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Abstract: Purpose:Ifosfamide can cause an unexplained encephalopathy. The incidence after intravenous infusion is 10%, but is much higher after oral administration. This study assesses the pharmacokinetics of oral ifosfamide in relation to neurotoxicity. Patients and Methods:Eleven patients received oral ifosfamide 500 mg twice daily for 14 days, with concurrent oral mesna. The concentrations of ifosfamide, isophosphoramide mustard, 2-dechloroethylifosfamide, 3-dechloroethylifosfamide, carboxyifosfamide, ketoifosfamide, chloroethylamine and 3-oxazolidine-2-one were measured using GC-MS. Patients were evaluated clinically, and also with the EEG, psychometric testing, the national adult reading test, and the mini-mental state examination. Results:A decrease in the electroencephalogram alpha frequency was observed, with the development of pathological slow wave activity. Psychometric performance was also impaired. Neurotoxicity was progressive during treatment, and the incidence of grade 3 neurotoxicity was 22%. The mean day 14 / day 1 Cmax ratios for 2-dechloroethylifosfamide and 3-dechloroethylifosfamide were 2.73 (± 2.11) and 2.04 (± 1.32) respectively. The metabolite with the lowest ratio was isophosphoramide mustard 1.07 (± 0.39). High chloroethylamine Cmax values were associated with lower alpha frequencies, and increased clinical neurotoxicity. Conclusion:Oral ifosfamide 500 mg twice daily for 14 days causes unacceptable neurotoxicity. It was not possible to identify one particular metabolite responsible for the neurotoxicity, although the dechloroethyl metabolites and chloroethylamine are implicated. Keywords: Oral ifosfamide, metabolites, pharmacology, encephalopathy, electroencephalogram, lung neoplasms, cervical neoplasmsa.Download Full Article |
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Abstract: Background: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancies, representing nearly one-third of all pediatric cancers. Thrombomodulin is a membrane glycoprotein expressed on endothelial cells, Its plasma level depends on the integrity of the endothelium. Soluble thrombomodulin is derived from injured endothelial cells or proteolytically cleaved from thrombomodulin by proteases. In the past, the endothelium was considered to be inert, described as a 'layer of nucleated cellophane', with only non-reactive barrier properties. However, it is now becoming clear that endothelial cells actively and reactively participate in hemostasis and immune and inflammatory reactions. They regulate vascular tone via production of nitric oxide, endothelin and prostaglandins. Severe endothelial dysfunction is present during the acute phase of acute lymphoblastic leukemia and it result from the disease itself, from treatment, or from other conditions (e.g. sepsis). Objective:The aim of this study was to determine the level of serum soluble thrombomodulin as a marker of endothelial activation in children with ALL at time of diagnosis and after the chemotherapy. Methods and Materials: A case - control study included Thirty patients with ALL and twenty healthy children. We analyzed serum soluble thrombomodulin levels by enzyme-linked immunosorbent assay. Results: In children with acute lymphoblastic leukemia, there was a significant increase in soluble thrombomodulin levels during the acute phase of the disease and during treatment. Conclusion: severe endothelial dysfunction is present during the acute phase of ALL and during treatment and appears to result from the disease itself and from the treatment. Keywords: Acute lymphoblastic leukemia (ALL), thrombomodulin, endothelial dysfunction, children, chemotherapy. |
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Abstract: Prostate cancer is the second most common lethal cancer in men worldwide. Despite the fact that the prognosis for patients with localized disease is good, many patients succumb to metastatic disease with the development of resistance to hormone treatments. This is normally termed castration-resistant prostate cancer (CRPC). The development of metastatic, castration-resistant prostate cancer has been associated with epithelial-to-mesenchymal transition (EMT), a process where cancer cells acquire a more mesenchymal phenotype with enhanced migratory potential, invasiveness and elevated resistance to apoptosis. The main event in EMT is the repression of epithelial markers such as E-cadherin and upregulation of mesenchymal markers such as N-cadherin, vimentin and fibronectin. The insulin-like growth factor (IGF) signalling axis is essential for normal development and maintenance of tissues, including that of the prostate, and dysregulation of this pathway contributes to prostate cancer progression and malignant transformation. It is becoming increasingly clear that one of the ways in which the IGF axis impacts upon cancer progression is through promoting EMT. This review will explore the role of EMT in prostate cancer progression with a specific focus on the involvement of the IGF axis and its downstream signalling pathways in regulating EMT in prostate cancer. Keywords: Epithelial-to-mesenchymal transition, insulin-like growth factor family, prostate cancer progression, lifestyle factors.Download Full Article |
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Abstract: The Wnt signalling pathway is involved in regulating cellular proliferation and differentiation, and aberrant activation has been described in several cancers including breast. Oestradiol up regulates Wnt pathway gene expression, and thereby activates the Wnt signalling pathway. We used the oestrogen-responsive breast cancer cell line MCF-7 to examine the effects of secreted frizzled related protein 4 (sFRP-4) on oestradiol-induced growth, including gene expression of the Wnt signalling pathway genes Frizzled Receptor, Wnt-10b, and β-catenin. We demonstrate here that sFRP-4 inhibits oestradiol-induced cell growth in the MCF-7 cell line and also down regulates oestradiol-induced expression of selected Wnt signalling genes including β-catenin. We propose that sFRP-4 is a potent inhibitor of the Wnt signalling pathway and may negatively regulate oestradiol-mediated proliferation in human breast cancer cells. Keywords: Breast cancer, sFRP4, Wnt signalling, oestradiol, β-catenin, cellular proliferation, growth inhibition.Download Full Article |
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Abstract: Objective: To investigate tobacco consumption induced changes in the in vivo Raman spectra of oral mucosa of healthy volunteers and to study its effect on the differential diagnosis of oral lesions. Materials and Methods: The clinical in vivo study involved 28 healthy volunteers and 171 patients having malignant and potentially malignant lesions of the oral cavity. Twenty of the healthy volunteers had habits of either smoking and/or of chewing tobacco while the rest did not have any tobacco consumption habits. The in vivo Raman spectra were measured using a compact and portable near-infrared Raman spectroscopic system. A probability based multi-class diagnostic algorithm, developed for supervised classification, was employed to classify the whole set of measured tissue Raman spectra into various categories. Results: It was found that the Raman spectra of healthy volunteers with tobacco consumption habits could be separated from the spectra of those without any habit of tobacco consumption with an accuracy of over 95%. Further, it was found that exclusion of the spectral data of the oral cavity of the healthy volunteers from the reference normal database considerably improved the overall classification accuracy (92.3% as against 86%) of the algorithm in separing the oral lesions from the normal oral mucosa. Conclusion: The results of the clinical study demonstrate the potential of Raman spectroscopy in screening tobacco users who are at an increased risk of developing dysplasia or malignancy. Further, the results also show that for accurate discrimination of oral lesions based on their Raman spectra, the reference normal database should exclude spectral data of tobacco using healthy subjects. Download Full Article |