Abstract

Adventures with hydroxysteroid dehydrogenases

J Ian Mason

The formation of steroid hormones can no longer be considered endocrine events associated with the classical steroidogenic organs, i.e., adrenal cortex, gonads and trophoblast. It is now recognized that the targets of steroid hormone action, so-called peripheral tissues, play vital roles not only in further activation of steroids but also in the moderation of steroid hormone action. In particular, various hydroxysteroid dehydrogenases can act as pre-receptor signalling devices controlling the availability of steroid hormones to their cognate hormone receptors. Thus these enzymes function as molecular 'switches' controlling processes including development, differentiation, proliferation and metabolism. The steroidogenesis process involves two superfamilies of enzymes, namely the cytochrome P450-dependent hydroxylases and the hydroxysteroid dehydrogenases. While the former are single gene products, the hydroxysteroid dehydrogenase families are frequently characterised by the multiplicity of gene products associated with a single biotransformation step. This feature raises the likelihood of multi-factorial regulated, tissueselective expression of multi-functional enzyme activities. Because of our interest in injury and repair in the female reproductive tract, our own focus has been on the two human 11b-hydroxysteroid dehydrogenases (11b-HSD1 and 11b-HSD2) as well as the 17bhydroxysteroid dehydrogenase (currently 11 human membersinthisfamily!)and3b-hydroxysteroid dehydrogenase (2 human isoforms) families. In particular, because the 11b-HSD1 functions predominantly as a cortisone reductase while 11b-HSD2 functions almost entirely as a cortisol dehydrogenase, the balance of these two activities at any inflammatory site may importantly influence the repair process.

Maturation of glutamatergic synapse and its implicationtopediatricneurological disorders

Akira Yoshii

PSD-95 is a postsynaptic density protein that clusters glutamate receptors and associates them with other signaling molecules. Thus PSD-95 plays a major role in glutamate mediated synaptic plasticity. PSD-95 moved to visual synapses within 2-6 hours of eye-opening in postnatal day 13 and this shift correlated with electrophysiological changes such as increased AMPA currents and long term potentiation. The synaptic increase of PSD-95 also correlated with eye-opening when controlled eye-opening occurred at postnatal day 11 or 16. Four days of visual deprivation starting at postnatal day 16 reduced synaptic PSD-95 that recovered within a few hours after re-opening of the eyes. This phenomenon was not present in young adults. Thus, the trafficking of PSD-95 is a major mechanism underlying synaptic maturation in the developing visual system. Furthermore, we show that synaptic delivery of PSD-95 inside the dendritic spines is dependent on the F-actin motor protein, Myosin Va (MyoVa). MyoVa forms a complex with PSD-95 as well as GKAP. MyoVa co-localized with PSD-95 in wild type visual cortical neuronal cultures. In dominant negative mutant mouse of MyoVa called flailer,PSD-95failedtobeenrichedinsynaptosomes upon eye-opening. In flailer neurons, the largest amount of PSD-95 immunoreactivity was in dendritic shafts and rarely present in the spines. Furthermore, flailer neurons showed altered electrophysiological findings and resistance to NMDA-induced excitotoxicity. These findings argue that trafficking of PSD-95 is regulated by MyoVa and that perturbing synaptic localization of PSD-95 alters regulation of glutamate receptor thus underlies neurological symptoms such as epilepsy and ataxia.

US practice for colon cancer screening

Jack A. Di Palma

Colon cancer screening in the United States is performed with the same enthusiasm as is screening for early gastric cancer in Japan. It is perceived that with the continued Westernization of the Japanese diet, colon cancer will become more prevalent and more important for screening in Japan. Worldwide, there are over 1 million new cases annually with 529,000 deaths. The geographic variation shows high prevalence in north America, Australia, Argentina, and western Europe. The prevalence is less in countries like Japan, Nigeria and the Indo-Asian peninsula. Epidemiology suggests an association with meat consumption. Approximately 75% of colon cancers occur sporadically. Twenty percent have a familial association and 3-5% have a genetic predisposition. Having a family member with colon cancer or the cancer precursor lesion adenomatous polyp doubles an individual’s lifetime risk of cancer. Genetic syndromes with colon cancer risk include familial adenomatous polyposis coli (FAP) and Hereditary Non-polyposis colorectal cancer (HNPCC). Continued study of the epidemiology, particular of Japanese, will encourage primary, secondary and tertiary prevention measures. For screening, the American College of Gastroenterology advises colonoscopy as the preferred modality to start at age 50 and every 10 years thereafter. Patients with family history and genetic risks should have colonoscopy at earlier ages and closer subsequent intervals. Additional study will define the roles of new technologies such as genetic screening, virtual colonography and capsule colonoscopy.

Aberrant p16 methylation, gastric carcinogenesis, and biomarker

Dajun Deng

Transcription silencing of tumor suppressor genes by methylation may involve in gastric carcinogenesis. Detection of aberrant methylation of CpG islands may be useful for predication of prognosis and diagnosis of gastric carcinoma (GC) and its precancerous lesions. The relationships between p16 methylation, gastric chemical carcinogenesis, progression of gastric dysplasia were studied in a series of investigations among experiment rat model and population of high risk of GC. Results show: A) In MNNG-induced rat gastric carcinogenesis model, p16 methylation frequency was positively correlated with the severity of gastric pathologic lesions, normal (2.7%, n = 36), chronic atrophy gastritis (16.7%, n = 24), dysplasia (37.5%, n = 24), gastric adenoma (67.4%, n = 43), and GC (85.2%, n = 27); B) In a population-based nested case-control study, p16 methylation was observed in 5 of 21 samples of low-grade dysplasia progressed to GC in 5 year follow-up and also observed in the 5 subsequent GC, but none of 21 ones without progression (p = 0:048, 2sides); In conclusion, these results indicated that aberrant p16 methylation is an early frequent event that can contribute to gastric carcinogenesis and that p16 methylation might be a very important biomarker to predict malignant potential of gastric dysplasia.