Tumor angiogenesis revisited: Regulators and clinical implications

Since Judah Folkman hypothesized in 1971 that angiogenesis is required for solid tumor growth, numerous studies have been conducted to unravel the angiogenesis process, analyze its role in primary tumor growth, metastasis and angiogenic diseases, and to develop inhibitors of proangiogenic factors. These studies have led in 2004 to the approval of the first antiangiogenic agent (bevacizumab, a humanized antibody targeting vascular endothelial growth factor) for the treatment of patients with metastatic colorectal cancer. This approval launched great expectations for the use of antiangiogenic therapy for malignant diseases. However, these expectations have not been met and, as knowledge of blood vessel formation accumulates, many of the original paradigms no longer hold. Therefore, the regulators and clinical implications of angiogenesis need to be revisited. In this review, we discuss recently identified angiogenesis mediators and pathways, new concepts that have emerged over the past 10 years, tumor resistance and toxicity associated with the use of currently available antiangiogenic treatment and potentially new targets and/or approaches for malignant and nonmalignant neovascular diseases

DISCOVERING NOVEL FACETS OF HCV-RELATED LIVER PATHOGENESIS

status: publishe

Niet - gravitaire 2DWA - systemen

Abstract ”Niet – gravitaire 2DWA – systemen” handelt over drukriolerings-, vacu¨umriolerings- en luchtpersrioolsystemen. In de praktijk doen zich een aantal problemen voor bij het gebruik van deze systemen. Het is dan ook belangrijk om te weten welke de oorzaken van deze problemen zijn en hoe deze in de toekomst kunnen vermeden worden. In een eerste hoofdstuk worden de theoretische aspecten omtrent niet - gravitaire 2DWA – systemen besproken. Het betreft hier vooral de opbouw, het werkingsprincipe en de voor- en nadelen van elk systeem. Het doel van dit hoofdstuk is het verwerven van een inzicht in de principes van niet - gravitaire 2DWA - systemen. Het tweede hoofdstuk behandelt het ontwerp van elk systeem. In eerste instantie worden enkele belangrijke hydraulische bedenkingen gemaakt. Hierbij wordt een vergelijking besproken die algemeen toepasbaar is voor de bepaling van het ontwerpdebiet van deze rioleringssystemen. Een belangrijk aspect hierbij is de nodige minimale stroomsnelheid om te kunnen spreken van zelfreinigende leidingen. Vervolgens wordt het ontwerp van elk systeem apart besproken. Hierbij komen vooral de volgende onderwerpen aan bod: dimensionering van de leidingen en de pompputten en pompen. De praktische aspecten worden in hoofdstuk 3 behandeld: de uitvoering, het onderhoud, het toepassingsgebied en de praktijkervaringen. Het voornaamste besluit dat hierbij gemaakt kon worden is dat drukrioleringssystemen de meeste bedrijfszekerheid bieden. Luchtpersrioolsystemen daarentegen vertonen enkele belangrijke beperkingen, waardoor ze een ”lage” bedrijfszekerheid hebben. In de meeste gevallen is de prijs de doorslaggevende factor bij de keuze van een systeem. Vandaar dat hoofdstuk 4 in het kort over de economische aspecten van niet – gravitaire 2DWA – systemen handelt. Hierbij worden de verschillende systemen met elkaar en met IBA’s vergeleken qua kostprijs. In een laatste hoofdstuk wordt voor een drukrioleringssysteem een case – studie uitgewerkt: het ontwerp, de uitvoering en de kostprijsberekening. De resultaten worden vergeleken met deze verkregen via het studiebureau. Voor luchtpersrioolsystemen wordt eveneens een case – studie uitgewerkt, maar enkel voor het ontwerp van de leidingen. Voor vacu¨umrioleringssystemen komt er geen case – studie aan bod, aangezien er geen projectplannen verkregen werden

Hemagglutinin cleavage profiles of human influenza A and B viruses, including that of 1918 influenza

status: publishe

Tumor angiogenesis revisited: Regulators and clinical implications

Since Judah Folkman hypothesized in 1971 that angiogenesis is required for solid tumor growth, numerous studies have been conducted to unravel the angiogenesis process, analyze its role in primary tumor growth, metastasis and angiogenic diseases, and to develop inhibitors of proangiogenic factors. These studies have led in 2004 to the approval of the first antiangiogenic agent (bevacizumab, a humanized antibody targeting vascular endothelial growth factor) for the treatment of patients with metastatic colorectal cancer. This approval launched great expectations for the use of antiangiogenic therapy for malignant diseases. However, these expectations have not been met and, as knowledge of blood vessel formation accumulates, many of the original paradigms no longer hold. Therefore, the regulators and clinical implications of angiogenesis need to be revisited. In this review, we discuss recently identified angiogenesis mediators and pathways, new concepts that have emerged over the past 10 years, tumor resistance and toxicity associated with the use of currently available antiangiogenic treatment and potentially new targets and/or approaches for malignant and nonmalignant neovascular diseases.status: publishe

Hepatitis C virus variants can by-pass PI3K inhibition by enviroxime

status: publishe

HCV-induced EGFR-ERK signaling promotes a pro-inflammatory and pro-angiogenic signature contributing to liver cancer pathogenesis

HCV is a major risk factor for hepatocellular carcinoma (HCC). HCC development in chronically infected HCV patients has until now been attributed to persistent inflammation and interference of viral proteins with host cell signaling. Since activation of the epidermal growth factor receptor (EGFR) presents a crucial step in HCV entry, we aimed at investigating whether EGFR signaling may contribute to the pathogenesis of HCV-related HCC. By applying microarray analysis, we generated a gene expression signature for secreted proteins in HCV-infected hepatoma cells. This gene signature was enriched for inflammatory and angiogenic processes; both crucially involved in HCC development. RT-qPCR analysis, conducted on the entire list of upregulated genes, confirmed induction of 11 genes (AREG, IL8, CCL20, CSF1, GDF15, IGFBP1, VNN3, THBS1 and PAI-1) in a virus titer- and replication-dependent manner. EGFR activation in hepatoma cells largely mimicked the gene signature seen in the infectious HCV model. Further, the EGFR-ERK pathway, but not Akt signaling, was responsible for this gene expression profile. Finally, microarray analysis conducted on clinical data from the GEO database, revealed that our validated gene expression profile is significantly represented in livers of patients with HCV-related liver pathogenesis (cirrhosis and HCC) compared to healthy livers. Taken together, our data indicate that persistent activation of EGFR-ERK signaling in chronically infected HCV patients may induce a specific pro-inflammatory and pro-angiogenic signature that presents a new mechanism by which HCV can promote liver cancer pathogenesis. A better understanding of the key factors in HCV-related oncogenesis, may efficiently direct HCC drug development.status: publishe

PI4KIII inhibitor enviroxime impedes the replication of the hepatitis C virus by inhibiting PI3 kinases

Objectives: Many positive-stranded RNA viruses, including HCV, drastically remodel intracellular membranes to generate specialized environments for RNA replication. Phosphatidylinositol 4-kinase III (PI4KIII)α plays an essential role in the formation of HCV replication complexes and has therefore been explored as a potential drug target. Here, we characterized the anti-HCV activity of the PI4KIII inhibitors enviroxime and BF738735 and elucidated their mechanism of action. Methods: Antiviral assays were performed using HCV subgenomic replicons and infectious HCV. Enviroxime- and BF738735-resistant HCV replicons were generated by long-term culture with increasing compound concentrations. Intracellular localization of phosphatidylinositol 4-phosphate (PI4P) lipids was analysed by confocal microscopy. Results: HCV subgenomic replicons resistant to either enviroxime or BF738735 proved cross-resistant and carried mutations in the NS3, NS4B and NS5A genes. Knockdown of PI4KIIIβ by small interfering RNA (siRNA) did not affect the replication of the HCV subgenomic replicon in this study. Furthermore, the compounds did not affect PI4P lipid levels at the replication complexes nor the phosphorylation status of NS5A, activities attributed to PI4KIIIα. Interestingly, the broad-spectrum phosphoinositide 3-kinase (PI3K) inhibitor LY294002 proved to be 10-fold less effective against the resistant replicons. In addition, enviroxime and BF738735 inhibited several PI3Ks in enzymatic assays. Conclusions: Contrary to assumptions, our data indicate that PI4KIIIα and PI4KIIIβ are not the main targets for the anti-HCV activity of enviroxime and BF738735. Instead, we demonstrated that both molecules impede HCV replication at least partially by an inhibitory effect on PI3Ks. Moreover, HCV is able to bypass PI3K inhibition by acquiring mutations in its genome.status: publishe