Dysregulated DNA methylation followed by abnormal gene expression is an epigenetic hallmark in cancer. DNA methylation is catalyzed by DNA methyltransferases, and the aberrant expression or mutations of DNA methyltransferase genes are found in human neoplasm. The enzymes for demethylating 5-methylcytosine were recently identified, and the biological significance of DNA demethylation is a current focus of scientific attention in various research fields. Ten-eleven translocation (TET) proteins have an enzymatic activity for the conversion from 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC), which is an intermediate of DNA demethylation. The loss-of-function mutations of TET2 gene were reported in myeloid malignancies, suggesting that impaired TET-mediated DNA demethylation could play a crucial role in tumorigenesis. It is still unknown, however, whether DNA demethylation is involved in biological properties in solid cancers. Here, we show the loss of 5-hmC in a broad spectrum of solid tumors: for example, a significant reduction of 5-hmC was found in 72.7% of colorectal cancers (CRCs) and 75% of gastric cancers compared to background tissues. TET1 expression was decreased in half of CRCs, and a large part of them was followed by the loss of 5-hmC. These findings suggest that the amount of 5-hmC in tumors is often reduced via various mechanisms, including the downregulation of TET1. Consistently, in the in vitro experiments, the downregulation of TET1 was clearly induced by oncogene-dependent cellular transformation, and loss of 5-hmC was seen in the transformed cells. These results suggest the critical roles of aberrant DNA demethylation for oncogenic processes in solid tissues. (Cancer Sci 2012; 103: 670-676) P atterns of DNA methylation, histone modification and chromatin structure are profoundly altered in human cancers.(1-5) In particular, aberrant promoter hypermethylation leading to inappropriate transcriptional silencing of genes, especially tumor suppressor genes, is often found in various types of human neoplasm, including colorectal and gastric cancers.(6-9) DNA methylation is catalyzed by DNA methyltransferases (DNMTs), and it is reported that the increased level of DNMT1 is correlated with the histological grade or poor prognosis of human cancers. (10)(11)(12) In addition, a recent report demonstrated somatic mutations in the DNMT3A gene from acute myeloid leukemia patients. (13) Global loss of methylated DNA in paternal genome after fertilization suggests active DNA demethylation pathway in mammalian cells, although the molecular mechanism has been unknown for a long time. The recent discovery of ten-eleven translocation (TET) proteins those are capable of converting from 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) gave a breakthrough to the epigenetic research field. (14)(15)(16)(17)(18)(19) Following studies showed that the activationinduced cytidine deaminase family convert cytosine to uracil and 5-hmC to 5-hydroxymethyluracil, (20,21) and that TET1 mediates further oxidation of 5-h...

In many gait applications, the focal events are the stance and swing phases. Although detecting gait events using electromyography signals will help the development of assistive devices such as exoskeleton, orthoses, and prostheses, stance and swing phases have yet to be observed using electromyography signals. The core of this study is to propose a classification system for both stance and swing phases based on electromyography signals. This is to be done by extracting the patterns of electromyography signals from time domain features and feeding them into an artificial neural network classifier. In addition, a different number of input features and two prominent training algorithm of artificial neural network have been employed in this study. Eight subjects that participated in this study were divided into two categories namely, learned (first seven subjects) and unlearned data (the remaining one subject). It was observed that Levenberg-Marquardt algorithm with five time domain features performed better than other features with an average percentage of classification accuracy of 87.4%. This system was further tested with electromyography signals of learned and unlearned data to identify the stance and swing phases in order to detect the timing of heel strike and toe off. The mean absolute different values between artificial neural network and footswitch data for learned data were 16 ± 18 ms and 21 ± 18 ms for heel strike and toe off, respectively. For this case, no significant differences (p < 0.05) were observed in mean absolute different for heel strike and toe off detections. Besides, the mean absolute different values of unlearned data were shown to be acceptable, 35 ± 25 ms for heel strike and 49 ± 15 ms for toe off. By the end of this experiment, basing the examination of gait events with electromyography signals using artificial neural network is possible.

Genetic mutations in pancreatic ductal adenocarcinoma (PDAC) with critical roles have been well examined. The recent discovery of alterations in genes encoding histone modifiers suggests their possible roles in the complexity of cancer development. We previously reported loss of heterozygosity of the KDM6B gene, which encodes a histone demethylase for trimethylated histone H3 lysine 27, a repressive chromatin mark, in PDAC cells. In this study, we demonstrated that loss of KDM6B enhanced aggressiveness of PDAC cells. KDM6B has been regarded as a tumor suppressor that mediates oncogenic KRAS-induced senescence. Consistently, KDM6B was highly expressed in pancreatic precancerous lesions (pancreatic intraepithelial neoplasms); then, the expression decreased as the malignant grade progressed. We found that knockdown of KDM6B in PDAC cells promoted tumor sphere formation and increased peritoneal dissemination and liver metastasis in vivo. Microarray and chromatin immunoprecipitation analysis implicated CEBPA for aggressiveness induced by KDM6B knockdown. CEBPA knockdown recapitulated the phenotypic change of PDAC cells after KDM6B knockdown, which was reversed by forced expression of C/EBPα. Moreover, similar protein expression patterns of KDM6B and C/EBPα in human PDAC emphasized their functional correlation. Notably, pharmacological inhibition of the H3K27 methylase EZH2 in PDAC cells inhibited tumor sphere formation along with the upregulation of CEBPA expression, and this effect was impaired in KDM6B knockdown cells, highlighting the role for KDM6B in the activation of CEBPA. Together, our results propose a significant role for the KDM6B-C/EBPα axis in the PDAC phenotype.

Abstract:It is a general assumption that pneumatic muscle-type actuators will play an important role in the development of an assistive rehabilitation robotics system. In the last decade, the development of a pneumatic muscle actuated lower-limb leg orthosis has been rather slow compared to other types of actuated leg orthoses that use AC motors, DC motors, pneumatic cylinders, linear actuators, series elastic actuators (SEA) and brushless servomotors. However, recent years have shown that the interest in this field has grown exponentially, mainly due to the demand for a more compliant and interactive human-robotics system. This paper presents a survey of existing lower-limb leg orthoses for rehabilitation, which implement pneumatic muscle-type actuators, such as McKibben artificial muscles, rubbertuators, air muscles, pneumatic artificial muscles (PAM) or pneumatic muscle actuators (PMA). It reviews all the currently existing lower-limb rehabilitation orthosis systems in terms of comparison and evaluation of the design, as well as the control scheme and strategy, with the aim of clarifying the current and on-going research in the lower-limb robotic rehabilitation field.

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