Kari Alitalo

Bio: Kari Alitalo is an academic researcher from University of Helsinki. The author has contributed to research in topics: Angiogenesis & Vascular endothelial growth factor C. The author has an hindex of 174, co-authored 817 publications receiving 114231 citations. Previous affiliations of Kari Alitalo include Mount Sinai Hospital, Toronto & Cornell University.

Vascular Endothelial Growth Factor D(VEGF-D) Antibodies and Vectors, and Methods of Uses

Abstract: VEGF-D, a new member of the PDGF family of growth factors, which among other things stimulates endothelial cell proliferation and angiogenesis and increases vascular permeability, as well as nucleotide sequences encoding it, methods for producing it, antibodies and other antagonists to it, transfected or transformed host cells for expressing it, pharmaceutical compositions containing it, and uses thereof in medical and diagnostic applications.

Ligands de recepteur 3 du facteur de croissance des cellules endotheliales de liaison a l'heparine

Abstract: La presente invention a trait a des procedes et des compositions pour la production et l'utilisation de polypeptides chimeriques comportant un ligand du recepteur 3 du facteur de croissance des cellules endotheliales et un domaine de liaison a l'heparine. Les molecules chimeriques de la presente invention preservent l'activite de liaison du recepteur 3 du facteur de croissance des cellules endotheliales et une activite de liaison a l'heparine accrue par rapport au facteur C de croissance des cellules endotheliales et/ou au facteur D de croissance de cellules endotheliales.

The angiopoietin receptor Tie2 is atheroprotective in arterial endothelium

Abstract: Abstract Leukocytes and resident cells in the arterial wall contribute to atherosclerosis, especially at sites of disturbed blood flow. Expression of endothelial Tie1 receptor tyrosine kinase is enhanced at these sites, and attenuation of its expression reduces atherosclerotic burden and decreases inflammation. However, Tie2 tyrosine kinase function in atherosclerosis is unknown. Here we provide genetic evidence from humans and from an atherosclerotic mouse model to show that TIE2 is associated with protection from coronary artery disease. We show that deletion of Tie2 , or both Tie2 and Tie1 , in the arterial endothelium promotes atherosclerosis by increasing Foxo1 nuclear localization, endothelial adhesion molecule expression and accumulation of immune cells. We also show that Tie2 is expressed in a subset of aortic fibroblasts, and its silencing in these cells increases expression of inflammation-related genes. Our findings indicate that unlike Tie1, the Tie2 receptor functions as the dominant endothelial angiopoietin receptor that protects from atherosclerosis.

Abstract 731: Sorafenib Induces Cardiotoxicity via Damage to Cardiac Endothelial Cells

Abstract: Aim: Sorafenib (Nexavar) is a multitargeted tyrosine kinase inhibitor that is used for treatment of hepatocellular carcinoma and renal cell carcinoma. Cancer treatment with sorafenib has been reported to be associated with cardiotoxic side effects such as hypertension, myocardial ischemia, thrombosis and pulmonary embolism, whereas incidence of LV dysfunction is rare. Aim of the current study was to identify the mechanism of sorafenib cardiotoxicity. Results: Healthy mice were treated with sorafenib (50 mg/kg/d) for 4 weeks. Echocardiography analysis revealed no difference in LV systolic function, but LV posterior wall thickness and relative wall thickness were significantly increased, and LV volume decreased in sorafenib treated mice. Hearts of sorafenib treated mice showed a 10-fold increase in expression of heart failure marker gene ANP and a 3-fold increase in the number of apoptotic cells. Electron microscopy analysis indicated damage to cardiac endothelial cells with no evidence of cardiomyocyte loss and co-staining of cardiac sections with endothelial marker CD31 revealed that ~80% of apoptotic cells in sorafenib treated hearts were endothelial cells (ECs). To assess for the time course for EC damage, we treated mice with sorafenib for 8h, 24h, 48h and 72h. The increase in EC death was already detected after 8h treatment and peaking at 24h-48h. RNA profiling analysis showed that expression of angiopoietin-1 (Angpt1) was reduced, whereas expression of Angpt2 was induced in hearts of mice treated with sorafenib for 4 weeks and in EC fractions from hearts of mice treated with sorafenib for 72h. Angpt-1 overexpression induced protective signaling pathways in hearts of mice treated with sorafenib for 48h, but did not rescue from acute EC injury. Treatment of Angpt1 overexpressing mice with sorafenib for 4 weeks resulted in capillary rarefaction and heart failure, evidenced by a decrease in LV systolic function and a 40-fold increase in ANP expression. Conclusion: our data shows that sorafenib cardiotoxicity is due to endothelial cell damage in the heart and results in heart failure with preserved ejection fraction. Furthermore, antagonizing the function of Angpt2 by overexpression of Angpt1 is detrimental during sorafenib treatment.

Endothelial TIE1 restricts angiogenic sprouting to coordinate vein assembly in synergy with its homologue TIE2

Abstract: Objective Vascular growth followed by vessel specification is crucial for the establishment of a hierarchical blood vascular network. We have here investigated mechanisms underlying venogenesis, particularly the molecular control over venous fate acquisition during vascular development. Approach and Results We analyzed the function of TIE1 as well as its synergy with TIE2 in the regulation of vein formation by employing genetic mouse models targeting Tie1 and Tek. Cardinal vein growth appeared normal in TIE1 deficient mice, whereas TIE2 deficiency altered the identity of cardinal vein endothelial cells with the aberrant expression of DLL4. Interestingly, the parallel growth of murine cutaneous veins along with arteries, which was initiated at approximately embryonic day 13.5, was retarded in mice lack of TIE1. Tie1 deletion disrupted also venous integrity, displaying increased sprouting angiogenesis and vascular bleeding. Abnormal venous sprouts with defective arteriovenous alignment were also observed in the mesenteries of Tie1 deleted mice. Mechanistically, TIE1 deficiency resulted in the decreased expression of venous regulators including TIE2 while angiogenic regulators were upregulated. The alteration of TIE2 level by TIE1 insufficiency was further confirmed by the siRNA-mediated knockdown of Tie1 in cultured endothelial cells. Additionally, combining the endothelial deletion of Tie1 with one null allele of Tek resulted in a progressive increase of vein-associated angiogenesis leading to the formation of vascular tufts in retinas, whereas the loss of Tie1 alone produced only a relatively mild venous defect. Conclusions Findings from this study imply that TIE1 and TIE2 act in a synergistic manner to restrict sprouting angiogenesis during vein formation.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Inflammation and cancer

Abstract: Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.

Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene

Abstract: The HER-2/neu oncogene is a member of the erbB-like oncogene family, and is related to, but distinct from, the epidermal growth factor receptor. This gene has been shown to be amplified in human breast cancer cell lines. In the current study, alterations of the gene in 189 primary human breast cancers were investigated. HER-2/neu was found to be amplified from 2- to greater than 20-fold in 30% of the tumors. Correlation of gene amplification with several disease parameters was evaluated. Amplification of the HER-2/neu gene was a significant predictor of both overall survival and time to relapse in patients with breast cancer. It retained its significance even when adjustments were made for other known prognostic factors. Moreover, HER-2/neu amplification had greater prognostic value than most currently used prognostic factors, including hormonal-receptor status, in lymph node-positive disease. These data indicate that this gene may play a role in the biologic behavior and/or pathogenesis of human breast cancer.