The Keio Journal of Medicine


Trends in American medical education
Karyn D. Baum and Sara Axtell
Medical education in the Unites States (US), and worldwide, is increasingly concentrating on the process and outcome of the educational experience. The first efforts to substantially improve medical education in the US resulted in the Flexner Report in the early 1900s. The release of this report led to significant advancements in the quality of curriculum content. However, in the past few decades there has been increasing realization that delivery of content will not, by itself, assure the development of excellent physicians. As a result, there has been an increasing emphasis on the process, and, most recently, the outcome, of medical education. Process outcomes have examined the context and methods for teaching and learning. The problem-based learning movement is perhaps the most widely-known example of process trends. The latest trends in US medical education focus on the outcomes of the learning process. At the forefront of this movement is the American Council on Graduate Medical Education (ACGME), which accredits all US postgraduate training programs. Recently, the ACGME has defined a set of six core clinical competencies that all graduates must demonstrate. A second emerging trend is inter-professional education. Increasingly, healthcare is provided by inter-professional healthcare team, and students must be competent to function effectively in this setting. Many academic health centers are developing joint curricula to address this need. Medical education has evolved from a primary focus on content to an emphasis on process of teaching and learning, and will increasingly concentrate on educational outcomes.

Analysis of the B cell repertoire against human cancers: what we have learnt from SEREX
Michael Pfreundschuh
The SEREX approach, the serological analysis of antigens by recombinant expression cloning, is based on the concept of "autologous typing" which was developed by Dr. Old's group in the late 70s. Like "autologous typing", SEREX exploits the patients' B cell repertoire for the identification and characterization of human tumor antigens that are immunogenic in the autologous host. The first human tumor antigen was identified by SEREX in 1993, when HOM-RCC-3.1.3, a new human carbonic anhydrase was shown to be overexpressed and immunogenic in a subpopulation of renal cancers. Since then, >2000 antigens have been defined by SEREX, demonstrating that most, if not all human cancers express multiple genes coding for proteins that are immunogenic in the autologous host. The specificities of tumor-associated antigens span the wide spectrum from strictly tumor-specific over differentiation antigens, products of mutated and viral genes, genes overexpressed or amplified in tumors to antigens which show the wide-spread distribution of common autoantigens without any differential expression between normal and malignant tissues. It has become evident that being presented in the context of "danger" (i.e. by a neoplasm) is of greater importance for the antigenicity of a molecule than its more or less restricted expression in a malignant tissue. From the clinical point of view, however, only antigens with a specific or preponderant expression in tumors are attractive candidates for vaccine strategies. Of the latter, the group of cancer testis antigens (CTA) has attracted special attention. With prominent members being the originally T-cell defined MAGE, BAGE and GAGE antigens, CTA represent a rapidly growing group of gene families that are expressed in a wide spectrum of human tumors, but not in normal tissues except for testis. Using reverse T-cell immunology, preexisting T-cell clonescould be shown to react with several of SEREX-defined CTA, e.g. NY-ESO-1 and HOM-MEL-40, and we expect all SEREX antigens to be shown to elicit T-cell responses if only looked for carefully enough. Moreover, we have just started to learn about the functional role of some antigens in the pathogenesis of malignant tumors, thus gaining important insights into their biologic relevance. The availability of monoclonal antibodies will reveal the expression of antigenic products at the single tumor cell level. However, the development of the SEREX data base indicates that the number of human tumor antigens detectable if expressed in bacteria is limited. We therefore have recently aimed at extending the antigen spectrum to posttranslationally modified antigens using a eukaryontic expression system in yeast (RAYS). First experiences with RAYS indicate that RAYS will not only increase the number of human cancer-associated antigens, but will also identify posttranslationally modified antigens that would have been missed using a bacterial expression system. A first example of such a novel tumor-associated antigen is the SBEM (small breast epithelial mucin). The majority of patients with breast cancer have antibodies against a deleted variant of SBEM expressed in yeast, but not if this antigen is expressed in E. coli. Similarly, against other structures which are exclusively expressed in malignant but not normal tissues, e.g. SSX-4 antibodies can be found in the sera of patients only if the antigen is expressed in an eukaryotic system, suggesting that posttranslationally modified structures (e.g. glycosylated sites) are the target of the antibody response. Thus RAYS holds promise to open a new dimension in cancer antigen research.

Tumor necrosis factor-mediated bone resorption
Brendan F. Boyce, Qian Zhang, I. Raul Badell, ZhenqiangYao, Li Fang, Ping Li, Teruhito Yamashita, Koichi Matsuo, Edward M. Schwarz and Lianping Xing
Postmenopausal bone loss and erosive joint disease are major clinical problems in Western communities and are growing problems in the developing world as life expectancy increases. Postmenopausal osteoporosis affects more than 30% of women over 65 years and is mediated by osteoclasts stimulated by proinflammatory cytokines, such as TNF, without a compensatory increase in bone formation by osteoblasts. Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disorder that causes joint destruction mediated by cytokines and afflicts approximately 1% of adults worldwide causing substantial pain and disability. TNF increases osteoclast formation either indirectly by stimulating accessory cells, such osteoblasts, synoviocytes, T and B lymphocytes, and endothelial cells to produce essential osteoclastogenic factors, particularly RANKL and MCSF, or by acting directly on osteoclasts or their precursors. Thus, there are multiple mechanisms whereby TNF can promote osteoclast formation and bone loss in these common bone diseases. However, the mechanism by which TNF causes osteoclastogenesis directly is controversial. TNF transgenic mice and patients with active erosive arthritis have chronic TNFa exposure and a marked increase in the frequency of osteoclast precursors in their peripheral blood. TNFa promotes bone resorption by inducing proliferation and differentiation of osteoclast precursors, which enter the peripheral blood and differentiate into osteoclasts at sites in bone where inflammatory cytokine production is increased. It also protects osteoclasts from the apoptosisinducing action of bisphosphonates by up-regulating Bcl-xL expression in osteoclasts, which we believe accounts in part for the lower efficacy of bisphosphonates in in.ammatory bone disease than in postmenopausal osteoporosis.

H2S as a novel gasotransmitter in cardiovascular system
Rui Wang
Recent advance in gasotransmitter research has revealed important physiological role of hydrogen sulfide (H2S), in addition to its well-known toxicological effect. The endogenous production of H2S has been demonstrated in vascular smooth muscle cells (SMCs), catalyzed by cystathionine γ-lyase (CSE). At physiologically relevant concentrations, H2S relaxes vascular tissues by directly acting on vascular SMCs. Inhibition of CSE induces a slowly developed hypertension. Increased endogenous production of H2S, on the other hand, reduced the contraction of isolated vascular tissues, and decreased blood pressure in whole animals. The vasorelaxant effect of H2S is partially mediated by endothelium but KATP channels in vascular SMCs are the major target of this gas. Pinacidil mimicked, but glibenclamide suppressed the vascular effect of H2S. The whole-cell patch clamp study revealed that H2S increased KATP channel currents and hyperpolarized membrane of single vascular SMCs. Since the known second messenger systems are not apparently altered by H2S, a direct interaction of KATP channels and H2S has been assumed. Dependent on types of vascular tissues, the production of H2S and the mechanisms for the vasorelaxant effects of H2S vary. Vasorelaxation of resistant arteries induced by H2S is much greater than that of conduit artery. Taken together, the importance of H2S as a gasotransmitter in homeostatic control of cardiovascular function has been greatly appreciated. Unmasking the molecular mechanisms for the effect of H2S on the structure and function of KATP channels will help understand the cellular effects of H2S.