We examined the RNA content of the gene encoding angiopoietin (Ang)-2, a modifier of angiogenesis, in hepatic metastases of colorectal cancer (CRC) to explore the role of this protein in neovascularization of metastatic foci. Metastatic CRC exhibited notable blood flow and tumor vessel formation at tumor frontiers. Reverse-transcription polymerase chain reaction assays indicated that the ANG2 RNA content was greater in metastatic CRC than in primary CRC. Investigation of metastatic foci using laser capture microdissection revealed that the RNA content of ANG2, but not ANG1, increased from the bordering liver region to the periphery of the metastatic disease, and also from the periphery to the intermediate portion of the metastatic lesion; immunohistochemical analysis confirmed that there was a corresponding gradual increase in Ang-2 protein expression. Tie-2, a receptor for angiopoietins, was preferentially expressed in the bordering liver region rather than in metastatic CRC. Vascular endothelial growth factor (VEGF) also exhibited an expression pattern similar to that of Ang-2, and there was a significant correlation between the RNA content of ANG2 and that of VEGF in dissected samples (P ؍ .002). Western blot analysis suggested that expression of Ang-1, Ang-2, Tie-2, and VEGF may be regulated at a transcriptional level. C olorectal cancer (CRC) is a common malignancy worldwide. Although 84%-92% of patients with CRC are treated with surgical resection, more than half of these patients subsequently develop disease recurrence, 1 the most common type of recurrence being CRC metastatic to the liver, which often is associated with mortality. 2,3 Metastasis of CRC to the liver is a complex multistep process, which includes adherence of metastatic cells to endothelial cells (ECs), invasion across the endothelial basement membrane, cell proliferation, and neovascularization. 4 It was reported that tumor vessels appeared in human liver metastases when metastatic foci grew to 200 m in diameter and that the density of tumor vessels increased as tumor size increased. 5 Angiogenesis is essential for tumor growth and expansion, because the resulting blood vessels supply malignant cells with sufficient oxygen and nutrition. 6,7 Therefore, interruption of this process is considered to be a strategy for preventing CRC metastases to the liver.Recent studies have focused on novel endothelial growth factors such as angiopoietins (Ang), which are ligands for the endothelium-specific tyrosine kinase receptor Tie-2. 8 -10 Ang molecules play crucial roles in normal vascular development and in embryonic angio-
It is known that p16 INK4 tumor suppressor gene expression in colon cancer cells is repressed by methylation at the CpG island of promoter, but in vivo silencing of p16 gene is not fully understood. Some studies showed that primary colorectal cancer (CRC) tissues often overexpress the p16 protein, while others showed the high incidence of p16 methylation. The aim of this study was to clarify p16 gene regulation in vivo. We used real-time methylationspecific PCR (MSP) to examine density of p16 methylation, and immunohistochemistry, Western blot analysis to determine p16 protein expression. Methylation was detected in 5 CRC cell lines tested and 9 of 21 (42.9%) CRCs. Four of 5 CRC cell lines did not express p16 mRNA, but 6 of 9 CRCs did express p16 mRNA even with methylation. Real-time MSP showed that CRC tissues had a wide variety in methylation density (methylation index: 0.28-0.91) and that highly methylated CRC tissues displayed significantly lower p16 mRNA expression than those with no-methylation or lowmethylation. Immunohistochemistry showed that the majority of CRCs (53 of 55: 96.4%) overexpressed the p16 protein. Low p16 expression was associated with lymph node metastasis (p=0.003) and large tumor size (p=0.048). Western blot in a subset of non-tumor and tumor samples showed a consistent overexpression of the p16 protein. These results showed that CRC tissues displayed variable methylation density, which may be characteristics of p16 gene methylation in vivo. Our data suggest that a low p16 expression due to methylation may contribute to tumor enlargement and expansion of CRC.
To elucidate the ventricular contractile state and function in patients with univentricular heart, the ventricular volume, mass, ejection phase index, and wall stress were evaluated with biplane ventriculography and pressure measurement in 41 patients: 18 with left ventricular (LV) type (age, 6.4±6.1 years) and 23 with right ventricular (RV) type (age, 5.7±4.1 years), and data from patients with univentricular heart were compared with data from 19 normal control subjects (age, 7.2 ±4.3 years). Although the end-diastolic and end-systolic volumes were significantly greater in both types of univentricular heart-than in the normal control group, the volumes for the LV and RV type patients did not differ from each other. The ejection fraction (EF) was depressed in both patient types of univentricular heart and was significantly (p<0.005) lower in the RV type than in the LV type patients (0.56±0.05 for LV type, 0.50±0.07 for RV type, and 0.64±0.03 for the control group). The ventricular mass was larger in both patient types of univentricular heart than in that of the control group, whereas the ratio of ventricular mass to end-diastolic volume was significantly (p
Clinical pictures of 21 cases with I‐cell disease patients, 12 males and 9 females, were analyzed. Characteristic coarse facial features and shortness of stature were observed in all cases. In general, the motor development was found to be more severely retarded than the mental development of the patients. Rather little involvement of the nervous system seemed to cause somewhat acceptable mental development in some cases, and also cause the absence of epileptic seizures in all cases. Involvement of the cardiovascular system, especially progressive hypertrophic cardiomyopathy, could be highly responsible for frequent sudden death of I‐cell disease patients.
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