De-N-acetyl-gangliosides in humans: unusual subcellular distribution of a novel tumor antigen. (73/40131)

The disialoganglioside GD3 is a major antigen in human melanomas that can undergo 9-O-acetylation of the outer sialic acid (giving 9-OAc-GD3). Monoclonal antibody SGR37 detects a different modification of the GD3, de-N-acetylation of the 5-N-acetyl group (giving de-N-Ac-GD3). We found that conventional immunohistochemistry of the SGR37 antigen is limited by a reduction in reactivity upon fixation with aldehydes (which presumably react with the free amino group) or with organic reagents (which can extract glycolipids). We optimized conditions for detection of this antigen in unfixed frozen tissue sections and studied its distribution in human tissues and tumors. It is expressed at low levels in a few blood vessels, infiltrating mononuclear cells in the skin and colon, and at moderate levels in skin melanocytes. In contrast, the antigen accumulates at high levels in many melanomas and in some lymphomas but not in carcinomas. In positive melanomas, expression is sometimes more intense and widespread than that of GD3. Both 9-O-acetylation and de-N-acetylation of GD3 seem to occur after its initial biosynthesis. Isotype-matched antibodies against GD3, 9-O-acetyl-GD3 and de-N-acetyl-GD3 were used to compare their subcellular localization and trafficking. 9-O-acetyl-GD3 colocalizes with GD3 predominantly on the cell surface and partly in lysosomal compartments. In contrast, de-N-acetyl-GD3 has a diffuse intracellular location. Adsorptive endocytosis of antibodies indicates that whereas GD3 remains predominantly on the cell surface, de-N-acetyl-GD3 is efficiently internalized into a compartment that is distinct from lysosomes. Rounding up of melanoma cells occurring during growth in culture is associated with relocation of the internal pool of de-N-acetyl-GD3 to the cell surface. Thus, a minor modification of the polar head group of a tumor-associated glycosphingolipid can markedly affect the subcellular localization and trafficking of the whole molecule. The high levels of the SGR37 antigen in melanomas and lymphomas, its selective endocytosis from the cell surface, and its relocation to the cell surface of rounded up cells suggest potential uses in diagnostic or therapeutic approaches to these diseases.  (+info)

The FEZ1 gene at chromosome 8p22 encodes a leucine-zipper protein, and its expression is altered in multiple human tumors. (74/40131)

Alterations of human chromosome 8p occur frequently in many tumors. We identified a 1.5-Mb common region of allelic loss on 8p22 by allelotype analysis. cDNA selection allowed isolation of several genes, including FEZ1. The predicted Fez1 protein contained a leucine-zipper region with similarity to the DNA-binding domain of the cAMP-responsive activating-transcription factor 5. RNA blot analysis revealed that FEZ1 gene expression was undetectable in more than 60% of epithelial tumors. Mutations were found in primary esophageal cancers and in a prostate cancer cell line. Transcript analysis from several FEZ1-expressing tumors revealed truncated mRNAs, including a frameshift. Alteration and inactivation of the FEZ1 gene may play a role in various human tumors.  (+info)

Effects of dioxins on human health: a review. (75/40131)

The toxicity of 2,3,7,8-tetrachlorodibenzodioxin (TCDD) has been known since 1950s. TCDD is a by-product of herbicide 2,4-dichloroacetophenol (2,4-D) and 2,4,5-trichloroacetophenol (2,4,5-T), but it was first found in fryash of municipal incinerator in 1979 in Japan. In 1998, the survey of municipal incinerators revealed that 105 out of 1,641 produced above the allowed emission level of 80 ng TEQ/m3. Total annual release of dioxins is estimated to be about 5,000 g TEQ in 1997 in Japan. Japanese government started a comprehensive survey for dioxin levels in milk and blood of residents around incinerators, and their health effects. Human effects by dioxin exposures in Western countries were mostly acute and at high level in accidentally and/or occupationally. Health effects of low-dose and long lasting exposure has not been well understood. Certain amount of polychlorinated dibenzo-p-dioxins (PCDD), dibenzofurans (PCDF) and polychlorinated biphenyls (PCB) is accumulated in our body. Mother's milk is also contaminated by PCDD/PCDF. Health effects of the polychlorinated chemicals are summarized, and the necessity of regulations and recommendations for making a guideline is discussed in this review.  (+info)

Photodynamic therapy with mTHPC and polyethylene glycol-derived mTHPC: a comparative study on human tumour xenografts. (76/40131)

The photosensitizing properties of m-tetrahydroxyphenylchlorin (mTHPC) and polyethylene glycol-derivatized mTHPC (pegylated mTHPC) were compared in nude mice bearing human malignant mesothelioma, squamous cell carcinoma and adenocarcinoma xenografts. Laser light (20 J/cm2) at 652 nm was delivered to the tumour (surface irradiance) and to an equal-sized area of the hind leg of the animals after i.p. administration of 0.1 mg/kg body weight mTHPC and an equimolar dose of pegylated mTHPC, respectively. The extent of tumour necrosis and normal tissue injury was assessed by histology. Both mTHPC and pegylated mTHPC catalyse photosensitized necrosis in mesothelioma xenografts at drug-light intervals of 1-4 days. The onset of action of pegylated mTHPC seemed slower but significantly exceeds that of mTHPC by days 3 and 4 with the greatest difference being noted at day 4. Pegylated mTHPC also induced significantly larger photonecrosis than mTHPC in squamous cell xenografts but not in adenocarcinoma at day 4, where mTHPC showed greatest activity. The degree of necrosis induced by pegylated mTHPC was the same for all three xenografts. mTHPC led to necrosis of skin and underlying muscle at a drug-light interval of 1 day but minor histological changes only at drug-light intervals from 2-4 days. In contrast, pegylated mTHPC did not result in histologically detectable changes in normal tissues under the same treatment conditions at any drug-light interval assessed. In this study, pegylated mTHPC had advantages as a photosensitizer compared to mTHPC. Tissue concentrations of mTHPC and pegylated mTHPC were measured by high-performance liquid chromatography in non-irradiated animals 4 days after administration. There was no significant difference in tumour uptake between the two sensitizers in mesothelioma, adenocarcinoma and squamous cell carcinoma xenografts. Tissue concentration measurements were of limited use for predicting photosensitization in this model.  (+info)

Cancer mortality in East and Southeast Asian migrants to New South Wales, Australia, 1975-1995. (77/40131)

Routinely collected data for New South Wales were used to analyse cancer mortality in migrants born in East or Southeast Asia according to duration of residence in Australia. A case-control approach compared deaths from cancer at particular sites with deaths from all other cancers, adjusting for age, sex and calendar period. Compared with the Australian-born, these Asian migrants had a 30-fold higher risk of dying from nasopharyngeal cancer in the first 2 decades of residence, falling to ninefold after 30 years, and for deaths from liver cancer, a 12-fold risk in the first 2 decades, falling to threefold after 30 years. The initial lower risk from colorectal, breast or prostate cancers later converged towards the Australian-born level, the change being apparent in the third decade after migration. The relative risk of dying from lung cancer among these Asian migrants was above unity for each category of duration of stay for women, but at or below unity for men, with no trend in risk over time. An environmental or lifestyle influence for nasopharyngeal and liver cancers is suggested as well as for cancers of colon/rectum, breast and prostate.  (+info)

Risk of breast cancer and other cancers in heterozygotes for ataxia-telangiectasia. (78/40131)

Mortality from cancer among 178 parents and 236 grandparents of 95 British patients with ataxia-telangiectasia was examined. For neither parents nor grandparents was mortality from all causes or from cancer appreciably elevated over that of the national population. Among mothers, three deaths from breast cancer gave rise to a standardized mortality ratio of 3.37 (95% confidence interval (CI): 0.69-9.84). In contrast, there was no excess of breast cancer in grandmothers, the standardized mortality ratio being 0.89 (95% CI: 0.18-2.59), based on three deaths. This is the largest study of families of ataxia-telangiectasia patients conducted in Britain but, nonetheless, the study is small and CIs are wide. However, taken together with data from other countries, an increased risk of breast cancer among female heterozygotes is still apparent, though lower than previously thought.  (+info)

Varicella zoster virus infection associated with high-dose chemotherapy and autologous stem-cell rescue. (79/40131)

A retrospective evaluation of 215 consecutive recipients of high-dose chemotherapy (HDC) and autologous stem cell rescue (ASCR) was conducted to ascertain the incidence, temporal course, and outcome of varicella zoster virus (VZV) infection. Herpes zoster was identified in 40 individuals at a median of 69 days following ASCR. Six of these cases occurred at a median of 33 days prior to ASCR but following the initiation of high doses of stem cell mobilization chemotherapy. Twenty-five percent of patients demonstrated cutaneous or systemic dissemination and 32.5% required medical intervention for post-herpetic neuralgia. All except two individuals received antiviral chemotherapy. One patient with active VZV infection died of multiorgan failure 39 days after ASCR. Multivariate analysis of risk factors disclosed the significance of prophylactic acyclovir use in Herpes simplex virus seropositive individuals in reducing the risk of VZV infection. Moreover, the use of busulfan, thiotepa and carboplatin as the conditioning chemotherapy regimen was associated with an increased risk of subsequent VZV infection. The incidence of VZV reactivation after HDC and ASCR is similar to that observed following bone marrow transplantation but has an earlier onset. This may be related to an earlier induction of immunosuppression by stem cell mobilization chemotherapy administered prior to ASCR. We demonstrated a marked reduction in the proliferative and synthetic capacities of peripheral blood mononuclear cells obtained prior to and following stem cell mobilizing chemotherapy. Moreover, greater than 80% of VZV infections occurred within 6 months following ASCR and late cases were seldom observed compared to allogeneic and autologous bone marrow transplantation. The role of antiviral chemoprophylaxis during the period of maximum immunocompromise needs to be studied further in the HDC-ASCR setting.  (+info)

Leukocytes and platelets of patients with cancer contain high levels of vascular endothelial growth factor. (80/40131)

Vascular endothelial growth factor (VEGF) is a secreted endothelial cell-specific mitogen and permeability factor. Malignant human tumors have been shown to produce VEGF. Elevated levels of VEGF have been detected in sera of cancer patients, but its origin is unsettled. We analyzed VEGF concentrations in serum, plasma, whole blood, and peripheral blood mononuclear cells (PBMNCs) and platelets in 56 cancer patients and 52 healthy controls using ELISA. The VEGF concentrations in the lysed whole blood samples [blood VEGF (B-VEGF)] were higher in cancer patients than in healthy controls (median, 464 versus 298 pg/ml; P<0.0001). The highest B-VEGF values were found in disseminated cancer. In cancer patients, a high B-VEGF concentration was associated with a high peripheral blood leukocyte count (P = 0.0012) and platelet count (P = 0.019). In healthy individuals, a high B-VEGF was associated with a high leukocyte count (P = 0.0001) but not with the platelet count (P>0.1). The cancer patients regularly had higher B-VEGF concentrations than healthy individuals with comparable leukocyte or platelet counts. The VEGF content of isolated PBMNCs and platelets was severalfold higher in cancer patients than in healthy controls (median, 10.6 versus 0.9 pg per 10(6) PBMNCs, and median, 1.6 versus 0.5 pg per 10(6) platelets; P<0.0001 and P = 0.0008, respectively). Serum VEGF and B-VEGF correlated strongly (P<0.0001). Very little or no VEGF was found in the plasma. The results indicate that VEGF in the bloodstream is transported by blood cells, including leukocytes and platelets. The blood cells of cancer patients contain greatly elevated amounts of this major angiogenic growth factor, and this reservoir of VEGF may have a role in tumor angiogenesis and metastasis formation. VEGF in serum samples originates from blood cells, and the use of VEGF of whole blood or of isolated blood cells may improve the clinical value of VEGF measurements.  (+info)