Pleiotrophin (PTN) is a secreted growth factor that induces neurite outgrowth and is mitogenic for fibroblasts, epithelial, and endothelial cells. During tumor growth PTN can serve as an angiogenic factor and drive tumor invasion and metastasis. To identify a receptor for PTN, we panned a phage display human cDNA library against immobilized PTN protein as a bait. From this we isolated a phage insert that was homologous to an amino acid sequence stretch in the extracellular domain (ECD) of the orphan receptor tyrosine kinase anaplastic lymphoma kinase (ALK). In parallel with PTN, ALK is highly expressed during perinatal development of the nervous system and down-modulated in the adult. Animal studies demonstrated that PTN can serve as a ratelimiting angiogenic factor during tumor growth, invasion, and metastasis (8 -12). Clinical studies showed elevated serum levels and tumor expression of PTN in samples from patients with colon, stomach, pancreatic, and breast cancer (5, 13). Furthermore, PTN has been implicated in neonatal brain development as well as in neurodegenerative disorders (reviewed in Ref. 14).Obviously, understanding of PTN-mediated signal transduction as well as identification of a receptor for PTN would enhance studies on the biology and pathology of this growth factor family. Our previous studies have shown that the activation of mitogen-activated protein kinase and PI 3-kinase pathways is required for mitogenic activity of PTN, and we had found that the adaptor molecule Shc participated in signal transduction (15). Based on the work of different laboratories in various cell types, it was hypothesized that proteins of 170 -220 kDa that are tyrosine-phosphorylated in response to PTN could be part of the receptor complex (15-17). More recently, several cell membrane-located proteins were shown to bind PTN at low affinity and serve as potential coreceptors or modulators of signal transduction (18 -21), but none of these molecules carried the hallmarks of a signal transducing receptor predicted from the earlier work.To identify a receptor for PTN, we rationalized that panning of a phage display cDNA library against immobilized PTN as a bait would allow us to isolate phage containing a ligand binding fragment of the receptor on their surface. Because of the high levels of expression of PTN during the perinatal development of the nervous system, we hypothesized that fetal brain would most likely also express a PTN receptor. We therefore panned a human fetal brain cDNA phage display library over several rounds against purified PTN that had been tested for biological activity (15). From this we isolated a phage insert homologous to an amino acid sequence stretch in the ECD of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK), a recently described orphan receptor with an apparent molecular mass of

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Overexpression of the HER2 (neu/c-erbB-2) oncogene frequently coincides with an aggressive clinical course of certain human adenocarcinomas. Expression and secretion of aberrant HER2 splice variants has been reported in various cell lines and tissues and can interfere with the oncogenic HER2 activity. Here we demonstrate, using two dierent approaches, that expression of a truncated 100 kDa HER2 variant which encodes the extracellular domain of HER2 (HER-ECD) inhibits growth factormediated tumour cell proliferation. A HER2-ECD cDNA encoding the truncated variant was overexpressed in MCF7 breast cancer cells. HER2-ECD overexpression decreased spontaneous proliferation of MCF7 cells as well as heregulin-mediated soft agar colony formation. Concomitantly, heregulin-induced phosphorylation of HER4 as well as downstream activation of p44/p42 MAP-kinases was decreased. To con®rm these data, ribozymes were targeted to the 3'-untranslated region of the 2.3 kb HER2-ECD mRNA which is spontaneously expressed in MKN7 gastric cancer cells. HER2-ECDtargeted ribozymes downregulated HER2-ECD expression and enhanced EGF-mediated soft agar colony formation of MKN7 cells. In parallel, EGF-induced activation of p44/p42 MAP-kinases and activation of cFos expression were increased in ribozyme-transfected MKN7 cells. Finally, in RT ± PCR we found a trend towards a progressive loss of 2.3 kb HER2-ECD mRNA expression in more advanced gastric tumours. These data show that the HER2-ECD variant inhibits growth factormediated tumour cell proliferation suggesting an important role during the progression of human cancer.

The epidemiology of invasive meningococcal disease varies geographically and in time and the risk of acquiring the disease varies regionally, as well as with living conditions and behavior. An area, in which meningococcal disease outbreaks have frequently occurred, is the "African meningitis belt", where epidemics of meningococcal disease with a peak incidence as high as 100-800/100,000 population/year have been reported. Another risk factor is mass gatherings including the Islamic pilgrimage to Makkah (Mecca), where outbreaks of meningococcal disease have repeatedly occurred. The latest outbreaks occurred during the Hajj pilgrimages of 2000 and 2001, when a shift from serogroup A disease to serogroup W135 occurred. Vaccination against serogroups A, C, W-135 and Y with novel conjugate vaccines may help protect individuals and reduce the spread of bacterial carriage and disease. Individuals who should be vaccinated include travelers to epidemic or hyperendemic areas (as identified by international health authorities), travelers for Umra or Hajj (Hajj pilgrims), travelers to high risk countries or regions (African meningitis belt) during the dry season or countries in sub-Saharan Africa outside the meningitis belt (where outbreak of meningitis has been reported in the preceding 2-3 years), military recruits or deployed military personnel, immunocompromized travelers and high school and college students. This review presents the global epidemiology of meningococcal disease, and discusses prophylaxis options including meningococcal ACWY vaccines.

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