The development of alternative therapies for melanoma treatment is of great interest as long-term tumour regression is not achieved with new targeted chemotherapies on selected patients. We previously demonstrated that radioiodinated heteroarylcarboxamide ([ 131 I]ICF01012) induced a strong anti-tumoural effect by inhibiting both primary tumour growth and dissemination process in a B16BL6 melanoma model. In our study, we show that a single injection of [ 131 I]ICF01012 (ranging from 14.8 to 22.2 MBq) was effective and associated with low and transient haematological toxicity. Concerning pigmented organs, cutaneous melanocytes and skin were undamaged. In 30% of treated animals, no histological alteration of retina was observed, and in the remaining 70%, damages were restricted to the optic nerve area. Using the Medical Internal Radiation Dose methodology, we determined that the absorbed dose in major organs is very low (<4 Gy) and that a delivery of 30 Gy to the tumour is sufficient for an effective anti-tumoural response. Molecular analyses of treated tumours showed a strong radiobiological effect with a decrease in proliferation, survival and pro-angiogenic-related markers and an increase in tumour suppressor gene expression, melanogenesis and anti-angiogenic markers. All these features are in accordance with a tumour cell death mechanism that mainly occurs by mitotic catastrophe and provide a better understanding of in vivo anti-tumoural effects of Metastatic melanoma has a poor prognosis with an estimated death rate ranging from 1.8 to 3.5 per 100,000 cases worldwide. 1,2 As with other cancers, chemotherapy (dacarbazine) remained the conventional treatment with poor benefit for over half a century. Two strategies have improved melanoma treatment, one using the tumour immune response by blocking cytotoxic T-lymphocyte activation (antibody anti-CTL4) 3 and the other targeting BRAF. 4 A recent multicentre phase 1 clinical trial testing a mutated BRAF (V600E) inhibitor showed complete or partial tumour regression in the majority of patients. 5 However, BRAF mutations are detected in only 60% of melanoma cases, and the therapy involves selection of patients with tumours that carry the V600E BRAF mutation. 5,6 Furthermore, most treated patients acquire resistance to this inhibitor after initial clinical response. 7 Metastatic melanoma is always described as a refractory disease, and new observations suggest that combined therapies will have a greater impact on melanoma residual activity. As the mechanisms of resistance to treatment rely on tumour adaptation by somatic mutations, 8 other non-protein targets such as melanin could be considered for future therapies.Melanin pigment is detected in more than 90% of primary melanoma cases, and thus, a strategy targeting this pigment
In the authors' model of retinal degeneration, photoreceptor cells die through a caspase-dependent mechanism. However, the molecular events involved during and after light exposure seemed to implicate different proteases.
In Sprague-Dawley rats, retinal ischemia was induced by occlusion of the central retinal artery, while reperfusion was initiated by unclamping and removing the occluder. Ninety minutes of regional ischemia followed by 24 h of reperfusion resulted in a development of retinal edema in the inner plexiform layer and a migration of neturophils into the retinal tissue. Oxygen free radicals have been implicated as inducers of cell damage in different tissues. This finding has led us to speculate that, if oxygen free radicals play an important role in the development of reperfusion injury, superoxide dismutase (SOD) and EGB 761 (Tanakan, extract of Ginkgobiloba, IPSEN) should be protective against reperfusion-induced injury. Under our experimental conditions, SOD dose-dependently reduced the development of edema formation (which was expressed in micrometers, measuring the thickness of the inner plexiform layer). Thus, 3,750, 7,500 and 15,000 U/kgof SOD reduced the reperfusion-induced edema formation from its drug-free ischemic value of 112 ± 4 to 107 ± 7, 91 ± 6 (p < 0.05) and 85 + 4 μm (p < 0.001), respectively. Furthermore, SOD significantly reduced the migration of neutrophils which can also contribute to the development of reperfusion-induced injury. The same protective effect was observed, concerning the edema formation and neutrophil migration, in the EGB 761-treated groups. Our results indicate that free radicals play an important role in the development of reperfusion-induced injury, and the treatment of ischemic and reperfused retina whith free radical scavengers may reduce the severity of reperfusion damage.
Airway inflammation is the principal abnormality in asthma and many other respiratory diseases. Eosinophils are the cells primarily involved in this process. The aim of this study was to analyze sequential changes in urinary eosinophil protein X (EPX) a biological marker of eosinophil activation in asthmatic children and chronic coughers, and to confirm the importance of such changes in evaluating the inflammatory process once regular treatment was initiated. Eighty-eight asthmatic children (AC), 33 children with chronic cough (CC), and 34 control children were included in the study. All those with respiratory disease underwent allergy tests (serum total IgE, serum-specific IgE for common allergens, peripheral blood eosinophil (PBE), and skin prick tests) and a pulmonary function test (PFT), and had chest X-ray and serum eosinophil cationic protein (s-ECP) and urinary EPX assays. All subjects attended the outpatient clinic every 3 months, irrespective of the treatment prescribed following inclusion in this investigation. At baseline, urinary EPX concentrations were higher in children with asthma and those with chronic cough than in controls (mean 171.1 and 131.3, respectively, vs. 60.2 microg/mmol creatinine, P < 0.001). CC children had lower eosinophil counts (0.25 vs. 0.39 x 10(9)/L, P < 0.02) than those with asthma. There was no significant difference between the AC and CC groups in urinary EPX and s-ECP levels. s-ECP concentrations were significantly higher (P < 0.01) in atopic vs. nonatopic patients (44 vs. 29.9 ng/mL), but no significant difference was observed for urinary EPX. Concentrations of urinary EPX were significantly correlated with s-ECP levels (r = 0.24, P < 0.025) and with PBE (r = 0.38, P < 0.01). No correlation was found between urinary EPX values and PFT results. In AC receiving inhaled steroids after the start of the study, there was a significant reduction after 3 months in urinary EPX (-54, P < 0.02). In contrast, there was no significant change in PBE levels. Urinary EPX concentrations are sensitive, noninvasive technique that could be useful to the clinician in the evaluation of manifestations of airway inflammation.
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