AKT/FOXO1 axis links cross-talking of endothelial cell and pericyte in TIE2-mutated venous malformations.

BACKGROUND: Venous malformations (VMs), most of which associated with activating mutations in the endothelial cells (ECs) tyrosine kinase receptor TIE2, are characterized by dilated and immature veins with scarce smooth muscle cells (SMCs) coverage. However, the underlying mechanism of interaction between ECs and SMCs responsible for VMs has not been fully understood. METHODS: Here, we screened 5 patients with TIE2-L914F mutation who were diagnosed with VMs by SNP sequencing, and we compared the expression of platelet-derived growth factor beta (PDGFB) and α-SMA in TIE2 mutant veins and normal veins by immunohistochemistry. In vitro, we generated TIE2-L914F-expressing human umbilical vein endothelial cells (HUVECs) and performed BrdU, CCK-8, transwell and tube formation experiments on none-transfected and transfected ECs. Then we investigated the effects of rapamycin (RAPA) on cellular characteristics. Next we established a co-culture system and investigated the role of AKT/FOXO1/PDGFB in regulating cross-talking of mutant ECs and SMCs. RESULTS: VMs with TIE2-L914F mutation showed lower expression of PDGFB and α-SMA than normal veins. TIE2 mutant ECs revealed enhanced cell viability and motility, and decreased tube formation, whereas these phenotypes could be reversed by rapamycin. Mechanically, RAPA ameliorated the physiological function of mutant ECs by inhibiting AKT-mTOR pathway, but also facilitated the nuclear location of FOXO1 and the expression of PDGFB in mutant ECs, and then improved paracrine interactions between ECs and SMCs. Moreover, TIE2 mutant ECs strongly accelerated the transition of SMCs from contractile phenotype to synthetic phenotype, whereas RAPA could prevent the phenotype transition of SMCs. CONCLUSIONS: Our data demonstrate a previously unknown mechanistic linkage of AKT-mTOR/FOXO1 pathway between mutant ECs and SMCs in modulating venous dysmorphogenesis, and AKT/FOXO1 axis might be a potential therapeutic target for the recovery of TIE2-mutation causing VMs. Video Abstract.

Concentration-dependent effects of rapamycin on proliferation, migration and apoptosis of endothelial cells in human venous malformation.

Rapamycin has been reported to be immunosuppressive and anti-proliferative towards vascular endothelial and smooth muscle cells. The purpose of the present study was to investigate the effects of rapamycin on the biological behaviors of endothelial cells that have been separated from the deformed vein in human venous malformation (VM). Cellular morphology was observed using inverted microscopy. An MTT assay was performed to measure the cell viability at different concentrations of rapamycin and different time points. Cell apoptosis and migration were detected using a terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling assay and a wound-healing assay, respectively. At 48 and 72 h, rapamycin inhibited proliferation of human VM endothelial cells, with the effects becoming more pronounced with increasing concentration. Only rapamycin at a concentration of 1,000 ng/ml had a significant effect at 24 h in repressing proliferation. At 48 h, compared with the blank group, the majority of cells maintained a clear nuclear boundary and a regular shape following treatment with 1 ng/ml rapamycin; 10 and 100 ng/ml rapamycin caused desquamation and rounded shape; and 1,000 ng/ml rapamycin caused even more marked desquamation, rounded shape and necrosis. Rapamycin at concentrations of 1, 10, 100 and 1,000 ng/ml reduced cell viability, increased the number of apoptotic cells and suppressed the migration capacity of human VM endothelial cells, and the effects became more pronounced with increasing concentration, when compared with the blank group. These findings provide evidence that rapamycin induces apoptosis and inhibits proliferation and migration of human VM endothelial cells in a concentration-dependent manner.

MicroRNA-31a-5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment.

The alteration of age-related molecules in the bone marrow microenvironment is one of the driving forces in osteoporosis. These molecules inhibit bone formation and promote bone resorption by regulating osteoblastic and osteoclastic activity, contributing to age-related bone loss. Here, we observed that the level of microRNA-31a-5p (miR-31a-5p) was significantly increased in bone marrow stromal cells (BMSCs) from aged rats, and these BMSCs demonstrated increased adipogenesis and aging phenotypes as well as decreased osteogenesis and stemness. We used the gain-of-function and knockdown approach to delineate the roles of miR-31a-5p in osteogenic differentiation by assessing the decrease of special AT-rich sequence-binding protein 2 (SATB2) levels and the aging of BMSCs by regulating the decline of E2F2 and recruiting senescence-associated heterochromatin foci (SAHF). Notably, expression of miR-31a-5p, which promotes osteoclastogenesis and bone resorption, was markedly higher in BMSCs-derived exosomes from aged rats compared to those from young rats, and suppression of exosomal miR-31a-5p inhibited the differentiation and function of osteoclasts, as shown by elevated RhoA activity. Moreover, using antagomiR-31a-5p, we observed that, in the bone marrow microenvironment, inhibition of miR-31a-5p prevented bone loss and decreased the osteoclastic activity of aged rats. Collectively, our results reveal that miR-31a-5p acts as a key modulator in the age-related bone marrow microenvironment by influencing osteoblastic and osteoclastic differentiation and that it may be a potential therapeutic target for age-related osteoporosis.

Thermal ablation in cancer.

Radiofrequency ablation (RFA) and cryoablation are alternative forms of therapy used widely in various pathological states, including treatment of carcinogenesis. The reason is that ablation techniques have ability of modulating the immune system. Furthermore, recent studies have applied this form of therapy on tumor microenvironment and in the systematic circulation. Moreover, RFA and cryoablation result in an inflammatory immune response along with tissue disruption. Evidence has demonstrated that these procedures affect carcinogenesis by causing a significant local inflammatory response leading to an immunogenic gene signature. The present review enlightens the current view of these techniques in cancer.

The difference on the osteogenic differentiation between periodontal ligament stem cells and bone marrow mesenchymal stem cells under inflammatory microenviroments.

Periodontitis is a major cause of tooth loss in adults and periodontal ligament stem cells (PDLSCs) is the most favorable candidate for the reconstruction of tissues destroyed by periodontal diseases. However, pathological alterations caused by inflammatory insults might impact the regenerative capacities of these cells. Bone-marrow-derived human mesenchymal stem cells (hBMSCs) would accelerate alveolar bone regeneration by transplantation, compared to PDLSCs. Therefore, a better understanding of the osteogenic differentiation between PDLSCs and BMSCs in inflammatory microenviroments is therefore warranted. In this study, human PDLSCs were investigated for their stem cell characteristics via analysis of cell surface marker expression, colony forming unit efficiency, osteogenic differentiation and adipogenic differentiation, and compared to BMSCs. To determine the impact of both inflammation and the NF-κß signal pathway on osteogenic differentiation, cells were challenged with TNF-α under osteogenic induction conditions and investigated for mineralization, alkaline phosphatase (ALP) activity, cell proliferation and relative genes expression. Results showed that PDLSCs exhibit weaker mineralization and ALP activity compared to BMSCs. TNF-α inhibited genes expression of osteogenic differentiation in PDLSCs, while, it stimulates gene expressions (BSP and Runx2) in BMSCs. Enhanced NF-κß activity in PDLSCs decreases expression of Runx2 but it does not impede the osteogenic differentiation of BMSCs. Taken together, these results may suggest that the BMSCs owned the stronger immunomodulation in local microenvironment via anti-inflammatory functions, compared to PDLSCs.

Efficacy of nimotuzumab combined with docetaxel-cisplatin-fluorouracil regimen in treatment of advanced oral carcinoma.

The present study aimed to evaluate efficacy and adverse effects of Nimotuzumab combined with docetaxel-cisplatin-fluorouracil regimen in the treatment of advanced oral carcinoma. Nine patients with advanced oral carcinoma were treated with Nimotuzumab combined with docetaxel-cisplatin-fluorouracil regimen (test group). The treatment was given as follows: Nimotuzumab 200 mg, given as intravenous infusion once a week for 6 weeks; docetaxel and cisplatin, 75 mg/m(2) each, on day 1 only; 5-fluorouracil, 750 mg/m(2) infused continually for 8 h, used from day 1 to 5; the total cycle was for 21 days. Another eight patients comprised control group (docetaxel-cisplatin-fluorouracil regimen alone). Study patients from both groups were evaluated for objective response. The response rate was significantly (p = 0.044) higher in test group (88.9 vs. 37.5 % in control group). The disease control rate also tended to be higher in test group (100 vs. 62.5 % in control group; p = 0.083). The major adverse effects were bone marrow suppression, nausea, vomiting, and alopecia. The incidence of adverse effects was similar between both study groups. In conclusion, Nimotuzumab combined with docetaxel-cisplatin-fluorouracil regimen is effective and safe in the treatment of advanced oral carcinoma.

Radioactive seed implantation combined with prosthesis denture in treatment of oral and maxillofacial malignancy.

We sought to evaluate the effect of (125)I radioactive seed implantation combined with prosthesis denture on the treatment of oral and maxillofacial malignancy. For this purpose, 10 patients with glandule palatine malignancy were selected and subjected to the treatment plan of radioactive seed implantation during CT examination. All patients were treated as follow. The tumor tissues were extracted first. After 2 weeks, radioactive seeds were implanted in the palatine tissue and the prosthesis denture was made and worn for the tissue defect. Several radioactive seeds were still embedded in the tissue surface of the prosthesis at the same time; 24-36 seeds (average: 28) were used for each patient. All patients were followed up for 3-16 months and the results were evaluated. We found no tumor recurrence or metastasis around the target area in all patients. Significant improvement was shown in terms of speech, mastication, and facial appearance in all cases. Therefore, we concluded that in patients with glandule palatine malignancy, tumorectomy followed by radioactive seed implantation and prosthesis denture are effective for preventing the recurrence and metastasis of malignancy and improving the quality of life.

[Clinical observation of Foley pressurized bladders in treating 32 cases of maxillary comminuted fractures].

PURPOSE: To discuss the application of Foley pressurized bladders with rigid internal fixation in treating 32 cases of maxillary comminuted fractures and analyze the clinical advantages. METHODS: All the 32 cases of maxillary comminuted fractures were approached with maxillary vestibular or coronary incision. The infraorbital border and maxillary forehead were replaced and fixed with titanium plate. Foley pressure bladders was placed through opening into the inferior meatus. Balloon dilatation was used to reposition the maxillary anterior, medial wall and orbital floor fracture. RESULTS: Thirty-two cases of maxillary comminuted fractures were treated with Foley pressurized bladders. The overall curative rate was 97.2%. Patients had less pain and bleeding with slight reaction after surgery. The facial swelling time was shorter and the recovery of the contour was good. CONCLUSIONS: Use of Foley pressurized bladders in maxillary fractures is simple, economical and practical. The result is satisfactory and the indication is wide.

Propranolol intervention therapy for infants with facial hemangioma.

AIM OF THE STUDY: The current study aimed to evaluate the clinical efficacy and adverse effects of small doses of propranolol intervention therapy for infants with infantile facial hemangioma in the proliferation stage. MATERIAL AND METHODS: A total of 22 patients including 9 males and 13 females with an average age of 5.5 months were enrolled. These patients were diagnosed with facial hemangioma. During the first week of hospitalization, the patients were requested to take propranolol according to their weight (1.0 mg/kg to 1.5 mg/kg once daily). After hospital discharge, the patients were requested to take propranolol consistently and were reassessed every two weeks. We closely observed the process, recorded information about the size, color, and texture of the hemangioma, coped with the adverse effect during the treatment, and evaluated the clinical efficacy of propranolol. RESULTS: The color of the hemangioma faded 24 h after taking propranolol. After 3 months to 9 months of observation, we obtained the following clinical efficacies: level I, 0; level II, 2; level III, 13; and level IV, 7. The effective rate was 100%. The heart rate of 22 patients became slower than before treatment, 2 patients had slight diarrhea that disappeared after treatment, and there was no serious adverse effect during the entire process. CONCLUSIONS: With the advantages of minor side effects, convenience, safety, and evident efficacy, the administration of small doses of propranolol is a good method for treating hemangioma in infants.