Clinical significance of VEGF-A, -C and -D expression in esophageal malignancies

Vascular endothelial growth factors ( VEGF)- A, - C and - D are members of the proangiogenic VEGF family of glycoproteins. VEGF-A is known to be the most important angiogenic factor under physiological and pathological conditions, while VEGF-C and VEGF-D are implicated in the development and sprouting of lymphatic vessels, so called lymphangiogenesis. Local tumor progression, lymph node metastases and hematogenous tumor spread are important prognostic factors for esophageal carcinoma ( EC), one of the most lethal malignancies throughout the world. We found solid evidence in the literature that VEGF expression contributes to tumor angiogenesis, tumor progression and lymph node metastasis in esophageal squamous cell carcinoma ( SCC), and many authors could show a prognostic value for VEGF-assessment. In adenocarcinoma (AC) of the esophagus angiogenic properties are acquired in early stages, particularly in precancerous lesions like Barrett's dysplasia. However, VEGF expression fails to give prognostic information in AC of the esophagus. VEGF-C and VEGF-D were detected in SCC and dysplastic lesions, but not in normal mucosa of the esophagus. VEGF-C expression might be associated with lymphatic tumor invasion, lymph node metastases and advanced disease in esophageal SCC and AC. Therapeutic interference with VEGF signaling may prove to be a promising way of anti-angiogenic co-treatment in esophageal carcinoma. However, concrete clinical data are still pending

Inhibition of the tyrosine phosphatase SHP-2 suppresses angiogenesis in vitro and in vivo

Endothelial cell survival is indispensable to maintain endothelial integrity and initiate new vessel formation. We investigated the role of SHP-2 in endothelial cell survival and angiogenesis in vitro as well as in vivo. SHP-2 function in cultured human umbilical vein and human dermal microvascular endothelial cells was inhibited by either silencing the protein expression with antisense-oligodesoxynucleotides or treatment with a pharmacological inhibitor (PtpI IV). SHP-2 inhibition impaired capillary-like structure formation (p < 0.01; n = 8) in vitro as well as new vessel growth ex vivo (p < 0.05; n = 10) and in vivo in the chicken chorioallantoic membrane (p < 0.01, n = 4). Additionally, SHP-2 knock-down abrogated fibroblast growth factor 2 (FGF-2)-dependent endothelial proliferation measured by MTT reduction ( p ! 0.01; n = 12). The inhibitory effect of SHP-2 knock-down on vessel growth was mediated by increased endothelial apoptosis ( annexin V staining, p ! 0.05, n = 9), which was associated with reduced FGF-2-induced phosphorylation of phosphatidylinositol 3-kinase (PI3-K), Akt and extracellular regulated kinase 1/2 (ERK1/2) and involved diminished ERK1/2 phosphorylation after PI3-K inhibition (n=3). These results suggest that SHP-2 regulates endothelial cell survival through PI3-K-Akt and mitogen-activated protein kinase pathways thereby strongly affecting new vessel formation. Thus, SHP-2 exhibits a pivotal role in angiogenesis and may represent an interesting target for therapeutic approaches controlling vessel growth. Copyright (C) 2007 S. Karger AG, Basel

Vascular endothelial growth factor (VEGF) upregulates BCL-2 and inhibits apoptosis in human and murine mammary adenocarcinoma cells

Tumour progression is regulated by the balance of proliferation and apoptosis in the tumour cell population. To date, the role of vascular endothelial growth factor (VEGF) in tumour growth has been attributed to the induction of angiogenesis. VEGF has been shown to be a survival factor for endothelial cells, preventing apoptosis by inducing Bcl-2 expression. In both murine (4T1) and human (MDA-MB-231) metastatic mammary carcinoma cell lines, we found that VEGF upregulated Bcl-2 expression and anti-VEGF antibodies reduced Bcl-2 expression. These alterations in Bcl-2 expression were reflected by the levels of tumour cell apoptosis. VEGF resulted in reduced tumour cell apoptosis, whereas its inhibition with anti-VEGF neutralizing antibodies induced apoptosis directly in tumour cells. Therefore, in addition to its role in angiogenesis and vessel permeability, VEGF acts as a survival factor for tumour cells, inducing Bcl-2 expression and inhibiting tumour cell apoptosis. © 2001 Cancer Research Campaign http://www.bjcancer.co

Influence of the oxygen microenvironment on the proangiogenic potential of human endothelial colony forming cells

Therapeutic angiogenesis is a promising strategy to promote the formation of new or collateral vessels for tissue regeneration and repair. Since changes in tissue oxygen concentrations are known to stimulate numerous cell functions, these studies have focused on the oxygen microenvironment and its role on the angiogenic potential of endothelial cells. We analyzed the proangiogenic potential of human endothelial colony-forming cells (hECFCs), a highly proliferative population of circulating endothelial progenitor cells, and compared outcomes to human dermal microvascular cells (HMVECs) under oxygen tensions ranging from 1% to 21% O2, representative of ischemic or healthy tissues and standard culture conditions. Compared to HMVECs, hECFCs (1) exhibited significantly greater proliferation in both ischemic conditions and ambient air; (2) demonstrated increased migration compared to HMVECs when exposed to chemotactic gradients in reduced oxygen; and (3) exhibited comparable or superior proangiogenic potential in reduced oxygen conditions when assessed using a vessel-forming assay. These data demonstrate that the angiogenic potential of both endothelial populations is influenced by the local oxygen microenvironment. However, hECFCs exhibit a robust angiogenic potential in oxygen conditions representative of physiologic, ischemic, or ambient air conditions, and these findings suggest that hECFCs may be a superior cell source for use in cell-based approaches for the neovascularization of ischemic or engineered tissues

Firefly distribution and abundance on mangrove vegetation assemblages in Sepetang estuary, Peninsular Malaysia

Pteroptyx fireflies are commonly reported to congregate in large numbers in mangroves. Not much is known about the relationships between firefly distribution and abundance with specific mangrove vegetation assemblages. We conducted a study to investigate the vegetation assemblages that structure the distribution and abundance of Pteroptyx tener in Peninsular Malaysia. The distribution and abundance of fireflies were assessed along an 8 km stretch of mangroves in Sepetang estuary using visual assessment. Statistical analysis was carried out to test the correlation between length of display section and percentage cover of P. tener colonies and the relationship between percentage cover of fireflies with different vegetation assemblages. Five distinct vegetation assemblages were identified comprising different combination of four mangrove species. It was found that shorter display sections had higher percentage cover of P. tener colonies. In addition, vegetation assemblage which consisting of mainly Sonneratia caseolaris and Nypa fruticans was the most preferred type. The results of this study point to the necessity to consider not only a single mangrove species but the entire vegetation assemblage for firefly conservation

Epidemiology, management, and outcomes of sepsis in ICUs among countries of differing national wealth across Asia

Rationale: Directly comparative data on sepsis epidemiology and sepsis bundle implementation in countries of differing national wealth remain sparse. Objectives: To evaluate across countries/regions of differing income status in Asia 1) the prevalence, causes, and outcomes of sepsis as a reason for ICU admission and 2) sepsis bundle (antibiotic administration, blood culture, and lactate measurement) compliance and its association with hospital mortality. Methods: A prospective point prevalence study was conducted among 386 adult ICUs from 22 Asian countries/regions. Adult ICU participants admitted for sepsis on four separate days (representing the seasons of 2019) were recruited. Measurements and Main Results: The overall prevalence of sepsis in ICUs was 22.4% (20.9%, 24.5%, and 21.3% in low- income countries/regions [LICs]/lower middle-income countries/ regions [LMICs], upper middle-income countries/regions, and high-income countries/regions [HICs], respectively; P , 0.001). Patients were younger and had lower severity of illness in LICs/ LMICs. Hospital mortality was 32.6% and marginally significantly higher in LICs/LMICs than HICs on multivariable generalized mixed model analysis (adjusted odds ratio, 1.84; 95% confidence interval, 1.00–3.37; P = 0.049). Sepsis bundle compliance was 21.5% at 1 hour (26.0%, 22.1%, and 16.2% in LICs/LMICs, upper middle-income countries/regions, and HICs, respectively; P , 0.001) and 36.6% at 3 hours (39.3%, 32.8%, and 38.5%, respectively; P = 0.001). Delaying antibiotic administration beyond 3 hours was the only element independently associated with increased mortality (adjusted odds ratio, 2.53; 95% confidence interval, 2.07–3.08; P , 0.001). Conclusions: Sepsis is a common cause of admission to Asian ICUs. Mortality remains high and is higher in LICs/LMICs after controlling for confounders. Sepsis bundle compliance remains low. Delaying antibiotic administration beyond 3 hours from diagnosis is associated with increased mortality

Anti-angiogenic effects of pterogynidine alkaloid isolated from Alchornea glandulosa

<p>Abstract</p> <p>Background</p> <p>Angiogenesis, a complex multistep process that comprehends proliferation, migration and anastomosis of endothelial cells (EC), has a major role in the development of pathologic conditions such as inflammatory diseases, tumor growth and metastasis. Brazilian flora, the most diverse in the world, is an interesting spot to prospect for new chemical leads, being an important source of new anticancer drugs. Plant-derived alkaloids have traditionally been of interest due to their pronounced physiological activities. We investigated the anti-angiogenic potential of the naturally occurring guanidine alkaloid pterogynidine (Pt) isolated from the Brazilian plant <it>Alchornea glandulosa</it>. The purpose of this study was to examine which features of the angiogenic process could be disturbed by Pt.</p> <p>Methods</p> <p>Human umbilical vein endothelial cells (HUVEC) were incubated with 8 μM Pt and cell viability, proliferation, apoptosis, invasion and capillary-like structures formation were addressed. Nuclear factor κB (NFκB), a transcription factor implicated in these processes, was also evaluated in HUVEC incubated with Pt. Quantifications were expressed as mean ± SD of five independent experiments and one-way analysis of variance (ANOVA) followed by the Dunnet test was used.</p> <p>Results</p> <p>A significant decrease in proliferation and invasion capacity and an effective increase in apoptosis as assessed by bromodeoxyuridine (BrdU), double-chamber and terminal transferase dUTP nick end labeling (TUNEL) assay, respectively, have been found. Pt also led to a drastic reduction in the number of capillary-like structures formation when HUVEC were cultured on growth factor reduced-Matrigel (GFR-Matrigel) coated plates. In addition, incubation of HUVEC with Pt resulted in reduced NFκB activity.</p> <p>Conclusion</p> <p>These findings emphasize the potential use of Pt against pathological situations where angiogenesis is stimulated as tumor development.</p