In the development of colorectal cancer (CRC), it is now widely accepted that some forms of genetic instability lead to the sequential accumulation of genetic alterations and consequently develop carcinomas. 1 RAS activation in the MAP kinase cascade is supposed to constitute a part of the primary events in colorectal carcinogenesis, and the KRAS gene mutations have been found in about 30 -40% cases of sporadic CRCs. [2][3][4] Recently, activating BRAF mutations have been found almost invariably in melanoma cells and sometimes in other types of carcinoma, including CRCs, 5-7 implying a function of BRAF as a protooncogene. The RAF genes are members of MAPK pathway, encoding serine/threonine kinases that integrate the upstream input signals. 8,9 Once recruited at the cell membrane by GTP-loaded RAS, RAF becomes activated and subsequently phosphorylates the downstream kinases, MEKs, which eventually induce transcriptional activation of the target genes. 9 More recently, frequent BRAF mutations and infrequent KRAS mutations have been reported in DNA-mismatch repair (MMR)-deficient CRCs. 10 Inactivation of MMR genes incurs instability of genomic microsatellite sequence (microsatellite instability, or MSI), which is found in the majority of patients with hereditary nonpolyposis colorectal cancer syndrome (HNPCC) and in 10 -15% of cases of sporadic CRCs. 11-13 Moreover, it was also reported that 70 -90% of sporadic CRCs with MSI (MSI ϩ CRCs) are associated with hypermethylation of hMLH1, one of DNA-MMR genes, and have distinct clinical and pathologic characteristics, i.e., occurrence in older females, location in the proximal colon and histopathology of mucious or poor differentiation. 14 -20 We have previously examined the methylation status of hMLH1 gene in sporadic CRCs by use of 5 sets of primer spanning the whole CpG sites within its promoter region and have classified the methylation status into 3 subtypes: full methylation, partial methylation and nonmethylation. 21,22 We reported that an extensive methylation, or full methylation, of hMLH1 promoter was found in about 80% of MSI ϩ CRC cases and was highly associated with loss of expression of its gene product. Interestingly, this type of CRC cells are rarely associated with KRAS mutations and loss of heterozygosity (LOH) of TP53 gene. 22 It is therefore possible that extensive methylation of hMLH1 promoter region may contribute to the carcinogenesis of the right-sided sporadic CRCs, independently of KRAS/p53 alterations.From these results, 2 questions may arise. First, does the activation of BRAF, instead of KRAS, take part in the carcinogenesis of CRCs with extensive hMLH1 methylation? Second, if so, does the BRAF activation have any relationship with the CRCs with partial methylation, although most of which are microsatellite stable (MSI Ϫ ), maintain MMR gene expression and show a relatively high incidence of KRAS and p53 alterations? 22 Additionally, in the melanoma cells, high frequency of mutations of ␤-catenin and BRAF has been recognized. 23 Some resea...

To investigate the relationship between the tumor growth rate of the primary breast cancer and its prognosis, records for 122 breast cancer patients in 9 hospitals in Japan were retrospectively reviewed. These records contained at least two measurements of the same tumor mass in the breast. So the growth rate was estimated from these measurements taken at different points in time. The doubling time of the breast tumors showed an approximately log‐normal distribution. The geometric mean of doubling times for all cases was 174 days. The solid‐tubular histologic type of carcinoma had the shortest geometric mean of doubling time (126 days), the scirrhous carcinoma had the second shortest one (205 days), and the papillotubular carcinoma had the longest one (252 days). The patients with shorter doubling time of tumor tended to have a poorer prognosis. The Cox multiple regression analysis showed that the tumor growth rate was related significantly with survival, after adjusting for other covariates such as clinical stage, lymph node metastasis, age of patient, histological type, and year of treatment.

Pancreatic ductal carcinoma (PDC) remains one of the most intractable human malignancies, mainly because of the lack of sensitive detection methods. Although gene expression profiling by DNA microarray analysis is a promising tool for the development of such detection systems, a simple comparison of pancreatic tissues may yield misleading data that reflect only differences in cellular composition. To directly compare PDC cells with normal pancreatic ductal cells, we purified MUC1-positive epithelial cells from the pancreatic juices of 25 individuals with a normal pancreas and 24 patients with PDC. The gene expression profiles of these 49 specimens were determined with DNA microarrays containing >44 000 probe sets. Application of both Welch's analysis of variance and effect size-based selection to the expression data resulted in the identification of 21 probe sets corresponding to 20 genes whose expression was highly associated with clinical diagnosis. Furthermore, correspondence analysis and 3-D projection with these probe sets resulted in separation of the transcriptomes of pancreatic ductal cells into distinct but overlapping spaces corresponding to the two clinical classes. To establish an accurate transcriptome-based diagnosis system for PDC, we applied supervised class prediction algorithms to our large data set. With the expression profiles of only five predictor genes, the weighted vote method diagnosed the class of samples with an accuracy of 81.6%. Microarray analysis with purified pancreatic ductal cells has thus provided a basis for the development of a sensitive method for the detection of PDC.

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S-1 was demonstrated to have high efficacy with low gastrointestinal toxicity even in older patients and will be a promising new chemotherapy drug for metastatic breast cancer.

Summary. Myelodysplastic syndrome (MDS) is a clonal disorder of haematopoietic stem cells. Despite the high incidence of MDS in the elderly, effective treatment of individuals in its advanced stages is problematic. DNA microarray analysis is a potentially informative approach to the development of new treatments for MDS. However, a simple comparison of 'transcriptomes' of bone marrow mononuclear cells among individuals at distinct stages of MDS would result in the identification of genes whose expression differences only reflect differences in the proportion of MDS blasts within bone marrow. Such a 'population shift' effect has now been avoided by purification of haematopoietic stem-like cells that are positive for the cell surface marker AC133 from the bone marrow of healthy volunteers and 30 patients at various stages of MDS. Microarray analysis with the AC133 + cells from these individuals resulted in the identification of sets of genes with expression that was specific to either indolent or advanced stages of MDS. The former group of genes included that for PIASy, which catalyses protein modification with the ubiquitin-like molecule SUMO. Induction of PIASy expression in a mouse myeloid cell line induced apoptosis. A loss of PIASy expression may therefore contribute directly to the growth of MDS blasts and stage progression.

The murine sak gene encodes a putative serine-threonine kinase which is homologous to the members of the Plk/Polo family. Although Sak protein is presumed to be involved in cell growth mechanism, efforts have failed to demonstrate its kinase activity. Little has been, therefore, elucidated how Sak is regulated and how Sak contributes to cell proliferation. Tec is a cytoplasmic protein-tyrosine kinase (

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