Abstract

Control of pathogenic T cells by regulatory T cells during chronic inflammation in the digestive tract

Peter B. Ernst and Makoto Naganuma

Chronic inflammatory disease in the gastrointestinal tract can develop due to an excess of pathogenic T cells or a relative lack of cells producing anti-inflammatory cytokines. Regulatory T cells (Treg) are one subset of The cells that suppress the ability of pathogenic T cells to induce disease. Fundamentally, it would be helpful to distinguish pathogenic and Treg as well as understand the factors that select for their development so that disease could be controlled by manipulating the mucosal T cell responses. Pathogenic T cells and Treg modify the integrity of epithelial cells in the context of colitis or gastritis associated with chronic Helicobacter pylori infection. In both cases, pathogenic T cells can express FasL and induce apoptosis in epithelial cells expressing Fas. The Fas/FasL interactions are complemented by inflammatory cytokines and oxidative stress than collaborate in mediating the injury to epithelial cells and the disruption of barrier function. In contrast, Treg do not express FasL after immune activation and they are able to protect epithelial cells from undergoing apoptosis and changes in barrier function. This is despite the fact that some Th cells with Treg function still including interferon-γ and TNF-α. IL-10 appears to be a major factor that protects epithelial cells from the effects of pathogenic T cells. The selection of Treg is dependent on the education of Th cells in the thymus that recognize antigen presented by class II MHC molecules. However, antigen-presenting cells can attenuate the ability of Treg to control inflammation due to cytokines or the expression of GITR ligand that binds to Treg and activated T cells resulting in a loss of tolerance. The significance of this is found in an animal model of inflammatory bowel disease in which pathogenic T cells can be regulated by Treg that appear to develop and function normally. However in the diseased animal, expression of GITR ligand by adjacent cells impairs Treg function resulting in the onset of chronic disease. In summary, Treg can modulate the damage mediated by pathogenic T cells during chronic inflammation. Strategies for the selection of Treg could include novel approaches to alter Th cell activation as well as targeted disruption of factors that impair Treg development and function.

The origin and evolution of vertebrate mineralized skeleton

Kazuhiko Kawasaki

Mammalian teeth form on extracellular matrix proteins; enamel on enamel-specific proteins, dentin and bone on collagen, with acidic proteins regulating their growth. We found that the enamel-specific proteins (amelogenin, AMEL; ameloblastin, AMBN; enamelin, ENAM) and dentin/bone acidic proteins (dentin sialophosphoprotein, DSPP; dentin matrix acidic phosphoprotein 1, DMP1; integrin-binding sialoprotein, IBSP; matrix extracellular phosphoglycoprotein, MEPE; secreted phosphoprotein 1, SPP1) are related to an avian eggshell matrix protein (ovocleidin-116, OC116), mammalian milk caseins, and salivary proteins. The genes for these proteins arose from SPARC that codes a noncollagenous bone matrix protein, and form the secretory Ca-binding phosphoprotein (SCPP) gene family. The duplication of SPARC generated SPARCL1 in ancient bony fish, and tandem duplications of SPARCL1 created the many SCPP genes. Bony fish developed adentin/bone SCPP; tetrapods enamel SCPPs; birds an eggshell SCPP; and mammals milk/saliva SCPPs. This suggests that the mechanism of mammalian tissue mineralization was developed in bony fish or tetrapods, and parallel functional specialization of duplicated genes facilitated adaptive evolution in vertebrates.

Latest advances in anti aging medicine

Terry Grossman

Rapid progress is being made in our ability to modify the aging process. Rather than serving as a period of debility and decreasing health, for many people, the later years of life are becoming a period of continued productivity, independence and good health. Progress is also being made in increasing average lifespan. The leading causes of death (cardiovascular disease, cancer, lung disease, diabetes) are the end result of decadeslong processes. With current knowledge, it is possible to delay the onset of these diseases. This can be assisted by lifestyle choices incorporating healthful diet, exercise, stress management, and nutritional supplementation. Emerging genomics technology will allow individuals to establish personalized programs, while early detection of heart disease and cancer will contribute to longevity. Biotechnological therapies involving stem cells, recombinant DNA, proteomics, therapeutic cloning and gene-based therapies are expected to play major roles in promoting successful aging. We are at the threshold of artificial intelligence (AI) and nanotechnology (NT). AI will allow for a merging of our biological thinking with advanced forms of non-biological intelligence to vastly expand our ability to think, create and experience. NT will ultimately allow us to build devices able to build molecules much like our current cellular machinery does, one atom at a time. It is the goal of today’s anti aging medicine to forestall disease and aging long enough for people to utilize the powerful biotechnology and nanotechnology therapies that will be developed over the decades ahead. These future therapies have the potential to greatly extend longevity.

γ-secretase dependent and independent functions of Presenilin 1 and their possible involvement in Alzheimer’s disease

Junichi Shioi

Mutations in Presenilin1 (PS1) accounts for most cases of familial Alzheimer’s disease (FAD) and more than 100 point mutations in PS1 gene have been reported among FAD patients. PS1 is a critical component of the γ-secretase complex which catalyzes cleavage of amyloid precursor protein to produce β-amyloid protein. We found that PS1 mediates also cleavage of E-, N- and VE-cadherins, Ephrin B2 ligand and Ephrin B2 receptor, all single transmembrane proteins. The produced cytoplasmic fragment of N-cadherin promotes proteosomal degradation of CBP (CREB binding protein), thus inhibiting CREB transcriptional activity. FAD mutations in PS1 decrease in production of the fragment implicating dysregulated transcription in the disease. E- and N-Cadherins are known to interact with PI3K and regulate PI3K/Akt cell survival signaling pathway. We found that PS1 forms complexes with the p85 subunit of PI3K and promotes cadherin/PI3K association. Consistently, elimination of PS1 suppresses Akt and glycogen synthase kinase 3 (GSK3) phosphrylation leading to tau overphosphorylation and apoptosis in confluent culture cells. PS1 FAD mutations inhibit the PS1-dependent PI3K/Akt activation thus promoting GSK3 activity and tau overphosphorylation. Interestingly, these roles of PS1 in the Akt signaling pathway are independent of γ-secretase activity. It is proposed that FAD mutations may promote AD pathology by inhibiting the PI3K/Akt signaling pathway.

The target volume concept and the sentinel node procedure in radiation oncology

Ion Christian Kiricuta, U Goetz and B Schicker

Background: The sentinel lymph node concept (SNC) and the sentinel node procedure (SNP) is crucial to the understanding the relationship of the primary tumor to its regional lymphatics. The adjuvant radiotherapy to lymphatic basins could spare a systematic lymphadenectomy in sentinel node positive patients. Purpose: To present data on the selection of lymphatic areas in the clinical target volume (CTV) in head and neck, breast and Mercel Cell cancer patients based on the pattern of lymphatic spread and the probability of involvement. To present adequate conformal irradiation techniques for adjuvant radiotherapy of the head and neck, axilla, internal mammary chain and inguinal and pelvic lymphatic areas. Material and Methods: Basic data about the lymphatic drainage and involvement of different lymph nodes for head and neck, breast and Merkel Cell cancers based on the SNP were used. The individual location of lymph nodes in axial CT slices for CTV delineation was used for planning. Results: The CT based nodal classifications of the head and neck, breast and pelvis will be reviewed and the topography of lymph nodes in axial CT slices will be presented. The data obtained using the SNP changed in a significant manner the selection of different lymphatic basins and inclusion in the CTV. In the Amsterdam breast cancer study of Estourgie, the therapeutic startegy was necessary to be changed in 29% of investigated patients considering the information gained by the SNP. In Merkel Cell Cancer patients the SNP is the only available method to describe the individual lymphatic basin and to addept the optimal treatment strategy. The conventional irradiation techniques for these carefully selected CTV’s should no longer be considered adequate and new techniques were developed and presented here. Conclusions: The individual selection of lymphatic areas to be included in the CTV based on the SNP is indicated. Sparing of organs at risc and a homogenous dose distribution in the CTV by new irradiation techniques is possible. References: Kiricuta I.C. (editor): The Target Volume Definition in Radiation Oncology; First Int. Symposium Limburg 2001, Estourgie et al. in Kiricuta I.C. (editor) The Target Volume Definition in Radiation Oncology and the Sentinel Node Procedure.Third Int Symposium, Limburg, 2003. Kiricuta I.C. (editor) The Lymphatic System - New Developments in Oncology and IMRT. Forth Int Symposium, Limburg 2004.

A paradigm shift from traditional to implant dentistry and from removable to fixed

Clarence C. Lindquist

A major shift has been occurring in dentistry in the United States. Since the introduction of fluoride into drinking water, dental caries has decreased dramatically in the United States as cause of tooth loss. Additionally, since the introduction of osseointegrated implants, there has been a shift from removable dental appliances to fixed, non-removable dental appliances. These two factors are contributing to the fact that dental implants being utilized routinely to replace missing teeth and to the decrease in the number of removable dental appliances. When osseointegrated implants were introduced in 1982 in the United States, they were very limited in their application, both for anatomic reasons and by implant design. Since that time, it is now possible to restore almost any patient, regardless of their status, with osseointegrated implants. The evolution of dental implants in the United States has been steady and the traditional implant design and others, which were the mainstay of implant dentistry in the 1980’s, have been almost replaced by newer designs with different surfaces or surface coatings. Case studies will show that there are very few anatomical barriers to the placement of implants. Missing bone can be replaced with allografts, xenografts or autografts. The floor of the maxillary sinus can be raised to allow implant placement. Ridge expansion, or rapid osseous distraction, has proved to be a major breakthrough in bone augmentation replacing bone grafting in many cases. It is even possible to move the mandibular nerve to insert implants or perform segmental osteotomies to insure implant placements.