Phase I/II study of oxaliplatin with oral S-1 as first-line therapy for patients with metastatic colorectal cancer

Two phase II studies of S-1 monotherapy have shown promising response rates (RR) of 35–40% with good tolerability in patients with untreated metastatic colorectal cancer. To investigate the usefulness of S-1 plus oxaliplatin (SOX) as an alternative to infusional 5-fluorouracil/leucovorin plus oxaliplatin, the recommended dose (RD) of SOX was determined, and its safety and preliminary efficacy were evaluated in a phase I/II study. Oxaliplatin was administered at a dose of 100 mg m−2 (level 1) or 130 mg m−2 (level 2) on day 1, and S-1 (80–120) was given twice daily for 2 weeks followed by a 1-week rest. This schedule was repeated every 3 weeks. Level 2 was determined to be the RD. For the 28 patients who received the RD, the median treatment course was 6.5 cycles (2–14), RR of 50% (1 CR and 13 PR: 95% CI 31–69%), with a median progression-free survival of 196 days. Survival rate (1 year) was 79%. Peripheral neuropathy was observed in all patients but with no functional disorders. Major grade 3 or 4 adverse reactions at the RD were neutropaenia (14%), thrombocytopaenia (28%), and diarrhoea (3%). SOX regimen is effective and easily manageable without central vein access

Irinotecan, cisplatin and mitomycin in inoperable gastro-oesophageal and pancreatic cancers – a new active regimen

Irinotecan, mitomycin and cisplatin all demonstrate activity in gastro-oesophageal cancers. This novel combination was administered to outpatients with previously untreated inoperable gastro-oesophageal or pancreatic cancer, in a 28-day cycle. A total of 26 out of 31 patients with gastro-oesophageal cancer and 12 out of 14 patients with pancreatic cancer have been treated with this combination, and were evaluable for response. The overall response rates for patients with gastro-oesophageal cancer was 42%, with a median survival of 9.5 months. In patients with pancreatic cancer, the overall response rate was 42% with a median survival of 8 months. There was a statistically significant increase in survival between those patients who achieved a stable disease response and those who achieved either a partial response or complete response. The toxicity profiles for both cancers were virtually identical. There were five treatment-related deaths, and a high admission rate (42%). Thus irinotecan, mitomycin and cisplatin is a new combination with activity in inoperable upper gastro-oesophageal cancers, but with a high toxicity profile. Future developments include reducing the dose of irinotecan and number of cycles of therapy to four

Lens epithelial cell apoptosis and intracellular Ca(2+) increase in the presence of xanthurenic acid

BACKGROUND: Xanthurenic acid is an endogenous product of tryptophan degradation by indoleamine 2,3-dioxygenase (IDO). We have previously reported that IDO is present in mammalian lenses, and xanthurenic acid is accumulated in the lenses with aging. Here, we studied the involvement of xanthurenic acid in the human lens epithelial cell physiology. METHODS: Human lens epithelial cells primary cultures were used. Control cells, and cells in the presence of xanthurenic acid grow in the dark. Western blot analysis and immunofluorescence studies were performed. RESULTS: In the presence of xanthurenic acid human lens epithelial cells undergo apoptosis-like cell death. In the control cells gelsolin stained the perinuclear region, whereas in the presence of 10 μM xanthurenic acid gelsolin is translocated to the cytoskeleton, but does not lead to cytoskeleton breakdown. In the same condition caspase-3 activation, and DNA fragmentation was observed. At low (5 to 10 μM) of xanthurenic acid concentration, the elongation of the cytoskeleton was associated with migration of mitochondria and cytochrome c release. At higher concentrations xanthurenic acid (20 μM and 40 μM) damaged mitochondria were observed in the perinuclear region, and nuclear DNA cleavage was observed. We observed an induction of calpain Lp 82 and an increase of free Ca(2+) in the cells in a xanthurenic acid concentration-dependent manner. CONCLUSIONS: The results show that xanthurenic acid accumulation in human lens epithelial cells disturbs the normal cell physiology and leads to a cascade of pathological events. Xanthurenic acid induces calpain Lp82 and caspases in the cells growing in the dark and can be involved in senile cataract development

Photosynthesis-dependent H₂O₂ transfer from chloroplasts to nuclei provides a high-light signalling mechanism

Chloroplasts communicate information by signalling to nuclei during acclimation to fluctuating light. Several potential operating signals originating from chloroplasts have been proposed, but none have been shown to move to nuclei to modulate gene expression. One proposed signal is hydrogen peroxide (H2O2) produced by chloroplasts in a light-dependent manner. Using HyPer2, a genetically encoded fluorescent H2O2 sensor, we show that in photosynthetic Nicotiana benthamiana epidermal cells, exposure to high light increases H2O2 production in chloroplast stroma, cytosol and nuclei. Critically, over-expression of stromal ascorbate peroxidase (H2O2 scavenger) or treatment with DCMU (photosynthesis inhibitor) attenuates nuclear H2O2 accumulation and high light-responsive gene expression. Cytosolic ascorbate peroxidase over-expression has little effect on nuclear H2O2 accumulation and high light-responsive gene expression. This is because the H2O2 derives from a sub-population of chloroplasts closely associated with nuclei. Therefore, direct H2O2 transfer from chloroplasts to nuclei, avoiding the cytosol, enables photosynthetic control over gene expression

Sex Differences in Neural Activation to Facial Expressions Denoting Contempt and Disgust

The facial expression of contempt has been regarded to communicate feelings of moral superiority. Contempt is an emotion that is closely related to disgust, but in contrast to disgust, contempt is inherently interpersonal and hierarchical. The aim of this study was twofold. First, to investigate the hypothesis of preferential amygdala responses to contempt expressions versus disgust. Second, to investigate whether, at a neural level, men would respond stronger to biological signals of interpersonal superiority (e.g., contempt) than women. We performed an experiment using functional magnetic resonance imaging (fMRI), in which participants watched facial expressions of contempt and disgust in addition to neutral expressions. The faces were presented as distractors in an oddball task in which participants had to react to one target face. Facial expressions of contempt and disgust activated a network of brain regions, including prefrontal areas (superior, middle and medial prefrontal gyrus), anterior cingulate, insula, amygdala, parietal cortex, fusiform gyrus, occipital cortex, putamen and thalamus. Contemptuous faces did not elicit stronger amygdala activation than did disgusted expressions. To limit the number of statistical comparisons, we confined our analyses of sex differences to the frontal and temporal lobes. Men displayed stronger brain activation than women to facial expressions of contempt in the medial frontal gyrus, inferior frontal gyrus, and superior temporal gyrus. Conversely, women showed stronger neural responses than men to facial expressions of disgust. In addition, the effect of stimulus sex differed for men versus women. Specifically, women showed stronger responses to male contemptuous faces (as compared to female expressions), in the insula and middle frontal gyrus. Contempt has been conceptualized as signaling perceived moral violations of social hierarchy, whereas disgust would signal violations of physical purity. Thus, our results suggest a neural basis for sex differences in moral sensitivity regarding hierarchy on the one hand and physical purity on the other

Neurodegenerative influence of oxidative stress in the retina of a murine model of diabetes

Aims/hypothesis: Diabetic retinopathy is a progressive neuro-degenerative disease, but the underlying mechanism is still obscure. Here, we focused on oxidative stress in the retina, and analysed its influence on retinal neurodegeneration, using an antioxidant, lutein. Methods: C57BL/6 mice with streptozotocin-induced diabetes were constantly fed either a lutein-supplemented diet or a control diet from the onset of diabetes, and their metabolic data were recorded. In 1-month-diabetic mice, reactive oxygen species (ROS) in the retina were measured using dihydroethidium and visual function was evaluated by electroretinograms. Levels of activated extracellular signal-regulated kinase (ERK), synaptophysin and brain-derived neurotrophic factor (BDNF) were also measured by immunoblotting in the retina of 1-month-diabetic mice. In the retinal sections of 4-month-diabetic mice, histological changes, cleaved caspase-3 and TUNEL staining were analysed. Results: Lutein did not affect the metabolic status of the diabetic mice, but it prevented ROS generation in the retina and the visual impairment induced by diabetes. ERK activation, the subsequent synaptophysin reduction, and the BDNF depletion in the diabetic retina were all prevented by lutein. Later, in 4-month-diabetic mice, a decrease in the thickness of the inner plexiform and nuclear layers, and ganglion cell number, together with increase in cleaved caspase-3- and TUNEL-positive cells, were avoided in the retina of lutein-fed mice. Conclusions/interpretation: The results indicated that local oxidative stress that has a neurodegenerative influence in the diabetic retina is prevented by constant intake of a lutein-supplemented diet. The antioxidant, lutein may be a potential therapeutic approach to protect visual function in diabetes

Cholesterol Perturbation in Mice Results in p53 Degradation and Axonal Pathology through p38 MAPK and Mdm2 Activation

Perturbation of lipid metabolism, especially of cholesterol homeostasis, can be catastrophic to mammalian brain, as it has the highest level of cholesterol in the body. This notion is best illustrated by the severe progressive neurodegeneration in Niemann-Pick Type C (NPC) disease, one of the lysosomal storage diseases, caused by mutations in the NPC1 or NPC2 gene. In this study, we found that growth cone collapse induced by genetic or pharmacological disruption of cholesterol egress from late endosomes/lysosomes was directly related to a decrease in axonal and growth cone levels of the phosphorylated form of the tumor suppressor factor p53. Cholesterol perturbation-induced growth cone collapse and decrease in phosphorylated p53 were reduced by inhibition of p38 mitogen-activated protein kinase (MAPK) and murine double minute (Mdm2) E3 ligase. Growth cone collapse induced by genetic (npc1−/−) or pharmacological modification of cholesterol metabolism was Rho kinase (ROCK)-dependent and associated with increased RhoA protein synthesis; both processes were significantly reduced by P38 MAPK or Mdm2 inhibition. Finally, in vivo ROCK inhibition significantly increased phosphorylated p53 levels and neurofilaments in axons, and axonal bundle size in npc1−/− mice. These results indicate that NPC-related and cholesterol perturbation-induced axonal pathology is associated with an abnormal signaling pathway consisting in p38 MAPK activation leading to Mdm2-mediated p53 degradation, followed by ROCK activation. These results also suggest new targets for pharmacological treatment of NPC disease and other diseases associated with disruption of cholesterol metabolism