in all 6 cases. No intraoperative or postoperative complications occurred. Mean follow-up has been 48 months (range, 32 to 69). In 1 patient, recurrence was noted at 3 years postoperatively. The patient's family declined further surgery, and the patient died, likely of rupture of the aneurysm at 41 months postoperatively. All other patients are currently alive and well. CONCLUSIONS: Our experience indicates that good outcomes can be obtained in children with AAAs with prompt and accurate diagnosis and surgical management with artificial grafts.

Clinical analysis of vascular anomalies: a hospital-based retrospective study of 592 patients in southeast China.

BACKGROUND: Vascular anomalies are common and multidisciplinary involved diseases. The greatest impediment to their treatment in the past was their confusing terminology and clinical heterogeneities. This hospital-based retrospective study assessed some clinical characteristics, diagnosis, therapies and outcomes of patients with vascular anomalies in southeast China. METHODS: A total of 592 vascular anomalies patients (patients with intracranial tissues or viscera involved were excluded), admitted to the First Affiliated Hospital of Sun Yat-sen University from January 2006 to September 2009, were enrolled in the study. Data for clinical characteristics, diagnosis, therapies and outcomes were collected and analyzed. RESULTS: Of the 592 patients, the male:female ratios in the vascular tumor group (n = 187) and the vascular malformation group (n = 405) were 1:1.49 and 1:1.06 respectively, with no significant difference between them. The mean onset age of the vascular tumor group was significantly younger than that of the vascular malformation group (p < 0.001). The head and neck were the most commonly (31.4%) involved areas in vascular anomalies. A total of 23.8% of the patients with vascular anomalies had definite symptoms caused by the vascular lesions. In the vascular tumor group, 94.1% of them were infantile hemangiomas. Venous malformation was the most common (41.0%) subtype of vascular malformations. Surgical therapy was undertaken in 94.2% of the patients with vascular anomalies. Of the 519 patients available for the 16 - 58 month follow-up, 322 patients (62.0%) were cured, 108 patients (20.8%) were markedly improved, 57 patients (11.0%) were partially improved, and 32 patients (6.2%) were uncured. CONCLUSIONS: Vascular anomalies are clinically heterogeneous. While the outcome is generally favorable, further effort should be made to determine the appropriate terminology and management.

Somatic mutations in exon 17 of the TEK gene in vascular tumors and vascular malformations.

OBJECTIVE: As a common disease, the molecular etiology of noninherited vascular anomalies is still poorly understood. Recently, somatic mutations in exon 17 of the endothelial cell tyrosine kinase receptor Tie-2 (encoded by TEK) were identified in 49.1% of patients with common sporadic venous malformation, a subtype of vascular anomalies. We assessed whether such a mutational region also had a role in the Chinese population or in other subtypes of noninherited vascular anomalies (vascular tumors and vascular malformations). METHODS: Direct sequencing of polymerase chain reaction (PCR)-amplified DNA, extracted from 139 lesions in 129 individuals with noninherited vascular anomalies (vascular tumors or vascular malformations) and 60 control samples, was used for detecting the mutations in exon 17 of the TEK gene. Mutations were confirmed by allele-specific PCR. Clone sequences were then used for the mutations identified for the first time. We also explored the associations between these mutations and clinical characteristics (gender, onset age, number of lesions, severity, category, and recurrence of the disease) in both vascular tumors and vascular malformations. RESULTS: Two somatic TEK mutations (Y897C, R915C) were identified in vascular tumors, and seven somatic TEK mutations (Y897H, Y897C, L914F, R915C, S917I, R918C, R918H) were identified in vascular malformations. Among these mutations, R918C (2,752 C > T) and R918H (2,753 G > A) were first identified in noninherited vascular anomalies. Somatic TEK mutations were detected in lesions from 4 of 23 (17.4%) vascular tumors and 35 of 106 (33.0%) vascular malformations, where most mutations were single substitutions in vascular tumors (100%) and vascular malformations (88.6%), while the remainders were double substitutions. In addition to the reported venous malformation, such mutations were identified in some other subtypes of vascular anomalies, including vascular tumors (infantile hemangioma, pyogenic granuloma, and epithelioid hemangioma) and vascular malformations (capillary malformation, arteriovenous malformation, capillary lymphatic malformation, and capillary arteriovenous malformation). By contrast, these mutations were absent from the control tissues or blood. However, mutations showed no association (P > .05) with clinical characteristics in vascular anomalies or either of its two types (vascular tumors or vascular malformations). CONCLUSIONS: Our study revealed that somatic mutations in exon 17 of the TEK gene were more common in noninherited vascular anomalies than previously reported. Furthermore, such substitutions may shed new light on the molecular etiology, diagnosis, and potential therapeutic targets of vascular anomalies.

Sphingosine kinase 1 is overexpressed and promotes proliferation in human thyroid cancer.

Sphingosine kinase 1 (SphK1), an oncogenic kinase, has been previously found to be elevated in various types of human cancer and play a role in tumor development and progression. Nevertheless, the biological and clinical significance of SphK1 in thyroid cancer is largely unknown. Here, we demonstrate that the expression of SphK1 is generally up-regulated in thyroid cancer and that its expression level is correlated with the degree of thyroid malignancy. Silencing SphK1 by specific RNA interference is able to suppress the proliferation of thyroid cancer cells, and SphK1 expression level is strongly associated with the expression of proliferation cell nuclear antigen in thyroid cancer tissues. Of particular note is that depletion of SphK1 results in dephosphorylation of protein kinase B and glycogen synthase kinase-3ß and subsequent inactivation of ß-catenin-T-cell factor/lymphoid enhancing factor transcriptional activity. Hence, taken together, our study has identified SphK1 as a proproliferative oncogenic kinase, an Akt/glycogen synthase kinase-3ß/ß-catenin activator, and probably a biomarker for thyroid cancer as well.

MicroRNA-21 regulates vascular smooth muscle cell function via targeting tropomyosin 1 in arteriosclerosis obliterans of lower extremities.

OBJECTIVE: The goal of this study was to determine the expression signature and the potential role of microRNAs in human arteries with arteriosclerosis obliterans (ASO). METHODS AND RESULTS: The expression profiles of microRNAs in human arteries with ASO and in normal control arteries were determined by quantitative reverse transcription-polymerase chain reaction array. Among the 617 detected microRNAs, multiple microRNAs were aberrantly expressed in arteries with ASO. Some of these dysregulated microRNAs were further verified by quantitative reverse transcription-polymerase chain reaction. Among them, microRNA-21 (miR-21) was mainly located in arterial smooth muscle cells (ASMCs) and was increased by more than 7-fold in ASO that was related to hypoxia inducible factor 1-α. In cultured human ASMCs, cell proliferation and migration were significantly decreased by inhibition of miR-21. 3'-Untranslated region luciferase assay confirmed that tropomyosin 1 was a target of miR-21 that was involved in miR-21-mediated cellular effects, such as cell shape modulation. CONCLUSION: The results suggest that miR-21 is able to regulate ASMC function by targeting tropomyosin 1. The hypoxia inducible factor-1 α/miR-21/tropomyosin 1 pathway may play a critical role in the pathogenesis of ASO. These findings might provide a new therapeutic target for human ASO.

[Endovascular repair of abdominal aortic aneurysm: a clinical report of 81 cases].

OBJECTIVE: To evaluate the efficacy and safety of endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA), and to compare the prognosis between patients of different ages. METHODS: The hospitalization and follow-up data of 81 AAA patients treated by EVAR from May 2005 to May 2011 were retrospectively analyzed. All the patients were divided into advanced age group (age ≥ 75 years, 24 cases) and relatively young group (age < 75 years, 57 cases). General conditions, comorbidity, procedure, in-hospital complications, and follow-up were compared between these two groups. RESULTS: All covered stents were successfully deployed, a technical success rate of 91.4% (74/81) was achieved. There was no intraoperative death. In-hospital mortality was 1.2% (1/81). The follow-up rate was 91.4% (74/81), with a mean follow-up of 47.5 months. Twelve deaths were recorded during follow-up, 1, 2, 3, 4, and 5-year survival rates were 98.6%, 92.2%, 80.8%, 58.7%, and 44.1%, respectively. When compared with relatively young group, the advanced age group had a lower rate of abdominal pain as the major symptom, but a higher rates of renal diseases and coronary artery diseases. Furthermore, the advanced age group had a longer stay in intensive care unit and higher morbidity of endoleaks, and also tended to have increased rates of pulmonary infection and access site hematoma, while the other parameters were similar between the two groups. CONCLUSIONS: EVAR of AAA is less invasive, safe, and effective during short to mid-tern follow-up. The patients of advanced age suffer from higher rates of some complications, thus careful perioperative preparation and intensive monitor are mandatory for preventing or treating potential complications and improving prognosis for these patients.

Gambogic acid induces G0/G1 cell cycle arrest and cell migration inhibition via suppressing PDGF receptor ß tyrosine phosphorylation and Rac1 activity in rat aortic smooth muscle cells.

AIM: Gambogic acid (GA) is the major active compound of Gamboge, a brownish or orange resin exuded from Garcinia hanburryi tree in Southeast Asia. Previous studies have demonstrated that GA exhibits potent anticancer effects by inducing cell cycle arrest or apoptosis in many types of cancer cell lines and blocking angiogenesis via inhibition of vascular endothelial cell proliferation and migration. Proliferation and migration of vascular smooth muscle cells (VSMCs) are critical steps in the progress of atherosclerosis and restenosis after angioplasty. In the present study, we investigated whether GA has an inhibitory effect on the proliferation and migration of VSMCs and its possible mechanism. METHODS: The inhibitory effect of GA on the proliferation induced by PDGF-BB and EGF was measured by using Cell number counting assay and [(3)H]-thymidine incorporation. The effects of GA on the cell cycle progression and viability stimulated by PDGF-BB and EGF were also analyzed by flow cytometry analysis. The inhibitory effect of GA on the migration stimulated by PDGF-BB was measured by transwell chamber assay. The effect of GA on the Cell cycle regulatory molecules (cyclinD1, cyclinE, CDK2, CDK4), PDGFR and its downstream signaling molecules including ERK1/2, PLCγ1, AKT and JNK was measured by western blotting. The effect of GA on the Rac1 activity was measured by using GST-pulldown assay. The effects of GA on the tyrosine phosphorylation stimulated by PDGF-BB and EGF and the capacity of GA binding with PDGF-BB and EGF were also measured. RESULTS: We found that GA significantly inhibited proliferation, migration and DNA synthesis in primary cultured rat aortic VSMCs at concentrations of 0.25, 0.5, 1.0 and 2.0 µmol/L after stimulation of 50 µg/L platelet-derived growth factor-BB (PDGF-BB). GA induced G0/G1 phase arrest in the cell cycle progression of VSMCs. No obvious necrosis or apoptosis was found with GA treatment. The expressions of CDK2, CDK4, cyclin D1 and cyclin E, cell cycle regulatory molecules, were significantly suppressed by GA treatment in a concentration-dependent manner. The phosphorylation of PDGF receptor ß (PDGFR-ß) and the activities of downstream intracellular signaling molecules including phospho-ERK, phospho-PLCγ1, phospho-AKT, phospho-JNK and GTP-Rac1 were also inhibited by GA pretreatment. GA inhibited PDGFR-ß phosphorylation through inhibiting the activity of tyrosine directly, rather than indirectly via binding PDGF-BB. CONCLUSIONS: The results of this study provide preliminary evidence that the inhibitory effects of GA on VSMCs proliferation and migration may be mediated through multiple signal pathways controlled by PDGF-Rß activation and its downstream intracelluar signaling.

[The value of regulated upon activation normal T cell expressed and secreted in the pathogenesis of varicose ulcer of lower limbs].

OBJECTIVE: To study the effectiveness of RANTES in the pathogenesis of venous ulceration. METHODS: 40 Chronic venous insufficiency (CVI) individuals were enrolled in the study and separated into the ulceration group (n=20) and non-ulceration group (n=20), according to CVI with or without ulceration, 10 healthy individuals were enrolled as control group. The expression of RANTES mRNA was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) in blood. Immunohistochemical staining of RANTES were carried in normal skin, in the tissue at the brim of ulceration and in the tissue of cured or curing ulceration. RESULTS: In ulceration group, the expression of RANTES mRNA in blood increased obviously. Compared with the other two groups, they were significant different (P < 0.05). The difference was also significance in the other two groups (P < 0.05). The average number of RANTES positive expression in normal skin is 28 +/- 13, in the tissue at the brim of ulceration is 107 +/- 44, and in the tissue of cured or curing ulceration is 35 +/- 20. There are significant difference between normal skin and the tissue at the brim of ulceration (P < 0.05). The average number of RANTES positive expression in the tissue of cured or curing ulceration is lower than that's in the tissue at the brim of ulceration. CONCLUSION: The high expression of RANTES may be one of the important mechanisms of varicose ulcer.

[Experience of surgical treatment of carotid body tumor after preoperative embolization of feeding vessels].

OBJECTIVE: To evaluate the effect of preoperative embolization of the feeding vessels of carotid body tumor in the treatment thereof. METHODS: 33 patients with carotid body tumors not less than 3 cm in diameter were examined by color Doppler ultrasound. Polyvinyl alcohol particle 250-1000 microm in diameter were suspended in meglumine diatrizoate or Ultravist and then injected via microcatheter into the feeding vessels until detainment or reflux was seen. Operation was performed 1 day later on 23 patients and 4 days later on 10 patients. External carotid artery to internal carotid artery bypass was performed on 1 case, anastomosis of common carotid to internal carotid artery with auto-saphenous vein interposition on 3 cases, and repair of internal carotid artery on 1 case. RESULTS: One-stage resection was completed on all tumors. One case suffered contralateral hemiplegia two times in the operative day, on the next day the contralateral lower limb could move, but the patient could not speak clearly and his tongue was not in right position, after 3 months he was completely recovered and MRI illustrated cranial infarction. CONCLUSION: An important adjunct in treating large carotid body tumor, preoperative embolization makes the surgical exploration proceed much smoother, blood loss become less, and morbidity lower.

Combination of stromal-derived factor-1alpha and vascular endothelial growth factor gene-modified endothelial progenitor cells is more effective for ischemic neovascularization.

BACKGROUND: Recruitment and entrapment of bone marrow-derived endothelial progenitor cells (EPCs) is important in vascular endothelial growth factor (VEGF)-induced angiogenesis. EPC mobilization and differentiation are modulated by stromal-derived factor-1alpha (SDF-1alpha/CXCL12), another important chemokine. In this study, we investigated the hypothesis that SDF-1alpha and VEGF might act synergistically on EPC-mediated vasculogenesis. METHODS: EPCs were isolated and cultured from human peripheral blood, then transduced with retroviral vectors pBabe containing human VEGF(165) complimentary DNA (Td/V-EPCs) and pBabe wild-type (Td/p-EPCs). EPC migration activity was investigated with a modified Boyden chamber assay. EPC apoptosis induced by serum starvation was studied by annexin V assays. The combined effect of local administration of SDF-1alpha and Td/V-EPC transplantation on neovascularization was investigated in a murine model of hind limb ischemia. RESULTS: Over-expression of hVEGF(165) increased SDF-1alpha-mediated EPC migration. SDF-1alpha-mediated migration was significantly increased when EPCs were modified with VEGF (Td/V-EPCs) vs when VEGF was not present (Td/p-EPCs) or when VEGF alone was present (Td/V-EPCs; 196.8 +/- 15.2, 81.2 +/- 9.8, and 67.4 +/- 7.4/mm(2), respectively P < .001). SDF-1alpha combined with VEGF reduced serum starvation-induced apoptosis of EPCs more than SDF-1alpha or VEGF alone (P < .001). To determine the effect of this combination in vivo, SDF-1alpha was locally injected alone into the ischemic hind limb muscle of nude mice or combined with systemically injected Td/V-EPCs. The SDF-1alpha plus VEGF group showed significantly increased local accumulation of EPCs, blood-flow recovery, and capillary density compared with the other groups. The ratio of ischemic/normal blood flow in Td/V-EPCs plus SDF-1alpha group was significantly higher (P < .01), as was capillary density (capillaries/mm(2)), an index of neovascularization (Td/V-EPCs plus SDF-1alpha group, 863 +/- 31; no treatment, 395 +/-13; SDF-1alpha, 520 +/- 29; Td/p-EPCs, 448 +/- 28; Td/p-EPCs plus SDF-1alpha, 620 +/- 29; Td/V-EPCs, 570 +/- 30; P < .01). To investigate a possible mechanistic basis, we showed that VEGF up-regulated the receptor for SDF-1alpha, CXCR4, on EPCs in vitro. CONCLUSION: The combination of SDF-1alpha and VEGF greatly increases EPC-mediated angiogenesis. The use VEGF and SDF-1alpha together, rather than alone, will be a novel and efficient angiogenesis strategy to provide therapeutic neovascularization.

[RANTES expression in venous ulceration of lower limbs].

OBJECTIVE: To investigate the expression of RANTES in venous ulceration. METHODS: From patients with lower limb venous ulceration, patients with non-ulcerous venous insufficiency, and healthy individuals, peripheral blood was collected from the lower limb veins for measurement of RANTES mRNA using RT-PCR. RESULTS: In the ulceration group, the expression of RANTES mRNA was significantly increased as compared with the other two groups (P<0.01). RANTES mRNA expression was also significant higher in the non-ulcerous group than the control group (P<0.01). CONCLUSION: High expression of RANTES mRNA may be one of the important mechanisms of venous ulceration.

Overexpression of macrophage migration inhibitory factor induces angiogenesis in human breast cancer.

Macrophage migration inhibitory factor (MIF) is known to be an important contributor to tumor progression. Overexpression of MIF has been reported in different types of tumors. However, the correlation between MIF expression and tumor pathologic features in patients with breast cancer has not been elucidated. In this study, we examined the expression of MIF, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) in human tissues with or without tumor. In addition, we investigated the expression of MIF in MDA-MB-231, MCF-7 (breast cancer cell lines) and MCF-10A (epithelial cell line) cells, and its effect on VEGF and IL-8. We found that MIF was overexpressed in breast cancer tissues compared with normal ones. The level of MIF showed the positive correlation between the expression of IL-8 and tumor microvessel density (MVD). The patients with positive MIF expression in tumor tissues showed a significantly worse disease-free survival compared with negative ones. Increased MIF serum levels were also found to correlate with higher levels of IL-8 in the sera of the patients with breast cancer. In vitro experiments successfully detected MIF in breast cell lines. However, the expression level of it by normal epithelial cells was much less than that of cancer cells. Exogenous MIF did not cause endothelial tube formation and migration but induced a dose dependent increase in VEGF and IL-8 secretion in breast cancer cell lines. In summary, our studies show that human breast cancer tissue expresses MIF. Its in vitro effect on VEGF and IL-8 indicates that MIF may contribute to tumor in angiogenesis and thus play an important role in the pathogenesis of breast cancer.

Role of interleukin-8 in the progression of estrogen receptor-negative breast cancer.

BACKGROUND: Estrogen receptor (ER) is a very important biomarker of breast cancer. ER deletion has been consistently associated with tumor progression, recurrence, metastasis and poor prognosis, but the biological mechanism is still unclear. ER negative breast cancer expresses high levels of interleukin-8 (IL-8). ER expression can downregulate IL-8 promotor activity. As a multifunctional cytokine, IL-8 has many important biological activities in tumor genesis and development. With the goal of investigating the role of IL-8 in ER-negative breast cancer progression, we applied RNA interference technology to specifically knockdown the IL-8 expression in ER-negative breast cancer cell line MDA-MB-231. METHODS: Interfering pRNA-IL-8 and the control was transfected into ER (-) MDA-MB-231. The proliferation, cell apotosis, and invasive ability were recorded in transfected, untransfected and negative transfected cells. These cells were injected into nude mice to assess tumorigenicity, proliferation, metastasis and microvessel density (MVD). RESULTS: In vitro, decreased expression of IL-8 was associated with reduced cell invasion (P < 0.001), but had no effect on cell proliferation (P > 0.05). In vivo, neutrophils infiltration was significantly inhibited in pRNA-IL-8 transfected cells compared with untransfected and negatively transfected cells (P = 0.001, P < 0.001). Less metastasis was found in transfected cells compared with negatively transfected cells (0% vs 80%, P = 0.048). Nevertheless, we observed less MVD in transfected cells compared with control in nude mice (P < 0.001). CONCLUSIONS: IL-8 inhibits ER-negative breast cancer cell growth and promotes its metastasis in vivo, which may be correlated with neutrophils infiltration induced by IL-8.

Interleukin-8 modulates growth and invasiveness of estrogen receptor-negative breast cancer cells.

Breast cancer, especially estrogen receptor (ER)-negative breast cancer, remains hard to treat despite major advances in surgery and adjuvant therapies. The deletion of ER has been consistently associated with tumor progression, recurrence, metastasis and poor prognosis. Among other differences in biological features, ER-negative breast cancers express high levels of interleukin-8 (IL-8), whereas their ER-positive counterparts do not. IL-8 is a multi-functional cytokine with many important biological functions in tumor formation and development. We aimed to study the role(s) of IL-8 in ER-negative breast cancer progression by using RNA interference to specifically knockdown IL-8 expression in ER-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468. In vitro, suppression of IL-8 led to significant reductions in cell invasion (p<0.001), but had no effects on cell proliferation or cell cycle. In vivo, suppression of IL-8 significantly reduced the microvessel density (p<0.05), and markedly reduced neutrophil infiltration into the tumors (p<0.05). In contrast to in vitro observations, suppression of IL-8 promoted tumor growth in nude mice (p<0.05). Our results imply that the complex roles of IL-8 in the regulation of ER-negative breast cancer progression may in part be related to its potent chemotactic effects on neutrophils, which in turn mediates many of the biological functions of IL-8.