To understand the mechanism of antineoplastic action of phytic acid, we investigated the absorption and distribution of myo-[inositol-2-3H(N)] hexakisphosphate in rats. The radioactivity was measured in urine, feces, blood, gastrointestinal tract contents and various organs and tissues at 1 and 24 h after intragastric administration. Of the total radioactivity, 79.0 +/- 10.0% was absorbed and at least 26.6% was degraded during the 24-h period following ingestion. The absorption was rapid; 11.0 +/- 2.6% of the radioactivity was detected in the wall of the stomach (4.4 +/- 3.7%) and upper small intestine (6.6 +/- 1.9%), 6.5 +/- 2.6% in the skeletal muscle and 4.0 +/- 1.5% in the skin after 1 h. Much of the radioactivity after 24 h was in the liver (4.0 +/- 0.9%), kidneys (2.2 +/- 1.1%), muscle (18.1 +/- 3.4%) and skin (10.1 +/- 3.3%). Analysis of plasma and urine demonstrated that most of the radioactivity was due to myo-inositol and small amounts of inositol monophosphate (InsP1). Gastric epithelial cells, however, contained inositol and various inositol phosphates (InsP1-6). Our data suggest that soluble InsP6 when administered in drinking water is rapidly absorbed through the stomach and upper small intestine, becomes quickly dephosphorylated within the mucosal cells and is distributed to various organs as inositol and InsP1.
Background: Low-grade cribriform cystadenocarcinomas (LGCCC) are rare salivary gland tumors, classified into a variant of cystadenocarcinoma by the 2005 WHO classification. All previously reported cases arose from parotid glands, except for a case from a minor salivary gland. We report here for the first time a case of LGCCC arising from the submandibular gland. Case: A 65-year-old man presented with a 4-cm multicystic mass in the left submandibular gland. Smears from fine-needle aspiration cytology showed tumor cells, appearing solitarily or partly in clusters, with thick cytoplasm and central nuclei. Some clustering tumor cells showed large cytoplasmic vacuoles and peripherally dislocated nuclei. Although these findings indicated a possible mucoepidermoid carcinoma in the submandibular gland, the final diagnosis of the resected specimen was LGCCC. Conclusion: LGCCC can arise not only from the parotid glands, but also in the submandibular glands. LGCCC is thought to be of low-grade malignancy; no reported cases have shown tumor metastasis and there are no patients who are known to have died of this disease. Thus, differential diagnosis of this tumor from other malignant salivary gland tumors is quite important; however, this might be difficult when based solely on cytological findings.
BACKGROUND Mutations of the transforming growth factor‐β type II receptor gene (TGF‐β RII) have been found in several replication error‐positive sporadic colorectal carcinomas and hereditary nonpolyposis colorectal carcinoma cell lines. The aim of this study was to clarify the role of TGF‐β RII in sporadic colorectal carcinogenesis. METHODS The authors screened for mutations at simple repeated sequences in the TGF‐β RII gene by polymerase chain reaction‐single strand conformation polymorphism. They also examined genomic instability, using five microsatellite DNA markers in 69 sporadic colorectal carcinomas. When the carcinomas exhibited the TGF‐β RII mutations, the authors screened further for mutations in two DNA mismatch repair genes, hMSH2 and hMLH1. RESULTS Seven of the 69 cancers (10%) showed one or two A deletions in TGF‐β RII and resultant frameshift mutations in nucleotide positions 709‐718 containing a (A)10 repeated sequence; but none of these appeared in the corresponding normal DNA, indicating a somatic mutation. All of the seven cancers were located in the proximal colon; there were none in the distal colon (P < 0.01). On the other hand, 22 of the 69 carcinomas (32%) showed the replication error‐positive phenotype. The frequency of replication errors in proximal colon carcinomas was higher than that in distal colon carcinomas (P < 0.05). All 7 cancers with TGF‐β RII mutations showed replication errors. One of them revealed a nonsense mutation at codon 413, and 1 revealed a loss of heterozygosity in hMSH2. CONCLUSIONS These data indicate that mutations of TGF‐β RII are strongly related to proximal colon carcinomas with microsatellite instability and that the mechanism of carcinogenesis in some proximal colon carcinomas is similar to that in hereditary nonpolyposis colorectal carcinoma. Cancer 1996; 78:2478‐84.
To identify additional alterations to c-kit or platelet-derived growth factor receptor α α α α (PDGFRA) genes in gastrointestinal stromal tumors (GIST), we investigated the methylation status of nine known methylation-sensitive CpG islands (p15, p16, p73, 0-6-methylguanine-DNA methyltransferase, E-cadherin, mutL homolog 1, colon cancer nonpolyposis type 2 (escherichia), methylated in tumors [MINT] 1, MINT2, and MINT31), and compared the results with the malignant potential and gain-of-function mutation types of GIST. Thirty-five GIST (c-kit mutations in 25 cases, PDGFRA mutations in seven cases, and lacking either mutation in three cases) were subjected to methylation-specific polymerase chain reaction to detect the methylation status of the nine methylation-sensitive CpG islands. Aberrant DNA methylation of these loci was found in 94% of all GIST. The rates of DNA methylation at each locus were as follows: hMLH1, 60%; MINT2, 51%; MGMT, 49%; p73, 49%; p16, 20%; Ecadherin, 14%; MINT1, 9%; p15, 6%; and MINT31, 0%. CpG islands methylator phenotype, which was defined as methylation involving more than three gene promoters, was found in 57% of GIST with c-kit or PDGFRA gene mutations. According to the risk categories, CpG islands methylator phenotype was present in 55% of low-risk GIST, and in 58% of high-risk GIST. Our results suggested that in addition to c-kit or PDGFRA mutations, the aberrant methylation of CpG islands, especially of mismatch-repair genes, may have a role in the tumorigenesis of GIST. (Cancer Sci 2008; 99: 253-259) G astrointestinal stromal tumors (GIST) are thought to be the most common nonepithelial tumors in the gastrointestinal tract with an annual incidence estimated at 10-20 cases per million.(1) During tumorigenesis of GIST, the most frequent changes are reported to be gain-of-function mutations in c-kit protooncogene. These mutations can result in autophosphorylation, namely KIT ligand-independent kinase activity.(2) C-kit mutations occur in up to 90% of GIST. Also, approximately 5% of GIST are characterized by a mutation in the related receptor tyrosine kinase platelet-derived growth factor receptor α (PDGFRA) exons 12 and 18.(3,4) Very recently, Lasota et al. reported PDGFRA exon 14 mutations in 11 of 200 GIST negative for mutations in c-kit exons 9, 11, 13, and 17, and PDGFRA exons 12 and 18.(5) However, approximately 5% of all GIST do not have a detectable mutation in either c-kit or PDGFRA genes.Although most GIST are characterized by a gene mutation in either c-kit or PDGFRA, the clinical behavior of each GIST differs widely from benign to malignant with widespread metastasis. Therefore, we speculated that additional genetic alterations, other than the c-kit and PDGFRA genes, were required for the progression of GIST.We previously reported allelic losses of 1p, 14q, and 22q in both low-and high-risk GIST.(6) Moreover, additional chromosomal losses and microsatellite instability (MSI) were observed in highrisk GIST. Fluorescence in situ hybridization (FISH) or comparative genomic hyb...
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