p53 mutations in tumor and non-tumor tissues of thorotrast recipients: a model for cellular selection during radiation carcinogenesis in the liver. (1/52)

Concerns over cancer development from exposure to environmental sources of densely ionizing, high linear energy transfer (LET) radiation, such as alpha-particles from radon, is a current public health issue. The study of tumors attributable to high LET irradiation would greatly augment our insights into the biological mechanisms of carcinogenesis. Chronic low-dose-rate internal exposure to alpha-radiation from thorium dioxide deposits following intravascular administration of the radiographic contrast agent Thorotrast is known to markedly increase the risk of cancer development, especially that of hepatic angiosarcomas and cholangiocarcinomas. Although the mechanism is hypothesized to be via cellular damage, DNA being a major target, wrought by the high LET alpha-particles, the specific genes and the actual sequence of events involved in the process of transforming a normal cell into a malignant one are largely unknown. To shed some light on the molecular mechanisms of cancer development during a lifetime exposure to alpha-radiation, we analyzed the most commonly affected tumor suppressor gene in humans, p53, in 20 Thorotrast recipients who developed cancer, mostly of hepatic bile duct and blood vessel origin. Of the 20 cases, 19 were found to harbor p53 point mutations. Moreover, the accompanying non-tumor tissues from these patients also had p53 mutations, albeit at lower frequency. The distribution pattern of the point mutations was significantly different between the non-tumor and tumor tissues, with most mutations in malignant tissues located in the highly conserved domains of the p53 gene. Our results support the idea that p53 mutations are important in the genesis of Thorotrast-induced tumors but that these point mutations are a secondary outcome of genomic instability induced by the irradiation. Additionally, non-tumor cells harboring p53 mutations may gain some survival advantage in situ but mutations in the domains responsible for the formation of structural elements critical in binding DNA may be necessary for a cell to reach full malignancy.  (+info)

A randomised clinical trial of high-intensity focused ultrasound ablation for the treatment of patients with localised breast cancer. (2/52)

High-intensity focused ultrasound (HIFU) is a noninvasive treatment that induces complete coagulative necrosis of a tumour at depth through the intact skin. This study was to explore the possibility of using HIFU for the treatment of patients with localised breast cancer in a controlled clinical trial. A total of 48 women with biopsy-proven breast cancer (T(1-2), N(0-2), M0) were randomised to the control group in which modified radical mastectomy was performed, and the HIFU group in which an extracorporeal HIFU ablation of breast cancer was followed by modified radical mastectomy. Short-term follow-up, pathologic and immunohistochemical stains were performed to assess the therapeutic effects on tumour and complications of HIFU. The results showed that no severe side effect was observed in the HIFU-treated patients. Pathologic findings revealed that HIFU-treated tumour cells underwent complete coagulative necrosis, and tumour vascular vessels were severely damaged. Immunohistochemical staining showed that no expression of PCNA, MMP-9, and CD44v6 was detected within the treated tumour cells in the HIFU group, indicating that the treated tumour cells lost the abilities of proliferation, invasion, and metastasis. It is concluded that, as a noninvasive therapy, HIFU could be effective, safe, and feasible in the extracorporeal treatment of localised breast cancer.  (+info)

Natural history of multifocal solitary fibrous tumors of the pleura: a 25-year follow-up report. (3/52)

We report this case with "multifocal solitary fibrous tumors of the pleura," which recurred at different sites in the left pleura at different time intervals over a span of 25 years, finally exhibiting features of malignant transformation. This patient was first seen in 1978, when she was 58 years of age, for episodic attacks of hypoglycemia and a mass occupying the entire left hemithorax. The operative findings and histologic appearance were that of a solitary fibrous tumor.  (+info)

Respiration under control of uncoupling proteins: Clinical perspective. (4/52)

The term 'uncoupling protein' was originally used for the mitochondrial membrane protein UCP1, which is uniquely present in mitochondria of brown adipocytes, thermogenic cells that regulate body temperature in small rodents, hibernators and mammalian newborns. In these cells, UCP1 acts as a proton carrier activated by free fatty acids and creates a shunt between complexes of the respiratory chain and ATP-synthase resulting in a futile proton cycling and dissipation of oxidation energy as heat. Recent identification of new homologues to UCP1 expressed in brown and white adipose tissue, muscle, brain and other tissues together with the hypothesis that these novel uncoupling proteins (UCPs) may regulate thermogenesis and/or fatty acid metabolism and furthermore may protect against free radical oxygen species production have generated considerable optimism for rapid advances in the identification of new targets for pharmacological management of complex pathological syndromes such as obesity, type 2 diabetes or chronic inflammatory diseases. However, since the physiological and biochemical roles of the novel UCPs are not yet clear, the main challenge today consists first of all in providing mechanistic explanation for their functions in cellular physiology. This lively awaited information may be the basis for potential pharmacological targeting of the UCPs in future.  (+info)

Thy-1 as a regulator of cell-cell and cell-matrix interactions in axon regeneration, apoptosis, adhesion, migration, cancer, and fibrosis. (5/52)

Thy-1 (CD90) is a 25-37 kDa glycosylphosphatidylinositol (GPI) -anchored glycoprotein expressed on many cell types, including T cells, thymocytes, neurons, endothelial cells, and fibroblasts. Activation of Thy-1 can promote T cell activation, and this role of Thy-1 is reviewed elsewhere. Thy-1 also affects numerous nonimmunologic biological processes, including cellular adhesion, neurite outgrowth, tumor growth, migration, and cell death. In reviewing the nonimmunologic functions of Thy-1, we discuss the phenotype of the Thy-1 null mouse, signaling pathways modulated by Thy-1, the role of the GPI anchor in Thy-1 localization to lipid rafts and signaling, and regulation of Thy-1 expression. Thy-1 is an important regulator of cell-cell and cell-matrix interactions, with important roles in nerve regeneration, metastasis, inflammation, and fibrosis.  (+info)

Heavy smoking and liver. (6/52)

Smoking causes a variety of adverse effects on organs that have no direct contact with the smoke itself such as the liver. It induces three major adverse effects on the liver: direct or indirect toxic effects, immunological effects and oncogenic effects. Smoking yields chemical substances with cytotoxic potential which increase necro-inflammation and fibrosis. In addition, smoking increases the production of pro-inflammatory cytokines (IL-1, IL-6 and TNF- alpha) that would be involved in liver cell injury. It contributes to the development of secondary polycythemia and in turn to increased red cell mass and turnover which might be a contributing factor to secondary iron overload disease promoting oxidative stress of hepatocytes. Increased red cell mass and turnover are associated with increased purine catabolism which promotes excessive production of uric acid. Smoking affects both cell-mediated and humoral immune responses by blocking lymphocyte proliferation and inducing apoptosis of lymphocytes. Smoking also increases serum and hepatic iron which induce oxidative stress and lipid peroxidation that lead to activation of stellate cells and development of fibrosis. Smoking yields chemicals with oncogenic potential that increase the risk of hepatocellular carcinoma (HCC) in patients with viral hepatitis and are independent of viral infection as well. Tobacco smoking has been associated with suppression of p53 (tumour suppressor gene). In addition, smoking causes suppression of T-cell responses and is associated with decreased surveillance for tumour cells. Moreover, it has been reported that heavy smoking affects the sustained virological response to interferon (IFN) therapy in hepatitis C patients which can be improved by repeated phlebotomy. Smoker's syndrome is a clinico-pathological condition where patients complain of episodes of facial flushing, warmth of the palms and soles of feet, throbbing headache, fullness in the head, dizziness, lethargy, prickling sensation, pruritus and arthralgia.  (+info)

The cancer stem cell hypothesis: a work in progress. (7/52)

There is a growing body of evidence that supports the idea that malignant tumors are initiated and maintained by a population of tumor cells that share similar biologic properties to normal adult stem cells. This model, the cancer stem cell (CSC) hypothesis, is based on the observation that tumors, like adult tissues, arise from cells that exhibit the ability to self-renew as well as give rise to differentiated tissue cells. Although the concept of the CSC is not entirely new, advances made over the past two decades in our understanding of normal stem cell biology in conjunction with the recent application of these concepts to experimentally define CSCs have resulted in the identification of CSCs in several human malignancies.  (+info)

Do we need to redefine a cancer metastasis and staging definitions? (8/52)

Metastasis is the most lethal attribute of cancer cells and clinical decisions regarding treatment are based largely upon the likelihood of developing metastases. However, improvements in detection as well as recent experimental data have raised questions about the most appropriate definition of a metastasis, especially whether the mere presence of cells at secondary sites constitute a metastatic lesion. After reviewing the experimental basis of metastasis, a definition of metastasis is proffered along with a proposal to consider regarding modification of staging parameters.  (+info)

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