Research progress of anti-vascular endothelial growth factor receptor 2 drugs in the treatment of retinal neovascularization disease / 中华眼底病杂志

Neovascularization is a characteristic manifestation of a variety of retinal diseases. Vascular endothelial growth factor (VEGF) mainly regulates the proliferation and migration of endothelial cells. VEGF receptor 2 (VEGFR2) is the main receptor to mediate this effect. The activation of downstream signals requires the binding of VEGF and VEGFR2, followed by receptor dimerization and autophosphorylation. Blocking this process and inhibiting neovascularization is very attractive treatment ideas. Monoclonal antibodies and fusion protein drugs currently used in ophthalmology can bind free VEGF. In addition, there are also macromolecular antibodies binding VEGFR2 and small molecule tyrosine kinase inhibitors, which is expected to further expand into the field of ophthalmology. Although anti-VEGFR2 therapy is a revolutionary method to inhibit neovascularization, there are no sufficient clinical evidences at present. In-depth understanding of the application status and progress of anti-VEGFR2 in the treatment of retinal neovascular diseases has important clinical significance.

Research progress of the effect of Salvia miltiorrhiza on VEGF/VEGFR in angiogenesis / 国际中医中药杂志

The signal transduction pathway of VEGF combing with vascular endothelial growth factor receptor (VEGFR) is not only key pathway to regulate angiogenesis, but also the focus of basic research and important target of clinical treatment. Salvia miltiorrhiza extract and its main compound salvianolic acid B also have two-way regulative effect on VEGF/VEGFR signal pathway in different diseases. Tanshinone Ⅰ , tanshinone Ⅱ A and cryptotanshinone could inhibit the angiogenesis throughthis pathway, and sodium tanshinone ⅡA sulfonate could promote the angiogenesis through this pathway.

Three versus five intravitreal aflibercept injections as the initial loading phase in the treatment of diabetic macular edema: one-year results / Três versus cinco injeções intravítreas de aflibercept como carga inicial do tratamento de edema macular diabético: resultados de um ano

ABSTRACT Purpose: To compare the efficacy of three initial monthly intravitreal aflibercept injections followed by pro re nata (3+PRN) dosing versus five initial monthly intravitreal aflibercept injections followed by pro re nata (5+PRN) dosing in patients with diabetic macular edema. Methods: A total of 60 treatment-naïve patients with macular edema who underwent intravitreal aflibercept injections (2 mg/0.05 mL) with at least one year of follow-up were analyzed in this retrospective and comparative study. The patients were divided into two groups according to the number of intravitreal aflibercept injections administered in the loading phase. The 3+PRN group comprised 27 patients, whereas the 5+PRN group comprised 33 patients. The visual and anatomical outcomes were compared between the two groups at baseline and at 3, 6, 9, and 12 months. Results: Both 3+PRN and 5+PRN, showed statistically significant improvements in the best-corrected visual acuity and central macular thicknesse throughout the study period (p<0.001 and, p<0.001, respectively). There were no significant differences between the two groups in terms of changes in the best-corrected visual acuity and central macular thickness (p=0.453 and, p=0.784, respectively). The mean number of intravitreal aflibercept injections was significantly greater in the 5+PRN group (6.1 ± 0.8) than in the 3+PRN group (3.9 ± 0.8) (p<0.001). Conclusion: The 3+PRN and 5+PRN regimens showed similar 12-month visual and anatomical outcomes following treatment with intravitreal aflibercept injections in patients with macular edema.

RESUMO Objetivo: Comparar a eficácia de três injeções intravítreas mensais iniciais de aflibercept, seguidas de dosagem de pro re nata (3+PRN) versus cinco injeções mensais iniciais intravítreas de aflibercept, seguidas de doses de pro re nata (5 + PRN) em pacientes com edema macular diabético. Métodos: Foram analisados neste estudo retrospectivo e comparativo 60 pacientes que não receberam tratamento prévio com edema macular e foram submetidos a injeções intravítreas de aflibercept (2 mg/0,05 mL) com pelo menos um ano de acompanhamento. Os pacientes foram divididos em dois grupos de acordo com o número de injeções intravítreas de aflibercept administradas na fase inicial. O grupo 3+PRN compreendeu 27 pacientes, enquanto o grupo 5+PRN compreendeu 33 pacientes. Os resultados visuais e anatômicos foram comparados entre os dois grupos no período inicial e aos 3, 6, 9 e 12 meses. Resultados: Tanto os grupos 3+PRN quanto 5+PRN mostraram melhoras estatisticamente significativas na acuidade visual melhor corrigida e na espessura macular central ao longo do período de estudo (p<0,001 e p <0,001, respectivamente). Não houve diferenças significativas entre os dois grupos em termos de alterações na acuidade visual melhor corrigida e na espessura macular central (p=0,453 e p=0,784, respectivamente). O número médio de injeções intravítreas de aflibercept foi significativamente maior no grupo 5+PRN (6,1 ± 0,8) do que no grupo 3+PRN (3,9 ± 0,8) (p <0,001). Conclusão: Os regimes 3+PRN e 5+PRN mostraram resultados visuais e anatômicos semelhantes em 12 meses após o tratamento com injeções intravítreas de aflibercept em pacientes com edema macular.

Survey among retina specialists in Brazil about inflammatory reactions after intravitreal antiangiogenic therapy / Levantamento entre especialistas em retina no Brasil sobre reações inflamatórias após terapia antiangiogênica intravítrea

ABSTRACT Purpose: This survey aimed at assessing the clinical characteristics of patients with inflammatory reactions after intravitreal injection of antiangiogenic agents and the techniques employed by Brazilian retina specialists. Methods: We sent an 18-item questionnaire electronically to retina specialists who are using antiangiogenic agents. We got the responses between September 21 and December 23, 2018. Results: A total of 58 retina specialists participated. Most of them were from Southeastern Brazil (50%), 82.8% were dedicated to both medical and surgical practices, and 86.2% had practiced for more than 5 years. Respondents reported a mean number of 2.14 ± 1.63 patients with inflammation, 44.8% with panuveitis, and 79.3% with onset of symptoms within 72 h. Specialists used aflibercept (53.4%), bevacizumab (29.3%), and ranibizumab (27.6%). Most patients were treated with steroid drops (70.7%), and their inflammation subsided after 11.5 ± 11.5 days (86.2% lacked irreversible complications). The specialists blamed the syringe as the cause of the inflammation in 25.9% of the cases, 41.4% used Becton-Dickinson Ultra-Fine syringes, 43.1% injected the drug at room temperature, and 37.9% removed the air (53.4% by flicking the syringe). Most specialists did not detect silicone oil (67.2%), but 17.2% of them performed vitrectomies to remove vitreous opacities. Finally, 44.8% of specialists injected the same antiangiogenic agent in an eye with prior inflammatory reaction without further inflammation. Conclusions: Most specialists reported cases of early-onset inflammation after intravitreal injection of antiangiogenic agents. The incidence of irreversible complications was low. Aflibercept was the most common agent used. The causes of inflammation remain unknown, but we formulated some relevant hypotheses.

RESUMO Objetivo: Esta pesquisa teve como objetivo avaliar as características clínicas de pacientes com reações inflamatórias após injeção intravítrea de agentes antiangiogênicos e as técnicas empregadas por especialistas em retina brasileiros. Métodos: Enviamos eletronicamente um questionário de 18 itens para especialistas em retina que usam agentes antiangiogênicos. Recebemos as respostas entre 21 de setembro e 23 de dezembro de 2018. Resultados: Um total de 58 especialistas em retina participaram. A maioria era do Sudeste do Brasil (50%), 82,8% eram dedicados a práticas médicas e cirúrgicas e 86,2% praticavam há mais de 5 anos. Os entrevistados informaram um número médio de 2,14 ± 1,63 pacientes com inflamação, 44,8% com panuveíte e 79,3% com início dos sintomas dentro de 72 horas. Especialistas utilizaram aflibercepte (53,4%), bevacizumabe (29,3%) e ranibizumabe (26=7,6%). A maioria dos pacientes foi tratada com colírios de esteroides (70,7%), e sua inflamação diminuiu após 11,5 ± 11,5 dias (86,2% não apresentaram complicações irreversíveis). Os especialistas responsabilizaram a seringa como causa da inflamação em 25,9% dos casos, 41,4% usaram seringas Becton-Dickinson Ultra-Fine, 43,1% injetaram a droga em temperatura ambiente e 37,9% removeram o ar (53,4% sacudindo a seringa). A maioria dos especialistas não detectou óleo de silicone (67,2%), mas 17,2% realizaram vitrectomias para remoção de opacidades vítreas. Finalmente, 44,8% dos especialistas injetaram o mesmo agente angiogênicos em um olho com reação inflamatória prévia, sem surgimento de nova inflamação. Conclusões: A maioria dos especialistas relatou casos de inflamação de início precoce após injeção intravítrea de agentes antiangiogênicos. A incidência complicações irreversíveis foi baixa. Aflibercepte foi o agente mais frequentemente usado. As causas da inflamação permanecem desconhecidas, embora formulamos algumas hipóteses relevantes.

Different effects of pravastatin on sFlt?1, PlGF and VEGF in different preeclampsia?like mouse models / 中华妇产科杂志

Objective To explore the pathways of preeclampsia by investigating different effects of pravastatin (Pra) on and soluble FMS tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) in different preeclampsia (PE)?like mouse models. Methods C57BL/6J mice were randomly subcutaneously injected with N?nitro?L?arginine methyl ester (L?NAME) or intraperitoneally injected with lipopolysaccharide (LPS) as PE?like mouse model, saline as normal pregnancy control (Con) respectively, daily at gestational 7-18 days. Pra was given daily at gestational 8-18 days in each model group and the mice were divided into Pra (L?NAME+Pra, LPS+Pra, Con+Pra) and saline (L?NAME+NS, LPS+NS, Con+NS) groups. Liver,placental tissue and blood of pregnant mice were collected on the 18th day of pregnancy. The levels of VEGF, PlGF and sFlt?1 in the liver, placenta and serum of mice in each group were compared by western blot, ELISA and real?time fluorescence quantitative PCR (RT-PCR). Results (1) ELISA: Serum VEGF (205.70±3.43, 154.60±2.31) and PlGF (131.5±3.75, 101.50± 4.31) levels were significantly increased in L?NAME+Pra group compared with L?NAME+NS group (all P<0.05). Serum VEGF (202.30 ± 4.90, 144.50 ± 6.71) and PlGF (121.50 ± 3.86, 95.41 ± 4.08) levels were significantly higher in LPS+Pra group than those in LPS+NS group (all P<0.05). Serum sFlt?1 level in LPS+Pra group was significantly lower than that in LPS+NS group (3.01±0.50, 776.60±80.06), serum sFlt?1 level in L?NAME+Pra group was significantly lower than that in L?NAME+NS group (2.60±0.06, 583.70±9.83;all P<0.05). (2) Western blot: the expression levels of PlGF (1.344±0.118, 0.664±0.143) and VEGF (1.34±0.12, 0.66 ± 0.14) in the liver of mice in the L?NAME+Pra group were significantly higher than those in the L?NAME+NS group (all P<0.05), but the expression levels of PlGF and VEGF in the placenta of L?NAME+Pra group were not significantly different from those of L?NAME+NS group (all P>0.05). The expression levels of PlGF and VEGF in placenta and liver of pregnant mice in LPS+Pra group were not significantly different from those in LPS+N group (all P>0.05). (3) RT?PCR: the mRNA expression of PlGF and VEGF in placenta and liver of L?NAME+Pra group were not significantly different from those in L?NAME+NS group (all P>0.05). The mRNA expression levels of PlGF and VEGF in placenta and liver of LPS+Pra group were not significantly different from those of LPS+NS group (all P>0.05). Conclusions Pra has different regulatory effects on vascular endothelial function in different PE?like models. It reveals that different pathogenesis and pathways exist in different PE?like changes.

Short-term clinical efficacy and analysis of quality of life of anlotinib in third-line and above treatment for advanced non-small cell lung cancer / 国际肿瘤学杂志

Objective To evaluate the short-term efficacy,safety and impact on the quality of life of anlotinib in third-line and above treatment for advanced non-small cell lung cancer (NSCLC) patients.Methods All the patients received alotinib 12 mg/d.One cycle was defined as 2 weeks on-treatment followed by 1 week off-treatment until disease progression or treatment intolerance.Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was used to assess tumor responses.Common Terminology Criteria for Adverse Events (CTCAE) 4.02 was used to assess the adverse events.The European Organization for Research on Treatment of Cancer (EORTC) QLQ-C30 and QLQ-LC13 were used to assess quality of life.Results Among 27 patients in study,no complete response (CR) was found,2 patients (7.4％) achieved partial response (PR),16 patients (59.3％) achieved stable disease (SD),9 patients (33.3％) achieved progressive disease (PD),objective response rate (ORR) was 7.4％,and disease control rate (DCR) was 66.7％.The scores of physical functioning (76.00 ± 10.55 vs.64.44 ± 11.59),emotional functioning (81.67 ± 8.71 vs.76.11 ±6.71) and global health status (48.87 ±7.97 vs.40.56 ± 12.49) of the QLQ-C30 scale after treatment were higher than those before treatment,with statistically significant differences (t =-4.516,P ＜0.001;t=-2.646,P=0.019;t=-3.872,P=0.002).Fatigue (50.37±8.95 vs.40.74±13.86),nausea and vomiting (26.54 ± 16.18 vs.14.20 ± 11.97),loss of appetite [M(QR):33.33 (33.33) vs.33(33.33)] were better than before (t =-2.476,P =0.027;t =-5.036,P ＜0.001;Z =-2.923,P =0.003);pain (28.88 ± 14.23 vs.33.33 ± 13.60) and dyspnea [33.33 (33.33) vs.33.33 (66.67)] scores were lower than before (t =3.674,P =0.003;Z =-3.266,P =0.001).The scores of cough (24.44 ±19.12 vs.45.24 ±20.34),shortness of breath [11.11(22.22) vs.33.33(22.22)] and chest pain [0.00(33.33)vs.33.33 (33.33)] in the QLQ-LC13 scale after treatment were lower than those before treatment,with statistically significant differences (t =4.000,P =0.001;Z =-4.125,P ＜0.001;Z =-1.890,P =0.034);the scores of sore mouth or tongue [0.00(33.33) vs.0.00(0.00)] and hands and feet tingling [33.33(33.33) vs.0.00(0.00)] were higher than before (Z=-2.000,P=0.046;Z=-2.264,P=0.024).Common adverse reactions included hypertension,fatigue,elevated thyroid stimulating hormone,proteinuria,hand-foot syndrome,oral mucositis,hemoptysis,etc,mainly grade 1-2,and they were all improved after the treatments.Conclusion Anlotinib as a third-line and further therapy is positive effected and well tolerated.It can alleviate the clinical symptoms and significantly improve the quality of life of NSCLC patients.

Expression of vascular endothelial growth factor receptors and invasion and metastasis of hepatocellular carcinoma / 临床肝胆病杂志

Vascular endothelial growth factor receptors (VEGFRs) consist of three receptor tyrosine kinase (RTK) superfamily members and two non-RTK superfamily members and bind to the ligand in a non-one-to-one way. VEGFRs mediate various signaling pathways such as Raf1→MAP2K1/2→ERK1/2 through cell surface receptor internalization and thus promote the proliferation of hepatocellular carcinoma cells, angiogenesis, and lymphangiogenesis. VEGFRs can be highly expressed in local cancerous lesions of liver cancer patients, which is a key factor mediating malignant proliferation, invasion, and metastasis of hepatocellular carcinoma, and the expression of VEGFRs is negatively correlated with progression-free survival. Matrix metalloproteinase-9 and heat shock protein 90β can upregulate VEGFRs to promote the proliferation and metastasis of hepatoma cells, while miR-203a, miR-378a, and miR-199a-3p can downregulate VEGFR expression and inhibit hepatoma cell infiltration. Targeted drug therapy based on VEGFR can induce the apoptosis of hepatoma cells, block tumor angiogenesis, and delay disease progression.

Different effects of pravastatin on sFlt-1, PlGF and VEGF in different preeclampsia-like mouse models / 中华妇产科杂志

Objective@#To explore the pathways of preeclampsia by investigating different effects of pravastatin (Pra) on and soluble FMS tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) in different preeclampsia (PE)-like mouse models.@*Methods@#C57BL/6J mice were randomly subcutaneously injected with N-nitro-L-arginine methyl ester (L-NAME) or intraperitoneally injected with lipopolysaccharide (LPS) as PE-like mouse model, saline as normal pregnancy control (Con) respectively, daily at gestational 7-18 days. Pra was given daily at gestational 8-18 days in each model group and the mice were divided into Pra (L-NAME+Pra, LPS+Pra, Con+Pra) and saline (L-NAME+NS, LPS+NS, Con+NS) groups. Liver,placental tissue and blood of pregnant mice were collected on the 18th day of pregnancy. The levels of VEGF, PlGF and sFlt-1 in the liver, placenta and serum of mice in each group were compared by western blot, ELISA and real-time fluorescence quantitative PCR (RT-PCR).@*Results@#(1) ELISA: Serum VEGF (205.70±3.43, 154.60±2.31) and PlGF (131.5±3.75, 101.50±4.31) levels were significantly increased in L-NAME+Pra group compared with L-NAME+NS group (all P<0.05). Serum VEGF (202.30±4.90, 144.50±6.71) and PlGF (121.50±3.86, 95.41±4.08) levels were significantly higher in LPS+Pra group than those in LPS+NS group (all P<0.05). Serum sFlt-1 level in LPS+Pra group was significantly lower than that in LPS+NS group (3.01±0.50, 776.60±80.06), serum sFlt-1 level in L-NAME+Pra group was significantly lower than that in L-NAME+NS group (2.60±0.06, 583.70±9.83; all P<0.05). (2) Western blot: the expression levels of PlGF (1.344±0.118, 0.664±0.143) and VEGF (1.34±0.12, 0.66±0.14) in the liver of mice in the L-NAME+Pra group were significantly higher than those in the L-NAME+NS group (all P<0.05), but the expression levels of PlGF and VEGF in the placenta of L-NAME+Pra group were not significantly different from those of L-NAME+NS group (all P>0.05). The expression levels of PlGF and VEGF in placenta and liver of pregnant mice in LPS+Pra group were not significantly different from those in LPS+N group (all P>0.05). (3) RT-PCR: the mRNA expression of PlGF and VEGF in placenta and liver of L-NAME+Pra group were not significantly different from those in L-NAME+NS group (all P>0.05). The mRNA expression levels of PlGF and VEGF in placenta and liver of LPS+Pra group were not significantly different from those of LPS+NS group (all P>0.05).@*Conclusions@#Pra has different regulatory effects on vascular endothelial function in different PE-like models. It reveals that different pathogenesis and pathways exist in different PE-like changes.

Inhibitory effect of luteolin on the growth, migration and vasculogenic mimicry formation of a melanoma cell line B16 / 中华皮肤科杂志

Objective To evaluate the effect of luteolin on the growth,migration and vasculogenic mimicry formation of a melanoma cell line B16.Methods In vitro cultured B16 melanoma cells were divided into 4 groups:low-,middle-and high-dose luteolin groups treated with 2.5,5,10 μmol/L luteolin respectively,and control group treated with 0.1％ dimethyl sulfoxide (DMSO).Scratch assay,Transwell invasion assay and vascular channel formation assay were performed to assess the migration,invasion of and vascular channel formation by melanoma cells.A model of subcutaneous transplanted B 16 melanoma was established in 12 C57 mice,which were randomly and equally divided into 4 groups:control group gavaged with ultrapure water,low-,middle-and high-dose luteolin groups gavaged with 10,20,40 mg/kg luteolin respectively every day.The above treatment for the tumor-bearing mice lasted till day 28,and then these mice were sacrificed.Meanwhile,the lung and tumor tissues of the mice were excised,and the growth,metastasis and vasculogenic mimicry of transplanted melanoma were observed.Immunofluorescence and immunohistochemical studies were performed to evaluate the effects of luteolin on the expression of vascular endothelial cadherin (VE-cadherin),vascular endothelial growth factor receptor 1 (VEGFR1),VEGFR2,matrix metalloproteinase-2 (MMP-2) and MMP-9 in the transplanted melanoma.Means were compared among several groups by using one-way analysis of variation or rank sum test.Results In vitro study showed that the relative scratch width at 48 hours significantly differed among the control group,low-,middle-and high-dose luteolin groups (0.47 ± 0.04,0.64 ± 0.04,0.73 ± 0.03,0.84 ± 0.04 respectively;F =34.51,P ＜ 0.001),and the migration ability of B16 cells was significantly lower in the low-,middle-and high-dose luteolin groups than in the control group (all P ＜ 0.05).At 24 hours,there were significant differences in the number of cells crossing the Transwell membrane among the control group,low-,middle-and high-dose luteolin groups (281.00 ± 8.79,169.00 ± 15.35,92.00 ± 14.79 and 57.00 ± 13.72 respectively;F =275.30,P ＜ 0.001),and the invasive ability was significantly lower in the low-,middle-and high-dose luteolin groups than in the control group (P ＜ 0.01).Meanwhile,the number of formed vascular channels also differed among the above 4 groups (20.00 ± 2.77,11.00 ± 1.28,7.00 ± 1.86 and 2.00 ± 1.32 respectively;F =48.61,P ＜ 0.001),and the number of vascular channels was significantly lower in the low-,middle-and high-dose luteolin groups than in the control group (all P ＜ 0.01).In vivo study showed that the tumor size significantly differed among the control group,low-,middle-and high-dose luteolin groups (5.10 ± 1.72,4.02 ± 2.13,2.98 ± 0.92,1.49 ± 1.13 cm3 respectively;F =28.76,P ＜ 0.001),and was significantly lower in the low-,middle-and high-dose luteolin groups than in the control group (t =3.86,7.11 and 13.06 respectively,all P ＜ 0.01).CD31-PAS double staining showed that the number of vasculogenic mimicry was significantly higher in the control group than in the low-,middle-and high-dose luteolin groups (all P ＜ 0.01).In vivo and in vitro studies both showed that the expression of vasculogenic mimicry-related markers in the cells or mouse tumor tissues was significantly lower in the high-dose luteolin group than in the control group (P ＜ 0.05).Conclusion Luteolin can effectively inhibit the growth,metastasis and vasculogenic mimicry formation of melanoma.

Research advances of cancer therapy targeting HIF-1α-VEGF-VEGFR-2 signaling pathway for malignant tumors / 国际肿瘤学杂志

Hypoxia inducible factor-1α (HIF-1α)-vascular endothelial growth factor (VEGF)-vascular endothelial growth factor receptor-2 (VEGFR-2) signaling pathway plays a vital role in the regulation of neovascularization,and the activation of this pathway is closely related with tumor invasion and metastasis.

Efficacy of VEGF and VEGFR pathway inhibitors in the treatment of advanced gastric cancer / 国际肿瘤学杂志

Anti-neovascularization is an important research direction in the current treatment of gastric cancer.The inhibitors of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) are main research focus.At present,the inhibitors of the pathways of VEGF and VEGFR in the treatment of advanced gastric cancer include bevacizumab,ramucirumab,apatinib,regorafenib,sorafenib,et al.These drugs provide more possibilities for the treatment of advanced gastric cancer.

Role of vascular endothelial growth factor and its receptors in the corneal tissue and corneal lesions / 中国组织工程研究

BACKGROUND: Vascular endothelial growth factors are a family of multifunctional cytokines that can enhance vascular permeability, induce angiogenesis, promote endothelial cel growth and migration, and inhibit cel apoptosis. OBJECTIVE:To elaborate the latest progress in the role of vascular endothelial growth factor and its receptors in the corneal tissue. METHODS:A computer-based search of PubMed databases was performed for relevant articles published from 2005 to 2015. The key words were “vascular endothelial growth factor, cornea”. According to the inclusion and exclusion criteria, 43 articles were included in result analysis. RESULTS AND CONCLUSION:Vascular endothelial growth factor and its receptors are involved in the regulation of corneal neovascularization by causing Tip cel activation that affects the Notch signaling pathways. Corneal lymphatic regeneration mainly relies on macrophages to secrete vascular endothelial growth factor-C or vascular endothelial growth factor-D that further activate vascular endothelial growth factor receptor-3 in the lymphatic endothelial cels to cause cel proliferation and migration, and eventualy lead to the formation of new lymphatic vessels. But herpes simplex keratitis HSK induces the corneal lymphatic regeneration by vascular endothelial growth factor-A/vascular endothelial growth factor receptor-2 pathway. Vascular endothelial growth factor family can significantly improve the damaged corneal nerve endings, epithelium and corneal sensitivity, has the function of nerve nutrition and promote restoration of the corneal epithelium.

The expressions of vascular endothelial growth factor receptor and Periostin in floor-of-mouth squamous cancer and its clinical significance / 中国医师进修杂志

Objective To investigate the mRNA expressions of vascular endothelial growth factor receptor (VEGFR) and Periostin in floor-of-mouth squamous cancer and explore its clinical significance.Methods Cancer tissues of 64 floor-of-mouth squamous cancer patients were enrolled as observation group,and the adjacent normal tissues were collected as control group.The mRNA expressions of VEGFR and Periostin were detected by fluorescent quantitation PCR analysis.Results The mRNA expressions of VEGFR and Periostin in observation group were significantly higher than those in control group (0.514 ±0.142 vs.0.204 ± 0.086 and 0.502 ± 0.125 vs.0.184 ± 0.064,P ＜ 0.01).The mRNA expressions of VEGFR and Periostin had no significantly related with gender,and they were significantly related with histological grade,lymphatic metastasis and clinical pathologic stage (P ＜ 0.05).The mRNA expression of VEGFR was significantly positive related with the mRNA expressions of Periostin in floor-of-mouth squamous cancer tissues (r =0.624,P ＜0.01).Conclusions VEGFR and Periostin maybe play a key role in the development of floor-of-mouth squamous cancer,and be used as the markers for estimating the degree of differentiation of floor-of-mouth squamous cancer.

Effect of artesunat on the expression of vascular endothelial growth factor and vascular endothelial growth factor receptors in SHI-1 cell line / 白血病·淋巴瘤

ObjectiveTo investigate the effect of artesunate on the expression of vascular endothlial growth factors(VEGF)and VEGFR in SHI-1 cell line.MethodsEnzyme-linked immunosorbent assay analysis was performed to detect the amount of VEGF in culture supernatants of SHI-1 cell in the condition of artesunate or not. The expression of VEGFR1 and VEGFR2 in SHI-1 cell in the condition of artesunate or not were detected by flow cytometry.ResultsWithout artesunate,the concentration of VEGF in the culture supernatant of SHI-1 cell were (980.3±2.2) pg/ml in 24 h and (982.4±2.3) pg/ml in 48 h. The expression of VEGFRI in SHI-1 cell were (6.40±3.11) ％ in 24 h and (6.45±2.85) ％ in 48 h. The expression of VEGFR2 in SHI-1 cell were (13.90±2.26) ％ in 24 h and (13.95±1.96) ％ in 48 h. With artesunate at 5, 10, 20 ng/ml, the concentration of VEGF in culture supematant of SHI-1 cell were (234.6±1.8)pg/ml, (114.9±1.6)pg/ml, (108.8±1.5) pg/ml in 24 h and (62.3±1.7) pg/ml, (60.9±1.6) pg/ml, (32.7±1.7) pg/ml in 48 h, respectively. The levels of VEGF in SHI-1 cells treated with artesunate at different concentrations decreased significantly (P ＜0.05).There was significant difference between 24 hours group and 48 hours group(P ＜0.05).The expression of VEGFR1 in SHI-1 cell were (4.30±2.21) ％, (4.20±1.37) ％, (3.90±1.86) ％ in 24 h and (3.80±2.87) ％, (3.60±1.73) ％, (3.00±1.82) ％ in 48 h, respectively. The expression of VEGFR1 in SHI-1 cell treated with artesunate at different concentrations were not significantly different (P ＞0.05). No significant difference between 24 hours group and 48 hours group was observed (P ＞0.05). VEGFR2 expression of SHI-1 cell were(4.40±1.15) ％, (3.10±0.68) ％, (1.10±0.72) ％ in 24 h and (3.00±1.68) ％, (2.20±0.93) ％, (0.60±0.92) ％ in 48 h, respectively. The results indicated that the expression of VEGFR2 in SHI-1 cells treated with artesunate at different concentrations reduced significantly (P ＜0.05),but there was no significant difference between 24 h group and 48 h group (P ＞0.05). ConclusionThe concentration of VEGF in SHI-1 cell was high, and artesunate can down-regulate the expression of VEGF and VEGFR2,but the effect of artesunate on the VEGFR1 was not significant.

Treatment effect and influence on the level of angiogenesis-associated factors in acute leukemia treated by thalidomide / 白血病·淋巴瘤

Objective To observe on the clinical effect and the influence of the level of plasma vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR) and basic fibroblast growth factor (bFGF) in acute leukemia before and after treatment by thalidomide combined with chemotherapy. Methods Thirty-six cases of acute leukemia patients were randomly divided into experimental group and control group by 18 cases each. Each group was treated with conventional chemotherapy in the standard-dose, meanwhile in the experimental group additional thalidomide 100 mg/day were taken orally. Before treatment and 8 weeks after treatment, plasma were collected for the detection of VEGF, VEGFR and bFGF content by double antibody sandwich enzyme-linked immunosorbent assay (ELISA).Results The ratio of experimental group and control group, were 88.9 % (16/18), 77.8 % (14/18)respectively and the difference was statistically significant (x2 =4.103, P ＜0.05). The level of plasma VEGF (389.78+249.94 pg/ml, 318.54±125.78 pg/ml) of experimental group and control group before treatment was statistically significant (t = 3.141, t =3.024, P ＜0.01) compared with healthy group [(132.91±26.66) pg/ml] respectively. The level of plasma VEGF of those groups after treatment [(211.74+36.72) pg/ml, (288.02±31.77) pg/ml] was statistically significant (t =2.413, t =2.324, P ＜0.05) compared with healthy group respectively. The difference of the level of plasma VEGF of experimental group and control group before treatment was not statistically significant (t =1.384, P ＞0.05). The difference of the level of plasma VEGF of experimental group and control group after treatment was statistically significant(t =2.793,P ＜0.05). The level of plasma VEGFR [(2490.75+1695.9) pg/ml, (2322.78+1105.87) pg/ml] of experimental group and control group before treatment was statistically significant (t =2.914, t =2.783, P ＜0.01) compared with healthy group [(1134.98+378.45) pg/ml] respectively. The level of plasma VEGFR of those groups after treatment [(1359.71± 390.24) pg/ml, (1753.89±337.04) pg/ml] was statistically significant(t =2.572, t =2.447, P ＜0.05) compared with healthy group respectively. The difference of the level of plasma VEGFR of experimental group and control group before treatment was not statistically significant (t =1.276, P ＞0.05). The difference of the level of plasma VEGFR of experimental group and control group after treatment was statistically significant (t = 2.486, P ＜0.05). The level of plasma bFGF [(2.43±0.27) ng/ml, (2.41±0.33) ng/ml] of experimental group and control group before treatment was statistically significant(t =4.982, t =4.171, P ＜0.05) compared with healthy group (1.83±0.44) ng/ml respectively; the level of plasma bFGF of those groups after treatment [(2.09±0.17) ng/ml,(2.11±0.31) ng/ml] was statistically significant (t =3.011, t =2.773, P ＜0.05) compared with healthy group respectively. The difference of the level of plasma bFGF of experimental group and control group before treatment was not statistically significant (t =0.953, P ＞0.05). The difference of the level of plasma bFGF of experimental group and control group after treatment was not statistically significant (t =1.282, P ＞0.05).Conclusion The remission rate could be improved by thalidomide combined with chemotherapy in acute leukemia, which could be an effective treatment by anti-angiogenesis and inhibiting the growth and infiltration of acute leukemia cells.

Roles of VEGF and Dll4-Notch signaling pathways in tumor angiogenesis / 国际肿瘤学杂志

Anti-angiogenesis therapies have emerged as new treatment strategies for several types of tumors. To date, the most studied programs are to find out effective medicines to block the vascular endothelial growth factor (VEGF) signaling pathway. However, VEGF inhibitors are not effective to all kinds of tumors.Thus there is a need to explore other angiogenesis signaling pathways. Recently, the Dll4-Notch pathway was identified as a new target in tumor angiogenesis. Moreover, an important feature in angiogenesis is the manifold ways in which the VEGF and Dll4-Notch pathways interact each other, which play critical roles in tumor angiogenesis. Therefore, the further exploration of these two pathways will provide more therapies for clinic to treat tumors.

A serum-stable branched dimeric anti-VEGF peptide blocks tumor growth via anti-angiogenic activity

Angiogenesis is critical and indispensable for tumor progression. Since VEGF is known to play a central role in angiogenesis, the disruption of VEGF-VEGF receptor system is a promising target for anti-cancer therapy. Previously, we reported that a hexapeptide (RRKRRR, RK6) blocked the growth and metastasis of tumor by inhibiting VEGF binding to its receptors. In addition, dRK6, the D-form derivative of RK6, retained its biological activity with improved serum stability. In the present study, we developed a serum-stable branched dimeric peptide (MAP2-dRK6) with enhanced anti-VEGF and anti-tumor activity. MAP2-dRK6 is more effective than dRK6 in many respects: inhibition of VEGF binding to its receptors, VEGF- and tumor conditioned medium-induced proliferation and ERK signaling of endothelial cells, and VEGF-induced migration and tube formation of endothelial cells. Moreover, MAP2-dRK6 blocks in vivo growth of VEGF-secreting colorectal cancer cells by the suppression of angiogenesis and the subsequent induction of tumor cell apoptosis. Our observations suggest that MAP2-dRK6 can be a prospective therapeutic molecule or lead compound for the development of drugs for various VEGF-related angiogenic diseases.

Vascular endothelial growth factor and cerebral infarction / 国际脑血管病杂志

Vascular endothelial growth factor is a vascular endothelial cell-specific mitogen.It is the most important angiogenic factor.VEGF expresses highly after cerebral infarction.It plays importmt roles in angiogenesis and neuroprotection.At the same time,its overexpression will also increase vascular permeability;thereby it may aggravate brain edema.This article reviews the advances in research on VEGF and its receptors and cerebral infarction.

Targeted killing of malignant melanoma cells by aclarubicin liposome conjugated with vascular endothelial growth factor / 中华皮肤科杂志

Objective To evaluate the targeted killing of malignant melanoma cells by aclarubicin liposomes conjugated with vascular endothelial growth factor(ADM-VEGF-SSL)in vitro.Metheds To detect the binding abilitv of liposomes to malignant melanoma(MM)cells,the human malignant melanoma cell line A375 was cultured in the presence of ADM-VEGF-3H-SSL or ADM-3H-SSL for 2 days followed by the detection of radioactivity of these cells.Then.A375 cells were cultured with various concentrations(0.01,0.1,1,10,100 mol/L)of ADM-VEGF-SSL,ADM-SSL or free ADM for 48 hours in the 48-hour cytotoxity test,or for 0.5 hour followed by another 48-hour culture in drug-free medium in the 0.5-hour cytotoxity test.After that,MTT assay was used to detect the survival rate of these cells.Results ADM-VEGF-SSL could specifically bind to and kill A375 cells.The binding rate of ADM-VEGF-SSL was 2.15 folds as high as that of ADM-SSL.The survival rate of A375 cells after being treated with ADM-VEGF-SSL for 48 hour was similar to that with flee ADM(P＞0.05).but lower than that with ADM-SSL(P＜0.05),while the survival rate of melanocytes treated with ADM-VEGF-SSL was higher than that with free ADM or ADM-SSL(both P＜0.05).As shown by the 0.5-hour cytotoxity test.shortening the treatment course did not attenuate the effect of ADM-VEGF-SSL on A375 cells.Conclusions ADM-VEGF-SSL can specifically recognize A375 cells.efficiently deliver adriamycin into tumor cells,markedly inhibit the proliferation of A375 cells,and eventually,a targeted kill of these cells is realized.

Expression of PTEN and VEGF gene in laryngeal squamous cell carcinoma and their clinical significance / 中国耳鼻咽喉头颈外科

OBJECTIVE To investigate the expression of PTEN and VEGF gene in laryngeal squamous cell carcinoma and their clinical significance. METHODS The expression of PTEN and VEGF gene were examined by using immunohistochemical S-P staining method in 10 cases of normal tissues, 20 cases of para-tumor tissues and 60 cases of LSCC. RESULTS The positive rates of PTEN in normal tissues, para-tumor tissues and LSCC were 100.0 %, 95.0 %, and 70.0 % respectively (P＜0.05),and VEGF protein showed positive expression of 20.0 %,50.0 %,73.3% in normal, para-tumor and LSCC tissues with statistical significance(P＜0.05), In LSCC, the expression of PTEN and VEGF was positively correlated with TNM stage, differentiation of tumor, cervical and distant metastasis of lymph node, 3-year survive rate of patients(P＜0.05),No significant association was observed in expression of PTEN and VEGF with tumor location,patient's age and sex(P＞0.05). Spearman correlation analysis revealed that PTEN was negatively correlated with VEGF expression(?=-0.3948, P=0.0018). CONCLUSION The aberrant expression of PTEN and VEGF may play a role in occurrence, progression and metastasis of LSCC.