Interaction of tumor cells and lymphatic vessels in cancer progression.

Metastatic spread of cancer through the lymphatic system affects hundreds of thousands of patients yearly. Growth of new lymphatic vessels, lymphangiogenesis, is activated in cancer and inflammation, but is largely inactive in normal physiology, and therefore offers therapeutic potential. Key mediators of lymphangiogenesis have been identified in developmental studies. During embryonic development, lymphatic endothelial cells derive from the blood vascular endothelium and differentiate under the guidance of lymphatic-specific regulators, such as the prospero homeobox 1 transcription factor. Vascular endothelial growth factor-C (VEGF-C) and VEGF receptor 3 signaling are essential for the further development of lymphatic vessels and therefore they provide a promising target for inhibition of tumor lymphangiogenesis. Lymphangiogenesis is important for the progression of solid tumors as shown for melanoma and breast cancer. Tumor cells may use chemokine gradients as guidance cues and enter lymphatic vessels through intercellular openings between endothelial cell junctions or, possibly, by inducing larger discontinuities in the endothelial cell layer. Tumor-draining sentinel lymph nodes show enhanced lymphangiogenesis even before cancer metastasis and they may function as a permissive 'lymphovascular niche' for the survival of metastatic cells. Although our current knowledge indicates that the development of anti-lymphangiogenic therapies may be beneficial for the treatment of cancer patients, several open questions remain with regard to the frequency, mechanisms and biological importance of lymphatic metastases.

Complement evasion by Borrelia burgdorferi: serum-resistant strains promote C3b inactivation.

The most characteristic features of the Lyme disease pathogens, the Borrelia burgdorferi sensu lato (s.l.) group, are their ability to invade tissues and to circumvent the immune defenses of the host for extended periods of time, despite elevated levels of borrelia-specific antibodies in serum and other body fluids. Our aim in the present study was to determine whether B. burgdorferi is able to interfere with complement (C) at the level of C3 by accelerating C3b inactivation and thus to inhibit the amplification of the C cascade. Strains belonging to different genospecies (Borrelia garinii, B. burgdorferi sensu stricto, and Borrelia afzelii) were compared for their sensitivities to normal human serum and abilities to promote factor I-mediated C3b degradation. B. burgdorferi sensu stricto and B. afzelii strains were found to be serum resistant. When the spirochetes were incubated with radiolabeled C3b, factor I-mediated degradation of C3b was observed in the presence of C-resistant B. afzelii (n = 3) and B. burgdorferi sensu stricto (n = 1) strains but not in the presence of C-sensitive B. garinii (n = 7) strains or control bacteria (Escherichia coli, Staphylococcus aureus, and Enterococcus faecalis). Immunoblotting and radioligand binding analyses showed that the C-resistant strains had the capacity to acquire the C inhibitors factor H and factor H-like protein 1 (FHL-1) from growth medium and human serum. A novel surface protein with an apparent molecular mass of 35 kDa was found to preferentially bind to the N terminus region of factor H. Thus, the serum-resistant B. burgdorferi s.l. strains can circumvent C attack by binding the C inhibitors factor H and FHL-1 to their surfaces and promoting factor I-mediated C3b degradation.

The complement regulator factor H binds to the surface protein OspE of Borrelia burgdorferi.

Spirochete bacteria of the Borrelia burgdorferi sensu lato complex cause Lyme borreliosis. The three pathogenic subspecies Borrelia garinii, Borrelia afzelii, and Borrelia burgdorferi sensu stricto differ in their disease profiles and susceptibility to complement lysis. We investigated whether complement resistance of Borreliae could be due to acquisition of the main soluble inhibitors of the alternative complement pathway, factor H and the factor H-like protein 1. When exposed to nonimmune EDTA-plasma, the serum-resistant B. afzelii and B. burgdorferi sensu stricto strains bound factor H/factor H-like protein 1 to their surfaces. Assays with radiolabeled proteins showed that factor H bound strongly to the B. burgdorferi sensu stricto strain. To identify factor H ligands on the borrelial surface, we analyzed a panel of outer surface proteins of B. burgdorferi sensu stricto with the surface plasmon resonance technique. The outer surface lipoprotein OspE was identified as a specific ligand for factor H. Using recombinant constructs of factor H, the binding site for OspE was localized to the C-terminal short consensus repeat domains 15-20. Specific binding of factor H to B. burgdorferi sensu stricto OspE may help the pathogen to evade complement attack and phagocytosis.

[The national biography - a comprehensive research project]. / Kansallisbiografia - historiantutkimuksen suurhanke.

This project was initiated by the Finnish Historical Society in 1993. The reason was an increasing interest in biographies. The aim is to write 6000 Finnish biographies in 11-12 volumes. The articles are planned to be published in the beginning of the year 2000. Selected historical characters from the Middle Ages to the present day are to be described. The most influential persons in politics, economy and the church as well as in art and sport are presented in articles of 20-30 pages. Certain persons representing the economy of life of previous times are presented in shorter articles as examples of the circumstances of their days. In addition extraordinary characters considered to be of special interest to the readers are introduced. The border between the groups is indistinct. The witches from the 17th Century are, for example, both typical representatives of their time and exceptional persons as seen by modern people. Similarities between old magic and modern "alternative" medicine are also obvious. An object of special interest is women's history, which previously has been almost overlooked. Female biographies now constitute about 15% of the articles. The National Biography is also available as a net version. The first articles were opened in late 1997 in the Internet. In the field of medical science, all the most prominent persons in the history of medicine and related professions are included, beginning from the king's physician Johan Copp in the 16th century. The medical profession is extended so as to consist of university professors and scientists, practitioners and promotors of administration as well as healers.

[Barbro Christina Hästesko-Fortuna (1698-1771), lady of a manor and physician]. / Barbro Christina Hästesko-Fortuna (1698-1771) kartanonrouva, kansanparantaja.

Barbro Christina Hastesko Fortuna's parents were Lorentz Hastesko-Fortuna, descendant from a famous military family, and Sofia Gios, the daughter of Lagman Johan Gios and Sofia Ille. The mother died in 1699 after the birth of Sofia's only brother. The father died in 1705. The orpahn girl was given in marriage almost as a child to an officer by name Carl Johan Norman. He was killed in 1710 in the Great Northern War. The young wife was in captivity in Russia until 1721. There she studied medicine. Soon after her release in the summer of 1721, she married Captain Johan Ventzel Rotkirch. The husband belonged to a well-known military family of German extraction. Barbro Christina Hastesko-Fortuna and her husband inhabited the Stensbole manor at Porvoo. A total of 10 children were born in the family. In spite of her duties as lady of a large manor and the mother of a big family, Barbro Christina Hastesko-Fortuna treated eye diseases in all social classes in a wide area. Her function was examined in 1769 by request of her son at a session of the Porvoo District Court. The Court issued a laudatory statement. The medicines prepared by her were effective as testified by both young and old witnesses, particularly when they were used according to her instructions.