Induction of angiogenesis by hyperplastic colonic mucosa adjacent to colon cancer

We determined whether hyperplastic mucosa adjacent to colon cancer contributes to neoplastic angiogenesis. Surgical specimens of human colon cancer (40 Dukes' stage B and 34 Dukes' stage C) were analyzed by immunohistochemistry for expression of proliferative and angiogenic molecules. The mucosa adjacent to Dukes' stage C tumors (but not Dukes' stage B tumors) had a higher Ki-67 labeling index and a higher expression of epidermal growth factor receptor and transforming growth factor-alpha than distant mucosa. The expression levels of vascular endothelial growth factor, basic fibroblast growth factor, interleukin-8, and the vascular density in the adjacent mucosa were similar to those in the tumor lesions and significantly higher than those in the distant mucosa. The expression of interferon-beta inversely correlated with the level of pro-angiogenic molecules and the vascular density. The injection of metastatic human colon cancer cells and murine colon cancer cells into the cecal wall of mice induced hyperplastic changes in the adjacent mucosa which expressed higher levels of epidermal growth factor receptor, basic fibroblast growth factor, and vascular endothelial growth factor, and lower levels of interferon-beta than did the control mucosa, which directly correlated with the degree of hyperplasia. These data suggest that metastatic human colon cancer cells can induce hyperplasia in the adjacent mucosa, which in turn produces angiogenic molecules that contribute to neoplastic angiogenesis.     

Evidence for the causal role of endogenous interferon-alpha/beta in the regulation of angiogenesis,tumorigenicity, and metastasis of cutaneous neoplasms

Primary tumor growth and metastasis depend on angiogenesis, which is determined by the balance between proangiogenic and antiangiogenic molecules. Interferon (IFN)-α and -β inhibit angiogenesis through downregulation of interleukin-8, matrix metalloproteinase-9, and basic fibroblast growth factor. To provide evidence for the causal role of IFN-α/β in the induction of neoplasms, their angiogenesis, and hence, progressive growth, we carried out experiments using 129S6 IFN-α/β receptor −/− mice back-crossed to BALB/c nude mice. Subcutaneous angiogenesis was determined following implantation of gelfoam sponges containing 0.4% agarose and several proangiogenic molecules. Tumorigenicity and production of lung metastasis were determined subsequent to subcutaneous and intravenous injections, respectively, of highly metastatic A375SM human melanoma cells. Carcinogenesis was induced by chronic exposure of mice to UVB radiation (5 kJ/m², 3 times/week). Angiogenesis, tumorigenicity, and production of metastasis, as well as development of autochthonous skin tumors, were all accelerated in IFN-α/β receptor −/− mice as compared to control mice. Collectively, the data show that inability to respond to endogenous IFN-α/β (through a mutation in the IFN-α/β receptor) leads to increased susceptibility to carcinogenesis, enhanced angiogenesis, tumorigenicity, and metastasis. This revised version was published online in July 2006 with corrections to the Cover Date.     

Modulation of Doxorubicin sensitivity and level of p-glycoprotein expression in human colon-carcinoma cells by ectopic and orthotopic environments in nude-mice

The purpose of the study was to determine whether the organ environment can influence the response of colon cancer cells to chemotherapy. The highly metastatic human colon cancer cell line KM12L4, previously selected for production of liver metastases in nude mice, was injected into the cecal wall and into the spleen to produce liver metastases, and into the subcutis of nude mice. Doxorubicin (DOX) at 10 mg/kg or saline (control) was injected intravenously on days 7 and 16 after tumor cell injection. The in vivo response of tumors growing in the cecum, liver, and subcutaneous (s.c.) sites as well as the DOX sensitivity of cell lines established from liver and s.c. tumors were compared. Colon cancers growing s.c. were more sensitive to DOX than tumors growing in the cecal wall or liver of nude mice. The difference in response to DOX between s.c. tumors (sensitive) and liver tumors (resistant) was not due to selection of cell populations with different sensitivity to DOX, or differences in DOX distribution. PKC activity was lower in tumors of the liver and the cecum than in s.c. tumors. The expression of P-glycoprotein as determined by flow cytometric analysis of tumor cells harvested from lesions in different organs correlated inversely with their sensitivity to DOX. Increased levels of P-glycoprotein correlated with mdr-1, mdr-3 mRNA expression as determined by Northern analysis. Collectively, the data show that the organ environment influences the response of human colon carcinoma cells to DOX and recommend that animal models of this disease for experimental therapeutic studies employ orthotopic implantation of tumor cells.     

Site-dependent expression of vascular endothelial growth factor, angiogenesis and proliferation in human gastric carcinoma

To determine the role of site of tumor implantation on tumor angiogenesis, we implanted gastric cancer cells in the orthotopic (stomach) and ectopic (subcutaneous) locations in nude mice. Tumors in the stomach demonstrated greater vascularization, higher levels of vascular endothelial growth factor (VEGF) expression, and greater proliferation compared with tumors in the subcutaneous tissues. These data suggest that the relationships among the expression of VEGF, vascularization, and proliferation of human gastric cancer cells are regulated by the organ microenvironment. In addition, VEGF may provide a target for anti-angiogenic therapy for gastric cancers.     

School health promotion in South‐East Asia by Japan and partners

School health promotion in South‐East Asia has developed rapidly in recent years, and Japan has been one of the significant contributors to the reinforcement of school health promotion in the region. Starting from the Hashimoto Initiative on global parasite control, Japan advocated for international partnerships with several agencies for the development of school health programs in South‐East Asia. Through a strengthened collaboration with international organizations, countries such as the Lao PDR, Cambodia, the Philippines, and Thailand have created and implemented school health programs on nutrition, sanitation, and deworming, among others. In addition to school health program formulation and implementation, the expanded network in South‐East Asia led to more capable school health personnel, with many workers in the education and health sectors benefitting from the training programs jointly held by collaborating organizations.     

The natural history of sex-linked recessive dystonia parkinsonism of Panay,Philippines (XDP)

Sex-linked dystonia parkinsonism (XDP) was reported by Lee et al. in 1975 occurring endemically in Panay, Philippines. It is an adult onset, sex-linked, predominantly male, severe, progressive movement disorder with high penetrance and a high frequency of generalization. The movement disorder is characterized by dystonic movements usually starting in the third or fourth decade, focal at the onset, spreading to generalization within 2-5 years. The dystonia co-exist or is replaced by parkinsonism usually beyond the 10th year of illness. As of June 2001, 376 XDP cases have been registered. One hundred and fifteen cases have died. The prevalence of XDP in the island of Panay is 5.24 per 100,000; 0.34/100,000 in the general population. The prevalence varies in the different provinces; it is highest in Capiz at 18.88/100,000, 7.46/100,000 in Aklan, 1.28 in Iloilo and 0.83 in Antique. The 376 cases are from 188 families and 92% of cases have positive family history. Ninety-nine percent of the cases are males. The mean age of onset is 39.48 years. Duration of illness is 12.95 years. Ninety-four percent of patients initially manifest with dystonic symptoms, while only 6% present with Parkinsonian traits. Among those presenting with dystonia, the initial presentation is in the lower extremities in 33%, craniofacial in 27%, cervical and shoulder in 25%, upper extremities in 14%, and trunk in 1%. Regardless of the site of onset, the dystonia spreads in 98% and generalizes within 5 years in 84%. Neuroimaging (magnetic resonance imaging, MRI) was done in 16 patients. In the patients who have just manifested the disease usually when dystonia predominates and parkinsonism is absent. MRI showed minimal atrophy of the caudate and putamen or subtle putaminal signal abnormality. In the late course, where Parkinsonism predominates, severe atrophy of the caudate and putamen as well as marked increase in signal abnormality are seen. There are six autopsied cases of XDP. Neuropathology revealed marked atrophy of the caudate and putamen mostly in the cases with longstanding illness. The sex-linked pattern of inheritance has been established. Genetic studies have located the affected gene (DYT3) to Xq13.1. Nemeth's group has mapped the XDP gene to a <350 kb locus in the DXS 7117-DX 559 region. To date, no treatment has been proven consistently effective.     

Adenovirus-E1A gene therapy enhances the in vivo sensitivity of Ewing's sarcoma to VP-16

This study determined the effect of Ad-E1A gene therapy in vivo. TC71 cells (2 x 10(6)) injected subcutaneously into nude mice resulted in tumor development (1-3 mm) 6 days later. Animals were then treated with Ad-E1A or Ad-beta-gal (5 x 10(9) plaque-forming units) by intratumoral injection twice weekly for 2 weeks. Animals received 8 mg/kg VP-16 given by intraperitoneal injection daily for 5 days following the first week of treatment with Ad-E1A or Ad-beta-gal. Control animals received no therapy or VP-16 only after tumor cells were injected. When tumors exceeded 2 x 2 cm, the mice were sacrificed and the tumors underwent histologic and immunohistochemical analysis. Tumors from mice treated with Ad-E1A plus VP-16 were 9.6-fold smaller than those treated with VP-16 alone and 6.3-fold smaller than those treated with Ad-E1A alone. HER2/neu p185 protein expression decreased in all tumors that received Ad-E1A therapy. TUNEL fluorescence staining revealed more apoptosis in the tumors from animals treated with Ad-E1A plus VP-16 than in those from animals treated with Ad-E1A alone, Ad-beta-gal plus VP-16, or VP-16 alone. These data demonstrated that Ad-E1A gene therapy down-regulated HER2/neu expression, increased tumor cell apoptosis induced by VP-16, and enhanced tumor cell sensitivity to VP-16. Ad-E1A may have potential in the treatment of relapsed drug-resistant Ewing's sarcoma.     

Multiparametric in situ mRNA hybridization analysis of gastric biopsies predicts lymph node metastasis in patients with gastric carcinoma.

We examined the expression level of several genes that regulate different steps in metastasis formation in formalin-fixed, paraffin-embedded biopsies of 189 primary human gastric carcinomas prior to surgical resection in patients in whom lymph node metastasis was not evident by endoscopic ultrasound or computed tomography (CT) scan. The expressions of epidermal growth factor receptor (EGF-R), vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2 and E-cadherin were examined by a colorimetric in situ mRNA hybridization technique. The integrity of the mRNAs was verified, leaving 161 (85.2%) patients for study. After gastrectomy, 82 patients had positive lymph nodes and 79 patients had negative lymph nodes. The concurrent expression levels of MMP-2 and E-cadherin mRNAs were significantly higher and lower, respectively, in the metastatic tumors than the non-metastatic tumors. Expression of EGF-R and VEGF was not different between the metastatic and non-metastatic tumors. However, when only the intestinal-type of gastric cancer was evaluated, the level of VEGF mRNA was significantly higher in tumors associated with lymph node metastasis than in those without metastasis. However, a high MMP-2:E-cadherin ratio significantly correlated with lymph node metastasis in both types of gastric cancer. These results suggest that multiparametric in situ hybridization analysis for several metastasis-related genes may allow the preoperative prediction of lymph node metastasis from gastric cancer.     

Abdominal muscle uptake on FDG PET secondary to multiple rib fractures and use of accessory muscles of respiration

A 69-year-old man with a history of lung cancer was referred for FDG whole body positron emission tomography (PET) with computed tomography (CT) fusion. Three days before the study, the patient was involved in a motor vehicle accident (MVA). In addition to hypermetabolic lesions representing metastatic lung cancer, PET scan showed marked anterior and lateral abdominal muscle uptake. Multiple focal abnormalities were seen on the PET scan that corresponded to multiple rib fractures on the CT scan that were secondary to the MVA. When the patient was interviewed, he stated that he had thoracic wall pain that prevented him from breathing properly. This case illustrates an unusual pattern of increased anterior and lateral abdominal muscle uptake as a result of pain while breathing.