Overcoming chemoresistance in non-angiogenic colorectal cancer by metformin via inhibiting endothelial apoptosis and vascular immaturity / 药物分析学报

The development of chemoresistance which results in a poor prognosis often renders current treatments for colorectal cancer(CRC).In this study,we identified reduced microvessel density(MVD)and vascular immaturity resulting from endothelial apoptosis as therapeutic targets for overcoming chemoresistance.We focused on the effect of metformin on MVD,vascular maturity,and endothelial apoptosis of CRCs with a non-angiogenic phenotype,and further investigated its effect in overcoming chemoresistance.In situ transplanted cancer models were established to compare MVD,endothelial apoptosis and vascular maturity,and function in tumors from metformin-and vehicle-treated mice.An in vitro co-culture system was used to observe the effects of metformin on tumor cell-induced endothelial apoptosis.Transcriptome sequencing was performed for genetic screening.Non-angiogenic CRC developed inde-pendently of angiogenesis and was characterized by vascular leakage,immaturity,reduced MVD,and non-hypoxia.This phenomenon had also been observed in human CRC.Furthermore,non-angiogenic CRCs showed a worse response to chemotherapeutic drugs in vivo than in vitro.By suppressing endo-thelial apoptosis,metformin sensitized non-angiogenic CRCs to chemo-drugs via elevation of MVD and improvement of vascular maturity.Further results showed that endothelial apoptosis was induced by tumor cells via activation of caspase signaling,which was abrogated by metformin administration.These findings provide pre-clinical evidence for the involvement of endothelial apoptosis and subsequent vascular immaturity in the chemoresistance of non-angiogenic CRC.By suppressing endothelial apoptosis,metformin restores vascular maturity and function and sensitizes CRC to chemotherapeutic drugs via a vascular mechanism.

Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells improves survival of ultra-long random skin flap / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Random flap is one kind of the most widely used skin flaps in reconstructive surgery; however, partial necrosis of its distal end remains a significant problem now. The aim of this study was to evaluate the effect of hypoxia preconditioned bone marrow mesenchymal stem cells (HpBMSCs) transplantation on ultra-long random skin flap survival in rats.</p><p><b>METHODS</b>Normoxic bone marrow mesenchymal stem cells (nBMSCs) were cultured under normoxia (20% O2) and HpBMSCs under hypoxia (1% O2) for 48 hours before transplantation. Thirty Sprague-Dawley rats were randomly divided into control group, nBMSCs group and HpBMSCs group with each consisting of 10 rats. Survival area of ultra-long random skin flap on the dorsal of rats was measured seven days after flap surgery and cell transplantation. Cell survival in vivo, microvessel density and vascular endothelial growth factor (VEGF) were evaluated by histological examination and enzyme-linked immunosorbent assay.</p><p><b>RESULTS</b>Compared with other two groups, flap survival area in HpBMSCs group was significantly larger (P < 0.05). Microvessel density in HpBMSCs group (36.20 ± 8.19) was higher than that in nBMSCs group (30.01 ± 5.68) and control group (17.60 ± 4.19) (P < 0.05). VEGF in HpBMSCs group ((300.05 ± 50.41) pg/g) was higher than those in nBMSCs group ((240.55 ± 33.64) pg/g) and control group ((191.65 ± 32.58) pg/g) (P < 0.05).</p><p><b>CONCLUSION</b>HpBMSCs transplantation improves ultra-long random skin flap survival via promoting angiogenesis of more survival cells.</p>

Transforming growth factor-β1 phage model peptides isolated from a phage display 7-mer peptide library can inhibit / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Transforming growth factor-β1 (TGF-β1) is known to have a role in keloid formation through the activation of fibroblasts and the acceleration of collagen deposition. The objective of this current study was to isolate TGF-β1 phage model peptides from a phage display 7-mer peptide library to evaluate their therapeutic effect on inhibiting the activity of keloid fibroblasts.</p><p><b>METHODS</b>A phage display 7-mer peptide library was screened using monoclonal anti-human TGF-β1 as the target to obtain specific phages containing ectogenous model peptides similar to TGF-β1. Enzyme-linked immunosorbent assay (ELISA) was performed to select monoclonal phages with good binding activity, which underwent DNA sequencing. MTT assay and apoptosis assessment were used to evaluate the biological effects of the phage model peptides on keloid fibroblasts. Immunofluorescence assay was employed to show the binding affinity of the model peptides on phages causing keloid fibroblasts. Quantitative real-time PCR analysis was carried out to detect the expressions of nuclear factor κB (NF-κB) mRNA, connective tissue growth factor (CTGF) mRNA and TGF-β receptor II (TβRII) mRNA in keloid fibroblasts.</p><p><b>RESULTS</b>Specific phages with good results of ELISA were beneficiated. Four phage model peptides were obtained. The data of MTT showed that TGF-β1 and one phage model peptide (No. 4) could promote keloid fibroblasts proliferation, however, three phage model peptides (No. 1 - 3) could inhibit keloid fibroblasts proliferation. The results of apoptosis assessment showed that the three phage model peptides could slightly induce the apoptosis in keloid fibroblasts. The data of immunofluorescence assay revealed that the model peptides on phages rather than phages could bind to keloid fibroblasts. The findings of quantitative real-time PCR analysis suggested that the expressions of NF-κB mRNA and CTGF mRNA in the three phage model peptide groups decreased, while the expression of TβRII mRNA slightly increased.</p><p><b>CONCLUSIONS</b>Three phage model peptides isolated from a phage display 7-mer peptide library can inhibit keloid fibroblasts proliferation and induce the apoptosis in keloid fibroblasts. They can inhibit the activity of keloid fibroblasts by blocking TGF-β1 binding to its receptor and then regulating the expressions of NF-κB, CTGF and TβRII.</p>

Keratinocyte growth factor phage model peptides can promote epidermal cell proliferation without tumorigenic effect / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Keratinocyte growth factor (KGF) significantly influences epithelial wound healing. The aim of this study was to isolate KGF phage model peptides from a phage display 7-mer peptide library to evaluate their effect on promoting epidermal cell proliferation.</p><p><b>METHODS</b>A phage display 7-mer peptide library was screened using monoclonal anti-human KGF antibody as the target. Enzyme linked immunosorbent assay (ELISA) was performed to select monoclonal phages with good binding activity. DNA sequencing was done to find the similarities of model peptides. Three-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, immunofluorescence assay and quantitative real-time PCR analysis were employed to evaluate the effect of the phage model peptides on epidermal cells.</p><p><b>RESULTS</b>Thirty-three out of fifty-eight (56.9%) of the isolated monoclonal phages exhibited high binding activity by ELISA. Ten of fifteen obtained phage model peptides were similar to KGF or epidermal growth factor (EGF). MTT assay data showed that four (No. 1 - 4) of the ten phage model peptides could promote epidermal cell proliferation. The expression of keratinocyte growth factor receptor (KGFR) mRNA in the KGF control group and the two phage model peptide groups (No. 1 and No. 2) increased. Expression of c-Fos mRNA and c-Jun mRNA in the KGF control group increased, but did not increase in the four phage model peptide groups (No.1 - 4).</p><p><b>CONCLUSION</b>Four phage model peptides isolated from the phage display 7-mer peptide library can safely promote epidermal cell proliferation without tumorigenic effect.</p>

Significance of location of mandibular canal by 3-dimensional CT in the mandibular angle osteotomy / 中华整形外科杂志

<p><b>OBJECTIVE</b>To decrease the incidence of inferior alveolar neurovascular bundle injury through location of mandibular canal by 3-dimensional (3-D) CT.</p><p><b>METHODS</b>30 female cases with prominent mandibular angle underwent 3-D CT before operation. The 3-D images were used to measure the distances between upper points of lower teeth to the inferior border of the canal. Then the osteotomy was designed according to the canal position to avoid the inferior alveolar neurovascular bundle injury. The canal protection was observed intraoperatively and postoperatively.</p><p><b>RESULTS</b>The mandibular canal was protected very well in all 30 cases without any injury to the inferior alveolar neurovascular bundle.</p><p><b>CONCLUSIONS</b>The 3-D CT can accurately locate the mandibular canal to guide the design of the mandibular angle osteotomy for patients with prominent mandibular angle.</p>

The measurement of the mandibular canal's location in the mandibular body of the young women / 中华整形外科杂志

<p><b>OBJECTIVE</b>To locate the mandibular canal accurately in the mandibular body of the young women and provide anatomic data for the mandibular angle plasty.</p><p><b>METHODS</b>60 women whose age ranged from 20 to 39 years old were randomly selected, the average was 25.32 years old. CT scanning and 3-D reconstruction were applied to their mandibles. After the points were determined, the distances of the points to inferior mandibular borders were measured. The data was analyzed by SPSS 11.5.</p><p><b>RESULTS</b>The distance between the mandibular canal and the inferior mandibular border was least in the area which responsed to the second premolar. It decreases from the posterior margin of the third molar to the anterior margin of the first molar. It increases from the posterior margin to the mental hole.</p><p><b>CONCLUSIONS</b>The mandibular canal between the posterior and anterior margins of the second pre-molar is prone to be injuried and should be paid more attention to during mandibular angle plasty.</p>

The influences on mandibular development after removing the outer cortex of mandibular body in childhood minitype pigs / 中华整形外科杂志

<p><b>OBJECTIVE</b>To study the influences on mandibular development after removing the outer cortex of mandibular body in childhood minitype pig.</p><p><b>METHODS</b>Six childhood minitype pigs were selected as the experimental animals. The outer cortex of mandibular body measured as 3.0 cm x 1.5 cm was removed in one side, and the other side remained intact as the control. The changes of mandibular modality and occlusion relationship as well as the histological and biomechanical changes were studied 24 weeks after operation.</p><p><b>RESULTS</b>There was no obvious difference compared with the control side in the height of the mandibular ramus and the length of the mandibular body, However, lateral deviation occlusion was found in some animals. The body thickness was thinner than that of the control side, there were no obvious biomechanical and histological differences between the two sides.</p><p><b>CONCLUSIONS</b>There was less influence on the growth of mandibular bone after removing one side of the outer cortex of the mandibular body in childhood minitype pig. But further study should be done for the cause of the lateral deviation of the mandible in part of the animals.</p>

Skeleton reconstruction of oblique facial clefts using mandibular outer table / 中华整形外科杂志

<p><b>OBJECTIVE</b>This paper presents a new method of skeleton reconstruction for oblique facial clefts using autogenous bone of the mandibular outer table.</p><p><b>METHODS</b>In the operation, the mandibular outer table was harvested through the intraoral approach. Assisted with internal rigid fixation technique, the mandibular outer table was used to reconstruct the naso-orbital framework as inlay or onlay bone graft.</p><p><b>RESULTS</b>From 1993 to 2001, seven cases of oblique facial clefts were repaired with mandibular outer table bone graft. Postoperative follow-up for 6 months to 3 years demonstrated that the grafted bone healed well with the adjacent bones. No obvious bone resorption was observed. The facial appearance was improved greatly.</p><p><b>CONCLUSIONS</b>The mandibular outer table, with similar bone density to the calvarium, is easy to harvest without donor site scar. The method is quite ideal for skeleton reconstruction of oblique facial clefts.</p>