Abstract

New approaches to pediatric brain tumors: development of a target therapy against the Shh pathway in a mouse model of medulloblastoma

Tom Curran

Genetically engineered mouse strains have been used to investigate tumor etiology and to elaborate the molecular pathways that contribute to human cancer. The greatest potential application of such models is to pioneer the development of novel therapies specifically targeted against growth control pathways altered in cancer. We developed a high incidence model for the pediatric brain tumor medulloblastoma. Medulloblastoma, a primitive neuroectodermal tumor (PNET) that arises in the cerebellum, accounts for approximately 20% of all pediatric brain tumors. Current treatment involves a combination of surgical resection, chemotherapy and radiation of the craniospinal axis4. Although the overall 5-year survival rate is approximately 70%, treatment is associated with long-term side effects including ataxia, neuroendocrine problems, intellectual deterioration, and neuropsychological difficulties. Therefore, there is a critical need for new, nontoxic therapies. In humans, mutation of genes in the sonic hedgehog (SHH) pathway, particularly the receptor for SHH, patched-1 (PTCH1), occur in sporadic medulloblastoma and heterozygous loss of PTCH1 in the germline predispose to disease. Similarly, mice with 20% incidence of medulloblastoma over a period of one year. We accelerated the incidence and decreased the latency of medulloblastoma by crossing Ptc1^+/- mice with p53^-/- mice. All Ptc1^+/-p53^-/- mice develop medulloblastoma and most die from brain tumors within 12 weeks of birth. P53 is mutated in approximately 10% of human medulloblastoma and the p53 pathway is defective in a larger subset of tumors. Thus, Ptc1^+/-p53^-/- mice provide a useful model to develop novel therapies for brain tumors targeted against the Shh pathway. We investigated the effect of inhibitors of the Shh pathway (HhAntag) on mouse medulloblastoma. We found that HhAntag inhibited Gli1 expression in a dose-dependent manner in tumor tissue in vivo. Furthermore, treatment of mice twice daily inhibited tumor cell proliferation. Tumors were completely eliminated in mice treated with the highest dose. In longer-term studies, HhAntag given once a day significantly enhanced brain tumor free survival. These results suggest that HhAntag may be beneficial for treatment of medulloblastoma and other tumors in which the Shh pathway is deregulated. (Presented at the 1342nd Meeting February 3, 2004.)

Jan Mikulicz-Radecki: one of the creators of world surgery

Wojciech Kielan, Bogdan Lazarkiewicz, Zygmunt Grzebieniak, Adam Skalski and Piotr Zukrowski

The intention of this paper is to present the life and achievements of Professor Jan Mikulicz-Radecki and his contribution to European and world surgery. Some surgeons may associate his name with a surgical clamp or a method of operation. He was born in 1850. In his surgical career four periods can be distinguished: (1) Vienna period, 1875-82, when he worked by the side of the great Theodor Billroth, he introduced a number of new diagnostic and operative techniques, aseptic and antiseptic procedures, published scienti?c papers. He constructed the ?rst endoscope for examining the esophagus and stomach. (2) Cracow period, 1882-87, when he was head of the Department of Surgery, he inaugurated his work with a lecture in Polish. It started: "Gentlemen, I have been accused that I do not know the Polish language - which is my mother tongue to me as well as to any of you." He published numerous publications on the use of iodophorm for healing wounds and was the ?rst surgeon in the world who sutured a perforated gastric ulcer (1885) and invented pyloroplasty (1887), nowadays called Heinecke-Mikulicz pyloroplasty. (3) Königsberg period, 1887-90, when he improved the technique of gastric resection, worked on surgery for peptic ulcer and promoted aseptic and antiseptic procedures. (4) Wroclaw period, 1890-1905, was the longest and the last one in his life. Mikulicz was appointed head of a newly founded Surgical Department. He rebuilt it, designing himself one of the largest and most modern operating theaters in Europe that time. He organized new chemical, bacteriology and pathology laboratories. He introduced wearing silk gloves he described bilateral swelling of salivary and lacrimal glands, called Mikulicz’s syndrome; in 1902 he published his experience with two-stage colon resection; and in 1904 he described ostitis ?brosa cystica juvenilis. Jan Mikulicz has left a very rich and relevant contribution to surgical literature, comprising 158 publications in German, Polish, English, and even in Russian. Called sometimes "a king in the kingdom of surgeons", he was one of the fathers of the world’s modern surgery; having a brilliant surgical mind, he was a pioneer of many new operations and an inventor of surgical tools, permanently assimilated in the world’s surgery. (Presented at the 1343rd Meeting, January 28, 2004.)

The power of marine genomics: the genome repertoire of the evolutionary earliest metazoan phylum the Sponges (Porifera)

Werner E.G. Müller

It was a long and painful scienti?c process to position the most enigmatic metazoan phylum, the porifera, to the correct phylogenetic place among the multicellular animals. Only after application of molecular biological techniques was it possible to place the porifera monophyletically with the other metazoan phyla, justifying a uni?cation of all multicellular animals to only one kingdom, the metazoa. Support came from the discovery that cell-cell- and cell-matrix adhesion molecules that were cloned from sponges (mainly the demosponges suberites domuncula and geodia cydonium) and were subsequently expressed, share high DNA sequence and protein function similarity with the corresponding molecules of other metazoans. Besides these evolutionary novelties sponges have also morphogens and transcription factors in common with the other metazoan phyla. It was surprising that even those elements exist which are characteristic for pattern and axis formation. Recent studies even showed that the epithelial layers of sponges are sealed against the extracellular milieu through tight junction proteins. Finally, stem cell marker genes were isolated which underscored that the sponge cells have the capacity to differentiate. In the relatively short period of time, approximately 200 million years (MYA), the basic pathways had to be established which allowed the transition for the multicellular organisms to a colonial system through the formation of adhesion molecules; based on the development of a complex immune system and the apoptotic machinery an integrated system, the urmetazoa, could be reached. These data caused a paradigmatic change; the porifera are complex and simple but by far not primitive. The sponges appeared on this planet 800 MYA and represent as living fossils a testimony of animal diversity prior to the ediacara period. (Presented at the 1344th Meeting February 10, 2004.)

Preliminary results of de-novo-bone formation by peptidomimetic receptor engineering and genetic screening: the new PepGen P15

Andreas H. Valentin

Modern implantology involves the application and optimization of bone engineering biomaterials and scaffolds to achieve predictability in quality and quantity of the regeneration result and to avoid the high morbidity factor of the present gold standard. The complete and authentic regeneration of bony structures using overdosages of single mitogenes (PRP, Growth factors) or morphogenes (BMP) has lead to mostly unsatisfactory results. This is due to the fact that the bony regeneration cascade is a highly complex metabolic event with many unknown variables, where overdosages of single cascade factors may disturb the natural stoechiometry and chain reactions leading to incomplete results or failures. Acceleration of (woven) bone formation and completeness of the regeneration result seems to be more adequate by multiplication of the whole cacscades by duplicating all phases of cell binding, migration, proliferation and differentiation. Collagen I is an extracellular matrix protein with multiple main binding domains for osteogenic progenitor cells and therefore plays a crucial role in osteogenesis. PepGen P15 is the ?rst man engineered collagen I binding domain for potential osteoblasts and is able to multiply the complete regeneration cascade. Individual Bone regeneration results are strongly dependent on genetic factors Collagen I alpha 1 gene, the VDR3 receptor gene, IL-1β and others. A simple screening technique of implant patients preoperatively would help to minimize surgical as well as prosthetic failures. The lecture elucidates the principles of receptor engineering as a new dimension in bone regeneration and presents the ?rst histodynamic and histomorphometric results of this new technology in sinus ?oor elevations. The future potential of individual bone regeneration will be discussed. (Presented at the 1346th Meeting February 11, 2004.)