Matrix Metalloproteinase-9 (MMP-9) polymorphisms in patients with cutaneous malignant melanoma

BACKGROUND: Cutaneous Malignant Melanoma causes over 75% of skin cancer-related deaths, and it is clear that many factors may contribute to the outcome. Matrix Metalloproteinases (MMPs) play an important role in the degradation and remodeling of the extracellular matrix and basement membrane that, in turn, modulate cell division, migration and angiogenesis. Some polymorphisms are known to influence gene expression, protein activity, stability, and interactions, and they were shown to be associated with certain tumor phenotypes and cancer risk. METHODS: We tested seven polymorphisms within the MMP-9 gene in 1002 patients with melanoma in order to evaluate germline genetic variants and their association with progression and known risk factors of melanoma. The polymorphisms were selected based on previously published reports and their known or potential functional relevance using in-silico methods. Germline DNA was then genotyped using pyrosequencing, melting temperature profiles, heteroduplex analysis, and fragment size analysis. RESULTS: We found that reference alleles were present in higher frequency in patients who tend to sunburn, have family history of melanoma, higher melanoma stage, intransit metastasis and desmoplastic melanomas among others. However, after adjustment for age, sex, phenotypic index, moles, and freckles only Q279R, P574R and R668Q had significant associations with intransit metastasis, propensity to tan/sunburn and primary melanoma site. CONCLUSION: This study does not provide strong evidence for further investigation into the role of the MMP-9 SNPs in melanoma progression

Fine-Tuning Roles of Endogenous Brain-Derived Neurotrophic Factor, TrkB and Sortilin in Colorectal Cancer Cell Survival

International audienceBACKGROUND: Neurotrophin receptors were initially identified in neural cells. They were recently detected in some cancers in association with invasiveness, but the function of these tyrosine kinase receptors was not previously investigated in colorectal cancer (CRC) cells. METHODS AND FINDINGS: We report herein that human CRC cell lines synthesize the neural growth factor Brain-derived neurotrophic factor (BDNF) under stress conditions (serum starvation). In parallel, CRC cells expressed high- (TrkB) and low-affinity (p75(NTR)) receptors at the plasma membrane, whereas TrkA and TrkC, two other high affinity receptors for NGF and NT-3, respectively, were undetectable. We demonstrate that BDNF induced cell proliferation and had an anti-apoptotic effect mediated through TrkB, as assessed by K252a, a Trk pharmacologic inhibitor. It suppressed both cell proliferation and survival of CRC cells that do not express TrkA nor TrkC. In parallel to the increase of BDNF secretion, sortilin, a protein acting as a neurotrophin transporter as well as a co-receptor for p75(NTR), was increased in the cytoplasm of primary and metastatic CRC cells, which suggests that sortilin could regulate neurotrophin transport in these cells. However, pro-BDNF, also detected in CRC cells, was co-expressed with p75(NTR) at the cell membrane and co-localized with sortilin. In contrast to BDNF, exogenous pro-BDNF induced CRC apoptosis, which suggests that a counterbalance mechanism is involved in the control of CRC cell survival, through sortilin as the co-receptor for p75(NTR), the high affinity receptor for pro-neurotrophins. Likewise, we show that BDNF and TrkB transcripts (and not p75(NTR)) are overexpressed in the patients' tumors by comparison with their adjacent normal tissues, notably in advanced stages of CRC. CONCLUSION: Taken together, these results highlight that BDNF and TrkB are essential for CRC cell growth and survival in vitro and in tumors. This autocrine loop could be of major importance to define new targeted therapies

Assessment of antioxidant enzymes and lipid peroxidation in experimental subarachnoid haemorrhage

WOS: 00017709630031

Evaluation of lipid peroxidation, cathepsin L and acid phosphatase activities in experimental brain ischemia-reperfusion

WOS: 000083214900003PubMed ID: 10528106This investigation was conducted in rat brain tissues to elucidate the free radical induced cellular and subcellular membrane injuries in two different depth of global ischemia. Global moderate (penumbral) ischemia was performed on rat brains by bilateral vertebral arteries cauterization and temporary occlusion of the bilateral carotid arteries. Global severe ischemia was produced by a neck tourniquet in addition to four vessel occlusion. Somatosensory evoked potentials (SSEPs) were used as a feed back parameter to monitor electrophysiologically the ischemia. Al the end of ischemic insult (0 min reperfusion) or various reperfusion periods (20, 60 and 240 min), all rats were decapitated and brains were frozen in liquid nitrogen. The brain tissues were prepared for the determination of cathepsin L (CL) and acid phosphatase (AP) activities in the supernatant (cytosolic) fraction (SF) and the fraction enriched with lysosomes (FEL). Further the level of thiobarbituric acid reactive substances (TEARS) of lipid peroxidation was assessed by the spectrophotometric methods. Severe ischemia-reperfusion was accompanied by a significant increase in TEARS levels and the SF/FEL ratio for CL and AP activities compared to the sham operated group and the concurrent reperfusion groups of moderate ischemia (p < 0.05). There were no significant differences between the sham operated and moderate ischemia-reperfusion groups for the same parameters. Our data clearly demonstrate that; in rat brain although severe ischemia-reperfusion causes lipid peroxidation in cellular membranes and redistribution of lysosomal enzymes from lysosomes to cytoplasm due to lysosomal membrane injury, there are no changes in lysosomal membrane stability in moderate ischemia-reperfusion. (C) 1999 Elsevier Science B.V. All rights reserved

Antioxidant enzyme activities in experimental brain ischemia-reperfusion

WOS: 00007330560331

Alterations in superoxide dismutase, glutathione peroxidase and catalase activities in experimental cerebral ischemia-reperfusion

WOS: 000084312200005PubMed ID: 10639700Free radicals are thought to be the most important cause of the reperfusion injury subsequent to ischemia. The antioxidant status of the tissue affected by ischemia-reperfusion is of great importance for the primary endogenous defense against the free radical induced injury. This investigation was performed to evaluate the antioxidant enzyme capacity of the brain tis sue in the ischemia-reperfusion period using an experimental global moderate (penumbral) ischemia model on rat brains. Experiments were performed on 45 male Sprague Dawley rats. Ischemia was induced by bilateral vertebral arteries cauterization and temporary bilateral carotid arteries occlusion and sustained for 10 minutes. At the end of ischemia (0 min reperfusion) and various reperfusion periods (20 min, 60 min, 240 min), rats were decapitated and brains were frozen in liquid nitrogen. Changes in the intracellular antioxidant enzyme (superoxide dismutase, glutathione peroxidase and catalase) activities were assessed in the rat brain tissues, by spectrophotometric methods. In all moderate ischemia-reperfusion groups, superoxide dismutase activities were found to have decreased significantly compared to the sham operated controls (P<0.05). During ischemia superoxide dismutase ac activity was lowered to 31% of that of the control group. The decreases were more significant in reperfusion groups, particularly in 60 min reperfusion (40%). Relatively smaller but still significant diminution was observed in glutathione peroxidase activities (P<0.05). The ratio of diminution was striking in 20 min and 60 min reperfusion groups with 26% of the sham operated:rats. Conversely, moderate ischemia-reperfusion caused significant increase in catalase activities (P<0.05). The increment was 63% of the preischemic level with 10 min of moderate ischemia. In conclusion, activities of the major antioxidant enzymes were changed significantly in moderate brain ischemia-reperfusion. These results suggest that the disturbance in oxidant-antioxidant balance might play a part in rendering the tissue more vulnerable to free radical induced injuries

Subcellular redistribution and activation of cathepsin L (CL) and acid phosphatase (AP) in experimental brain ischemia-reperfusion

WOS: 00007330560266

Unilateral pallidal stimulation in cervical dystonia

Meeting of the American-Society-for-Stereotactic-and-Functional-Neurosurgery -- JUL 08-10, 1999 -- SNOWBIRD, UTAHWOS: 000086897600029PubMed ID: 10853088Cervical dystonia (spasmodic torticollis) is a focal dystonia of the cervical region. Various treatment modalities have been performed with variable success rates. We present a 42-year-old woman complaining of involuntary head rotation for the last 3 years. Different medical treatments had been used for 3 years. Botulinum toxin injections resulted in temporary and moderate improvement for periods of 3-4 months. Pallidal stimulation was performed using a quadripolar electrode and a battery-operated programmable pulse generator. We conclude that a unilateral pallidal lesion or stimulation is an effective method of treatment in focal dystonia. The target must be the pallidum contralateral to the contracted sternocloidomastoid muscle. Deep brain stimulation is superior to lesioning because of the capability of manipulating the stimulation parameters which can modify the pallidotomy effect. Copyright (C) 2000 S. Karger AG, Basel.Amer Soc Stereotact & Funct Neurosur