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INTRODUCTION: Blood samples were collected to explore potential serum biomarkers associated with neurocognitive function in small-cell lung cancer (SCLC) patients who received prophylactic cranial irradiation (PCI). METHODS: This pre-specified study included patients with blood samples available, who participated in a phase III trial (NCT01780675). Blood samples were collected before PCI and 3-days post-initiating PCI. Neurocognitive decline was defined as a decrease of ≥ 5 points on total recall in the Hopkins Verbal Learning Test-Revised (HVLT-R) assessed from pre-PCI to 4-months post-PCI. Biomarkers were screened using univariate logistic regression analysis. P < .1 was considered statistically significant. RESULTS: Forty-eight enrolled patients who had blood samples at baseline were included and 27 were available for analysis as the other 21 did not assess neurocognitive function at 4-months. Lower levels of Tie-2 (OR = 0.999, 90% CI 0.998-1.000, P = .062), and higher levels of MIP-1b (OR = 1.022, 90% CI 1.000-1.044, P = .093), CCL-17 (OR = 1.004, 90% CI 1.001-1.006, P = .029), and IL-1α (OR = 1.597, 90% CI 1.077-2.367, P = .05) before PCI were correlated with neurocognitive decline at 4-months. Decrease of VEGF-C (OR = 0.972, 90% CI 0.949-0.996, P = .055), CCL-17 (OR = 0.993, 90% CI 0.988-0.999, P = .036), IL-1α (OR = 0.788, 90% CI 0.635-0.979, P = .071), and VEGF (OR = 0.981, 90% CI 0.965-0.997, P = .051) 3-days post-initiating PCI were also associated with neurocognitive decline at 4-months. CONCLUSIONS: Biomarker levels before PCI and changes in their levels 3-days post-initiating PCI may be linked to subsequent neurocognitive decline at 4-months. If validated, these biomarkers could be used to predict the risk of neurocognitive decline and act as a decision aid for personalized PCI in SCLC.

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Hepatocyte growth factor (HGF)/c-Met pathway is implicated in embryogenesis and organ development and differentiation. Germline or somatic mutations, chromosomal rearrangements, gene amplification, and transcriptional upregulation in MET or alterations in autocrine or paracrine c-Met signalling have been associated with cancer cell proliferation and survival, including in renal cell carcinoma (RCC), and associated with disease progression. HGF/c-Met pathway has been shown to be particularly relevant in tumors with bone metastases (BMs). However, the efficacy of targeting c-Met in bone metastatic disease, including in RCC, has not been proven. Therefore, further investigation is required focusing the particular role of HGF/c-Met pathway in bone microenvironment (BME) and how to effectively target this pathway in the context of bone metastatic disease.

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BACKGROUND: Hereditary hemorrhagic telangiectasia is an autosomal dominant vascular disorder caused by heterozygous, loss-of-function mutations in 4 transforming growth factor beta (TGFß) pathway members, including the central transcriptional mediator of the TGFß pathway, Smad4. Loss of Smad4 causes the formation of inappropriate, fragile connections between arteries and veins called arteriovenous malformations (AVMs), which can hemorrhage leading to stroke, aneurysm, or death. Unfortunately, the molecular mechanisms underlying AVM pathogenesis remain poorly understood, and the TGFß downstream effectors responsible for hereditary hemorrhagic telangiectasia-associated AVM formation are currently unknown. METHODS: To identify potential biological targets of the TGFß pathway involved in AVM formation, we performed RNA- and chromatin immunoprecipitation-sequencing experiments on BMP9 (bone morphogenetic protein 9)-stimulated endothelial cells (ECs) and isolated ECs from a Smad4-inducible, EC-specific knockout ( Smad4-iECKO) mouse model that develops retinal AVMs. These sequencing studies identified the angiopoietin-Tek signaling pathway as a downstream target of SMAD4. We used monoclonal blocking antibodies to target a specific component in this pathway and assess its effects on AVM development. RESULTS: Sequencing studies uncovered 212 potential biological targets involved in AVM formation, including the EC surface receptor, TEK (TEK receptor tyrosine kinase) and its antagonistic ligand, ANGPT2 (angiopoietin-2). In Smad4-iECKO mice, Angpt2 expression is robustly increased, whereas Tek levels are decreased, resulting in an overall reduction in angiopoietin-Tek signaling. We provide evidence that SMAD4 directly represses Angpt2 transcription in ECs. Inhibition of ANGPT2 function in Smad4-deficient mice, either before or after AVMs form, prevents and alleviates AVM formation and normalizes vessel diameters. These rescue effects are attributed to a reversion in EC morphological changes, such as cell size and shape that are altered in the absence of Smad4. CONCLUSIONS: Our studies provide a novel mechanism whereby the loss of Smad4 causes increased Angpt2 transcription in ECs leading to AVM formation, increased blood vessel calibers, and changes in EC morphology in the retina. Blockade of ANGPT2 function in an in vivo Smad4 model of hereditary hemorrhagic telangiectasia alleviated these vascular phenotypes, further implicating ANGPT2 as an important TGFß downstream mediator of AVM formation. Therefore, alternative approaches that target ANGPT2 function may have therapeutic value for the alleviation of hereditary hemorrhagic telangiectasia symptoms, such as AVMs.

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BACKGROUND: The Angiopoietin/Tie (Tyrosine kinase with Ig and EGF homology domains) signaling axis has crucial influences on angiogenesis and the vasculature's reorganization. Moreover, angiopoietin-2 (Ang2) is discussed as a biomarker for diseases' severity and development. Previous studies reported increased Ang2 levels in patients with inflammatory diseases and associations of Ang2 with inflammation markers in relatively small samples. We aimed to assess the relation of Ang2 and Tie2 with inflammation markers in the general population. METHODS AND RESULTS: Data of 6624 participants of the population-based Study of Health in Pomerania (SHIP-1) and the independent SHIP-Trend were used. Ang2, Tie2 and inflammatory biomarkers, including fibrinogen, high-sensitive C-reactive protein (hsCRP) and white blood cell count (WBC), were measured. Adjusted analysis of variance (ANOVA) and linear/logistic regression models were performed in the entire sample and in individuals free of hypertension and diabetes. ANOVA [adjusted means of the 1st vs. 4th Ang2 quartile: fibrinogen 3.0 vs. 3.2 g/l; hsCRP 1.2 vs. 1.6 mg/l; WBC 5.9 vs. 6.6 Gpt/l] and regression models adjusted for potential confounders revealed positive relations of Ang2 with all considered inflammation markers. These associations persisted after the exclusion of individuals with hypertension and diabetes. In contrast, Tie2 showed no clear association pattern with the investigated inflammatory markers even if a trend toward a positive relation with fibrinogen became apparent. CONCLUSION: Ang2 was positively associated with fibrinogen, hsCRP and WBC in a large population-based setting. These findings partly agree with previous results, largely obtained in clinical samples. Ang2 has diverse postulated effects on inflammation processes, like increase of vascular leakage or influences on the adhesion of leukocytes to the vessel wall. The proinflammatory character of these effects is similar to these of fibrinogen which conforms to our findings of relations between the markers. However, further research is needed to elucidate possible functional mechanisms.

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OBJECTIVE: To identify the intervention mechanism of the effect of electroacupuncture on the expression of Ang/Tie-2 mRNA and protein in rats with acute cerebral infarction induced by middle cerebral artery occlusion (MCAO). METHODS: Altogether 120 Wistar rats were subjected to MCAO by inserting a nylon filament, and then divided into 3 groups: control group, injured group and electroacupuncture group. The injured and electroacupuncture groups were further divided into the following 7 subgroups according to the time after MCAO: 3, 6, 12, 24 h, 3, 7 and 12 d, with 8 rats in each subgroup. The electroacupuncture group was given electroacupuncture treatment at Shuigou (GV 26) instantly after operation. The rats were killed at different time points according to their groups, and then the expression levels of Ang/Tie-2 mRNA and protein were detected using Real-Time polymerase chain reaction and immunohistochemical staining. RESULTS: The mRNA and protein expression levels of Ang/Tie-2 in the electroacupuncture group were significant higher than that in the injured group. CONCLUSION: The results suggested that electroacupuncture could significantly regulate the expression of Ang/Tie-2 mRNA and protein in the rats with acute cerebral infarction induced by MCAO, and enhance angiogenesis after ischemic penumbra.

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Objective To observe the expression changes of peripheral endothelial progenitor cells (EPCs) and Ang-1/Tie2 in patients with pulmonary arterial hypertension (PAH).Methods From Jun 2011 to Dec 2012,45 patients with PAH charged in Affiliated Hospital of Hangzhou Normal University were divided into 3 groups according to mean pulmonary arterial blood pressure (15 per group):mild(Group L),moderate(Group M),and severe(Group S),with another 15 normal people as control group(Group C).The EPCs were isolated from peripheral blood of every patient,number counting using fluorescence activated cell sorter (FACS),function test using cell culture in vitro.Expression of Ang-1 and Tie2 in the peripheral EPCs were measured by RT-PCR or Western-blot.Non normal data was analyzed by non parametric statistical test.Results The statistical discrepancy existed among Group L,M,S and the control in the number of EPCs [32.0 (27.0,37.0),26.0 (19.0,31.0),24.0 (22.0,26.0) vs 40.0 (37.0,51.0),P ＜ 0.05].The ability of migration [32.1 (26.5,37.5),26.8 (22.4,35.4),21.0 (17.8,34.0) vs 39.0 (33.3,42.4),P＜0.05] and adhesion of the EPCs [57.1(50.9,61.8),51.8(45.2,58.7),46.0 (37.2,55.1) vs 64.1 (56.2,75.0),P ＜ 0.05] among study groups and control group was different in statistic,the same with the proliferation activity of EPCs in different groups [0.6 (0.5,0.7),0.5 (0.4,0.6),0.4(0.3,0.5) vs 0.7(0.6,0.8),P ＜0.05].The mRNA expression of Ang-1 and Tie2 in Group M & S were significantly reduced compared with control [4.33 (2.49,4.62) and 2.89 (2.39,3.44) vs 5.31(3.78,6.22),P＜0.05],Tie2 mRNA[1.32(1.23,1.34)and 1.23(1.08,1.42)vs 1.49(1.25,1.66),P ＜ 0.05],and the protein expression of the phosphorylated Tie 2 in Group M &S were decreased [0.16 (0.15,0.24) and 0.12 (0.08,0.18) vs 0.22 (0.19,0.28),P ＜ 0.05].No significant difference of Ang-1 and Tie2 expression was observed between Group L and control [5.42 (4.72,5.95),1.54 (1.43,1.66) and0.23(0.19,0.33),P=0.674,0.867 and 0.674].Conelusion With the severity of PAH,the number and function of circulating EPCs decreased,as consistent with Ang-1 and Tie2 expression changes,suggesting that function decrease of EPCs in patients with PAH may be associated with the decrease of Ang-1/Tie2 expression.

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AIMS: To assess the association of circulating concentrations of angiopoietin-2 (Ang-2) and its soluble receptor Tie-2 (sTie-2) with all-cause, cardiovascular, and cancer mortality in a population-based sample. METHODS AND RESULTS: Angiopoietin-2 and sTie-2 were measured in 3220 participants (1665 women; mean age 54.4 years) in the Study of Health in Pomerania (SHIP). Multivariable adjusted hazard ratios (HRs) for mortality were estimated using Cox proportional hazard models. During a median follow-up of 6.2 years, 217 participants died. Ang-2 levels were positively associated with all-cause mortality [HR 1.29; 95% confidence interval (CI) 1.19-1.39 per 1 SD increment; P < 0.001] and cardiovascular mortality (HR 1.32; 95% CI 1.18-1.49; P < 0.001), but not with cancer mortality (HR 1.08; 95% CI 0.89-1.32; P = 0.416). Levels of sTie-2 were not significantly related to all-cause mortality (HR 1.12; 95% CI 0.98-1.27; P = 0.102). Adding Ang-2 to a prediction model for all-cause mortality with standard risk factors slightly improved discrimination (Δ Harrell's C, 0.008; P < 0.001) but not risk reclassification (continuous net reclassification improvement, -0.015; P = 0.571). CONCLUSION: In our community-based sample, higher serum Ang-2 concentrations were associated with greater risk for all-cause and cardiovascular mortality, suggesting that subtle increases in Ang-2 levels might reflect processes such as vascular remodelling that are associated with higher mortality risk. Adding Ang-2 to a mortality prediction model only modestly improved discrimination.

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Objective To investigate the effect of cerebral ischemic preconditioning (IP) on the expressions of angiopoietin-1 (Ang-1) and its receptor Tie-2 mRNA in cerebral ischemia in rats.Methods Ninety-nine Wistar rats were randomly assigned to three groups:sham operation (n =9),non-ischemic preconditioning (NIP) (n =45),and IP (n =45).The latter two groups were redivided into 5 subgroups:ischemia-reperfusion 1,3,7,14,and 21 days (n =9 in each group).A model of transient middle cerebral artery occlusion (MCAO) was induced by the intraluminal suture method for focal IP (ischemia for 10 minutes and restoring perfusion).Infarct volume was determined by 2,3,5-triphenyltetrazolium staining.The expression levels of Ang-1/Tie-2 mRNA were detected by in situ hybridization.Results The infarct volumes in the 1 -,3-,and 7-day subgroups of the IP group were significantly smaller than those in the relative subgroups of the NIP group (all P＜ 0.05).The expression of Ang-1 mRNA in the 3- and 7-day subgroups of the IP group and the expression of Tie-2 mRNA in the 1-,3-,and 7-day subgroups of the NIP group were upregulated significantly (all P ＜ 0.05).The infarct volume in the 3-day subgroup of the IP group was reduced most significantly (P ＜ 0.05).The expression of Ang-1 mRNA in the 7-day subgroup was upregulated significantly,and the peak expression of its receptor Tie-2 mRNA appeared at day 3 after IP and continued to day 7.Pearson correlation analysis showed that the expression levels of Ang-1/Tie-2 mRNA were significantly negatively correlated with infarct volume (P ＜0.01).Conclusions The expression of Ang-1/Tie-2 mRNA in the IP group was upregulated within the time window of ischemic tolerance (1 - 7 days after preconditioning),in which Ang-1 may mainly act on the later stage of the cerebral ischemic tolerance.

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Objective To investigate the correlation of the expressions of angiopoietin-2 (Ang-2) and angiopoietin-2 receptor(Tie-2)in serum and placenta with preeclampsia. Methods From May 2009 to April 2010, 62 women with preeclampsia who delivered in Affiliated Hospital of Qingdao University Medical College were recruited in the study, including 30 women with moderate preeclampsia (MPE group) and 32 women with severe preeclampsia (SPE group). Another 30 healthy pregnant women were taken as control group. ELISA was used to measure the serum Ang-2 in these women. Semiquantitative reverse transcription (RT)-PCR was used to investigate the expressions of Ang-2 mRNA and Tie-2 mRNA in placenta. Western blot was used to determine the expression of Ang-2 protein in placenta. Results (1) The serum concentrations of Ang-2 in MPE group and SPE group were (5.4 ± 1.8) μg/L and (5. 1 ± 1.7) μg/L,respectively. Both were significantly lower than that in control group (16. 2 ± 4. 5) μg/L (P<0. 01).There was no significant difference between MPE group and SPE group (P > 0. 05). (2) The expressions of Ang-2 mRNA in placenta of MPE group (2. 1 ± 0. 7) and SPE group (2. 0 ± 0. 6) were both significantly lower than that of control group (5.8 ± 0. 8; P<0. 01). But there was no significant difference in Ang-2 mRNA expression between MPE group and SPE group (P>0. 05). (3) No significant difference was found in the expressions of Tie-2 mRNA in placenta among MPE group (1. 33 ±0. 04), SPE group (1.35 ±0. 05) and control group (1.34 ± 0. 04; P > 0. 05). (4) The expressions of Ang-2 protein in placenta of MPE group (2.0 ± 0. 8) and SPE group (2. 0 ± 0. 8) were both significantly lower than that of control group (5.7 ±0. 9; P <0. 0l), while no significant difference was found between MPE group and SPE group (P >0. 05) . (5) In MPE group and SPE group, the serum concentrations of Ang-2 were positively correlated with the levels of Ang-2 mRNA and Ang-2 protein in placenta(r =0. 651, 0. 627; P <0. 01). Conclusions Decreased expressions of Ang-2 mRNA and Ang-2 protein in placenta reduced serum concentration of Ang-2. Low expression of Ang-2 may be involved in the pathophysiological process of preeclampsia by affecting the formation of placenta in early pregnancy.

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Angiopoietin-2 levels were 5. 80 ( 3. 83-8. 00 ) , 4. 42 ( 2. 56-5. 55 ) , and 2. 75 ( l. 40-4. 64 )ng/ml in type 2 diabetic patients with proliferative retinopathy, patients with non-proliferative retinopathy, and patients without retinopathy, respectively. Statistical significances existed between any two groups (all P ＜0. 01 ). Angiopoietin-1 level in patients with non-proliferative retinopathy was higher than that in patients without retinopathy [10. 57 ( 8. 99-12. 05 ) vs 9. 21 (7. 71-11.2 ) ng/ml, P＜0. 05]. No difference in receptor Tie-2 was found among the 3 groups (P＞0. 05 ). The results suggested that serum angiopoietin-2 level might be associated with the severity of retinopathy in type 2 diabetic patients.

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Angiopoietin-1 (Ang1) binds to and activates Tie2 receptor tyrosine kinase. Ang1-Tie2 signal has been proposed to exhibit two opposite roles in the controlling blood vessels. One is vascular stabilization and the other is vascular angiogenesis. There has been no answer to the question as to how Tie2 induces two opposite responses to the same ligand. Our group and Dr. Alitalo's group have demonstrated that trans-associated Tie2 at cell-cell contacts and extracellular matrix (ECM)-anchored Tie2 play distinct roles in the endothelial cells. The complex formation depends on the presence or absence of cell-cell adhesion. Here, we review how Ang1-Tie2 signal regulates vascular maintenance and angiogenesis. We further point to the unanswered questions that must be clarified to extend our knowledge of vascular biology and to progress basic knowledge to the treatment of the diseases in which Ang1-Tie2-mediated signal is central.

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Inflammation of the asthmatic airway is usually accompanied by increased vascular permeability and plasma exudation. Angiopoietin-1 (Ang1) has potential therapeutic applications in preventing vascular leakage. Recently, we developed a soluble, stable, and potent Ang1 variant, COMP-Ang1. COMP-Ang1 is more potent than native Ang1 in phosphorylating the tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 receptor in lung endothelial cells. We have used a mouse model for allergic airway disease to determine effects of COMP-Ang1 on allergen-induced bronchial inflammation and airway hyper-responsiveness. These mice develop the following typical pathophysiological features of allergic airway disease in the lungs: increased numbers of inflammatory cells of the airways, airway hyper-responsiveness, increased levels of Th2 cell cytokines (IL-4, IL-5, and IL-13), adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1), and chemokines (eotaxin and RANTES), and increased vascular permeability. Intravenous administration of COMP-Ang1 reduced bronchial inflammation and airway hyper-responsiveness. In addition, the increased plasma extravasation in allergic airway disease was significantly reduced by the administration of COMP-Ang1. These results suggest that COMP-Ang1 attenuates airway inflammation and hyper-responsiveness, prevents vascular leakage, and may be used as a therapeutic agent in allergic airway disease.

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PURPOSE: Breast carcinomas are highly malignant tumor that the angiogenesis factor, vascular endothelial growth factor and its receptors are overexpressed. To elucidate the role of Angiopoietin-2 (ANG2) and ANG2 receptor Tie-2 in invasive ductal carcinoma, we examined the expression of ANG2, and Tie-2 at the mRNA and protein levels in human breast cancer cell lines and samples. METHODS: Total RNA from 22 breast cancer patient biopsies were extracted. ANG2 and Tie-2 mRNA expression was measured by means of reverse transcription-PCR assay. RESULTS: RT-PCR indicated that the ANG2 and Tie-2 mRNA levels in carcinoma samples were significantly higher than those of the adjacent non-neoplastic breast tissues. For ANG2 and Tie-2, 41 of 71 invasive ductal carcinomass (58%) showed high expressions in Immunohistochemistry. Immunohistochemical analysis demonstrated that ANG2 and Tie-2 were expressed by both tumor cells and endothelial elements. Expression in tumor cells were confirmed by studying a panel of human breast carcinoma cell lines cultured by RT-PCR. Our study showed that the ANG2 positivity was correlated with axillary lymph node metastasis among the clinicopathological parameter and confirmed that high expressions of ANG2 correlated highly with the axillary lymph node metastases, histological grade, positive PR status, and age, and Tie-2 expression correlated significantly with the p53 status. Moreover, ANG2 and Tie-2 co-expression correlated significantly with the axillary lymph node metastases, compared with ANG2(-)/Tie-2 (-) and ANG2 (+)/Tie-2 (-) or ANG2 (-)/Tie-2 (+) cases. CONCLUSION: These findings suggested that ANG2 and Tie-2 might be involved in the progression of invasive ductal carcinomas through autocrine and paracrine signaling and that it may be clinically useful in selecting patients who could benefit from adjuvant treatment by further study.

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