Expression and regulatory effects on cancer cell behavior of NELL1 and NELL2 in human renal cell carcinoma

We thank Professors Michael Rehli, Yoshiaki Ito, and Kristian Helin for gifting plasmids, Dr. Alasdair MacKenzie (University of Aberdeen) for helpful discussion, and Mr. Takashi Mizukami, Ms. Ryoko Tokuda, and Ms. Sanae Funaoka (Kanazawa University) for technical assistance.Peer reviewedPublisher PD

Inflammatory Diseases and the Role of n-7 Unsaturated Fatty Acids as Functional Lipids

With the increasing childbearing age, the number of mothers with diabetes and gestational diabetes is escalating. Maternal hyperglycemia creates an intrauterine hyperglycemic environment via the placenta, which causes signaling abnormalities in various fetal organs due to excessive glycation. This is associated with future disease development in the child. We have shown that insulin signaling defects are induced in fetal cardiomyoblasts using a rat gestational diabetes mellitus model and cellular models. Furthermore, we reported that maternal intake of eicosapentaenoic acid (EPA), an n-3 unsaturated fatty acid, during pregnancy can ameliorate this signaling defect. However, EPA has anti-coagulant effects, and the pollution of marine fish oil, the source for EPA supplements, raises concerns about active intake by pregnant women. Recently, palmitoleic acid, an n-7 unsaturated fatty acid, garnered attention as a candidate functional lipid alternative to EPA because it has been reported to have anti-obesity, lipid metabolism improvement, and cardioprotective effects similar to those of EPA. Palmitoleic acid has cis and trans structural isomers, which differ in their food intake route and metabolism in humans. This article introduces recent findings on the biological functions of palmitoleic acid in lifestyle-related diseases and cardiovascular diseases, ranging from basic research to clinical studies

Future Risks for Children Born to Mothers with Gestational Diabetes: Elucidation Using the Cell Model Approach

A number of studies have shown that foetal nutritional status significantly impacts an unborn child’s long-term health. The developmental origins of health and disease (DOHaD) hypothesis proposes that if a child is undernourished in the foetal period, the child will develop diabetes and hypertension in the future if adequate nutrition is given after birth. Moreover, hyperglycaemia (e.g. gestational diabetes mellitus [GDM]) experienced during foetal life can reportedly cause various complications in children. As diabetes is increasing worldwide, so is GDM, and many studies have been conducted using GDM animal models and GDM cell lines. We examined the effects of streptozotocin-induced diabetes, particularly on the heart of offspring, in rat GDM animal models. We also analysed primary cardiomyocyte cultures isolated from these GDM rats and found that insulin signalling was inhibited in GDM cells, as in the GDM animal models, by increased advanced glycation end products. Furthermore, the effect of eicosapentaenoic acid during pregnancy has been reported in GDM animal models and cells, and the findings indicated the importance of nutritional management for GDM during pregnancy

Advanced Glycation End Products and Oxidative Stress in a Hyperglycaemic Environment

Protein glycation is the random, nonenzymatic reaction of sugar and protein induced by diabetes and ageing; this process is quite different from glycosylation mediated by the enzymatic reactions catalysed by glycosyltransferases. Schiff bases form advanced glycation end products (AGEs) via intermediates, such as Amadori compounds. Although these AGEs form various molecular species, only a few of their structures have been determined. AGEs bind to different AGE receptors on the cell membrane and transmit signals to the cell. Signal transduction via the receptor of AGEs produces reactive oxygen species in cells, and oxidative stress is responsible for the onset of diabetic complications. This chapter introduces the molecular mechanisms of disease onset due to oxidative stress, including reactive oxygen species, caused by AGEs generated by protein glycation in a hyperglycaemic environment

Analysis of the phenomenon of speculative trading in one of its basic manifestations: postage stamp bubbles

We document and analyze the empirical facts concerning one of the clearest evidence of speculation in financial trading as observed in the postage collection stamp market. We unravel some of the mechanisms of speculative behavior which emphasize the role of fancy and collective behavior. In our conclusion, we propose a classification of speculative markets based on two parameters, namely the amplitude of the price peak and a second parameter that measures its ``sharpness''. This study is offered to anchor modeling efforts to realistic market constraints and observations.Comment: 9 pages, 5 figures and 2 tables, in press in Int. J. Mod. Phys.

Task-Guided Selection of the Dual Neural Pathways for Reading

SummaryThe visual perception of words is known to activate the auditory representation of their spoken forms automatically. We examined the neural mechanism for this phonological activation using transcranial magnetic stimulation (TMS) with a masked priming paradigm. The stimulation sites (left superior temporal gyrus [L-STG] and inferior parietal lobe [L-IPL]), modality of targets (visual and auditory), and task (pronunciation and lexical decision) were manipulated independently. For both within- and cross-modal conditions, the repetition priming during pronunciation was eliminated when TMS was applied to the L-IPL, but not when applied to the L-STG, whereas the priming during lexical decision was eliminated when the L-STG, but not the L-IPL, was stimulated. The observed double dissociation suggests that the conscious task instruction modulates the stimulus-driven activation of the lateral temporal cortex for lexico-phonological activation and the inferior parietal cortex for spoken word production, and thereby engages a different neural network for generating the appropriate behavioral response

A detection method for latent circadian rhythm sleep-wake disorder

Background Individuals with typical circadian rhythm sleep-wake disorders (CRSWDs) have a habitual sleep timing that is desynchronized from social time schedules. However, it is possible to willfully force synchronisation against circadian-driven sleepiness, which causes other sleep problems. This pathology is distinguishable from typical CRSWDs and is referred to here as latent CRSWD (LCRSWD). Conventional diagnostic methods for typical CRSWDs are insufficient for detecting LCRSWD because sufferers have an apparently normal habitual sleep timing. Methods We first evaluated the reliability of circadian phase estimation based on clock gene expression using hair follicles collected at three time points without sleep interruption. Next, to identify detection criteria for LCRSWD, we compared circadian and sleep parameters according to estimated circadian phases, at the group and individual level, between subjects with low and high Pittsburgh Sleep Quality Index (PSQI) scores. To validate the reliability of identified detection criteria, we investigated whether the same subjects could be reproducibly identified at a later date and whether circadian amelioration resulted in sleep improvement. Findings We successfully validated the reliability of circadian phase estimation at three time points and identified potential detection criteria for individuals with LCRSWD attributed to delayed circadian-driven sleepiness. In particular, a criterion based on the interval between the times of the estimated circadian phase of clock gene expression and getting out of bed on work or school days was promising. We also successfully confirmed the reproducibility of candidate screening and sleep improvement by circadian amelioration, supporting the reliability of the detection criteria. Interpretation Although several limitations remain, our present study demonstrates a promising prototype of a detection method for LCRSWD attributed to delayed circadian-driven sleepiness. More extensive trials are needed to further validate this method

Dual Antiplatelet Therapy Can Be Discontinued at Three Months after Implantation of Zotarolimus-Eluting Stent in Patients with Coronary Artery Disease

Dual antiplatelet therapy (DAPT) after percutaneous coronary intervention increases the risk of bleeding. We studied the safety and clinical outcomes of switching from DAPT to aspirin monotherapy at 3 months after ZES implantation. We retrospectively evaluated 168 consecutive patients with coronary artery disease who had been implanted with a ZES from June 2009 through March 2010. After excluding 40 patients according to exclusion criteria such as myocardial infarction, 128 patients were divided into a 3-month DAPT group (67 patients, 88 lesions) and a 12-month conventional DAPT group (61 patients, 81 lesions). Coronary angiographic followup and clinical followup were conducted at more than 8 months and at 12 months after ZES implantation, respectively. Minor and major bleeding events, stent thrombosis (ST), and major adverse cardiac events (MACE) (death, myocardial infarction, cerebrovascular accident, target lesion revascularization, and target vessel revascularization) were evaluated. There were no statistically significant differences in the incidences of ST and MACE between the two groups. The incidence of bleeding events was significantly lower in the 3-month group than in the 12-month group (1.5% versus 11.5%, ). DAPT can be safely discontinued at 3 months after ZES implantation, which reduces bleeding risk

Semi-comprehensive analysis of gene amplification in gastric cancers using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization

The prognosis of patients with gastric carcinomas at an advanced stage still remains dismal, and therefore novel therapeutic modalities are urgently needed. Since the successful targeting of amplified ERBB2 with a humanized monoclonal antibody, the amplified genes of other receptor tyrosine kinases such as EGFR, FGFR2, and MET, as well as those of other cell regulator genes, are being considered as candidate targets of molecular therapy. The aim of the present study was to determine the amplification status of 26 genes, which are frequently amplified in solid cancers, in advanced gastric cancers. A total of 93 formalin-fixed and paraffin-embedded advanced gastric cancer tissues were examined by multiple ligation-dependent probe amplification, and 32 cases with ‘gain’ or ‘amplified’ status of 16 genes were further examined for the respective gene amplification by fluorescence in situ hybridization (FISH) and for the respective protein overexpression by immunohistochemistry. The frequencies of gene amplifications in advanced gastric cancers were as follows: ERBB2 (13 cases, 14%), FGFR2 (7 cases, 8%), MYC (7 cases, 8%), TOP2A (7 cases, 8%), MET (4 cases, 4%), MDM2 (4 cases, 4%), CCND1 (3 cases, 3%), FGF10 (2 cases, 3%), and EGFR (1 case, 1%). Amplification of the receptor tyrosine kinases genes occurred in a mutually exclusive manner except for one tumor in which ERBB2 and FGFR2 were both amplified but in different cancer cells. Co-amplification of ERBB2 and MYC, and EGFR and CCND1, in single nuclei but on different amplicons, was confirmed in one case each. Attempts at correlating the FISH status with the immunohistochemical staining pattern showed variable results from complete concordance to no correlation. In conclusion, combination of multiple ligation-dependent probe amplification and FISH analysis is a feasible approach for obtaining the semi-comprehensive genetic information that is necessary for personalized molecular targeted therapy.Modern Pathology advance online publication, 6 March 2015; doi:10.1038/modpathol.2015.33

Expression and regulatory effects on cancer cell behavior of NELL1 and NELL2 in human renal cell carcinoma

Neural epidermal growth factor-like like (NELL) 1 and 2 constitute a family of multimeric and multimodular extracellular glycoproteins. Although the osteogenic effects of NELL1 and functions of NELL2 in neural development have been reported, their expression and functions in cancer are largely unknown. In this study, we examined expression of NELL1 and NELL2 in renal cell carcinoma (RCC) using clinical specimens and cell lines. We show that, whereas NELL1 and NELL2 proteins are strongly expressed in renal tubules in non-cancerous areas of RCC specimens, their expression is significantly downregulated in cancerous areas. Silencing of NELL1 and NELL2 mRNA expression was also detected in RCC cell lines. Analysis of NELL1/2 promoter methylation status indicated that the CpG islands in the NELL1 and NELL2 genes are hypermethylated in RCC cell lines. NELL1 and NELL2 bind to RCC cells, suggesting that these cells express a receptor for NELL1 and NELL2 that can transduce signals. Furthermore, we found that both NELL1 and NELL2 inhibit RCC cell migration, and NELL1 further inhibits RCC cell adhesion. These results suggest that silencing of NELL gene expression by promoter hypermethylation plays roles in RCC progression by affecting cancer cell behavior. We found that the down-regulation of NELL1 and NELL2 in renal cell carcinoma (RCC) is in part due to the hypermethylation of CpG islands in their putative promoter regions. Furthermore, we found that NELL1 suppresses and NELL2 partially suppresses RCC cell migration, and NELL1 further inhibits RCC cell adhesion. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association