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Targeting Interleukin-4 Receptor Alpha by Hybrid Peptide for Novel Biliary Tract Cancer Therapy
Kahori Seto,Junichi Shoda,Tomohisa Horibe,Eiji Warabi,Masayuki Kohno,Toru Yanagawa,Hiroki Bukawa,Yasuni Nakanuma,Koji Kawakami
International Journal of Hepatology , 2014, DOI: 10.1155/2014/584650
Abstract: It is known that the interleukin-4 receptor α (IL-4Rα) is highly expressed on the surface of various human solid tumors. We previously designed novel IL-4Rα-lytic hybrid peptide composed of binding peptide to IL-4Rα and cell-lytic peptide and reported that the designed IL-4Rα-lytic hybrid peptide exhibited cytotoxic and antitumor activity both in vitro and in vivo against the human pancreatic cancer cells expressing IL-4Rα. Here, we evaluated the antitumor activity of the IL-4Rα-lytic hybrid peptide as a novel molecular targeted therapy for human biliary tract cancer (BTC). The IL-4Rα-lytic hybrid peptide showed cytotoxic activity in six BTC cell lines with a concentration that killed 50% of all cells (IC50) as low as 5?μM. We also showed that IL-4Rα-lytic hybrid peptide in combination with gemcitabine exhibited synergistic cytotoxic activity in vitro. In addition, intravenous administration of IL-4Rα-lytic hybrid peptide significantly inhibited tumor growth in a xenograft model of human BTC in vivo. Taken together, these results indicated that the IL-4Rα-lytic hybrid peptide is a potent agent that might provide a novel therapy for patients with BTC. 1. Introduction Biliary tract cancer such as gallbladder cancer and extrahepatic bile duct cancer as well as intrahepatic bile duct cancer (one of the primary liver cancers) is likely to undergo metastasis to the peritoneum (peritoneal dissemination) or the liver at early stages and is often resistant to conventional chemotherapy and radiotherapy. These cancers have been thus viewed as intractable cancers unlikely to be cured completely. In Japan, the incidence of biliary tract cancer and intrahepatic bile duct cancer is about 10 out of every 100,000 people [1]. As for intrahepatic bile duct cancer, both the incidence and death rate have been rising in Japan in recent years, resembling the trend observed in western countries [2, 3]. In Japan, gemcitabine and S-1 have recently begun to be used for anticancer chemotherapy, and these drugs are expected to prolong the survival period of patients as compared to existing anticancer drugs [4]. However, because of frequent adverse events of the hematological system arising from these drugs and because of compromised hepatic function often noted in patients with intrahepatic bile duct cancer due to accompanying liver cirrhosis and in those with extrahepatic bile duct cancer or gallbladder cancer due to accompanying obstructive cholestasis, treatment with these drugs has to be discontinued or stopped. To improve the outcome of treatment of these cancers, it is very
Optic Nerve and Spinal Cord Are the Major Lesions in Each Relapse of Japanese Multiple Sclerosis
Yoko Warabi
ISRN Neurology , 2011, DOI: 10.5402/2011/904706
Abstract: For the purpose of predicting multiple sclerosis (MS) and neuromyelitis optica (NMO) relapses in Japanese population, we evaluated the localization and age of each demyelinating attack. We retrospectively analyzed the 78 medical records of Japanese MS and NMO patients. Then we identified 49 cases of relapsing-remitting-type patients and defined each of 116 demyelinating attacks. NMO had an older age at onset than MS, although the initial symptoms cannot predict the clinical phenotypes. Only 21.3% of demyelinating attacks were localized in the cerebrum and 78.7% were optic-spinal lesions, although MS comprised 70% and NMO comprised 30% of these 78 cases. Brainstem lesion had a relative male predominancy and a young age at attack. Our findings showed that optic nerve and spinal cord lesions are the major and critical lesions in each attack of Japanese CNS demyelinating diseases. There might be distinctive Japanese pathogenic features even in Western type MS. 1. Introduction Multiple sclerosis (MS) and neuromyelitis optica (NMO) are inflammatory demyelinating diseases of the central nervous system (CNS). Although MS and NMO are characterized by dissemination of lesions in space and dissemination in time, it has not been able to predict when and where the next relapse will appear. One of the possibilities that suggests where the next relapse occurs is due to the clinical phenotype of the CNS inflammatory demyelinating diseases in the Japanese population. Japanese CNS demyelinating disease has two major clinical phenotypes. One is NMO [1, 2] which is characterized by lesions confined to the optic nerve and spinal cord, especially, longitudinally extensive spinal cord lesions [3], positive aquaporin-4 (AQP4) autoantibody seropositivity [4], and the astrocytic impairment associated with the loss of AQP4 in the NMO lesions [5]. The other is conventional Western type MS which is known to be the same pathophysiology as MS in western countries and frequently involves cerebral lesions [6]. Human leukocyte antigen (HLA)-DR2 antigen is reported to associate with MS both in Japan and western countries [7], whereas DPB1 ? 0501 is associated with NMO in Asian population [8, 9]. There is a consensus that NMO comprises about one-third or one-fourth of the Japanese CNS inflammatory demyelinating diseases [10]. In this paper, for the purpose of predicting the lesions of the demyelinating relapses, we evaluated the localization, sex ratio, and age of each demyelinating attack, retrospectively. As the results, we found that the attacks in optic nerve and spinal cord accounted
Cognitive processes involved in smooth pursuit eye movements: behavioral evidence, neural substrate and clinical correlation
Kikuro Fukushima,Tateo Warabi,Graham R. Barnes
Frontiers in Systems Neuroscience , 2013, DOI: 10.3389/fnsys.2013.00004
Abstract: Smooth-pursuit eye movements allow primates to track moving objects. Efficient pursuit requires appropriate target selection and predictive compensation for inherent processing delays. Prediction depends on expectation of future object motion, storage of motion information and use of extra-retinal mechanisms in addition to visual feedback. We present behavioral evidence of how cognitive processes are involved in predictive pursuit in normal humans and then describe neuronal responses in monkeys and behavioral responses in patients using a new technique to test these cognitive controls. The new technique examines the neural substrate of working memory and movement preparation for predictive pursuit by using a memory-based task in macaque monkeys trained to pursue (go) or not pursue (no-go) according to a go/no-go cue, in a direction based on memory of a previously presented visual motion display. Single-unit task-related neuronal activity was examined in medial superior temporal cortex (MST), supplementary eye fields (SEF), caudal frontal eye fields (FEF), cerebellar dorsal vermis lobules VI–VII, caudal fastigial nuclei (cFN), and floccular region. Neuronal activity reflecting working memory of visual motion direction and go/no-go selection was found predominantly in SEF, cerebellar dorsal vermis and cFN, whereas movement preparation related signals were found predominantly in caudal FEF and the same cerebellar areas. Chemical inactivation produced effects consistent with differences in signals represented in each area. When applied to patients with Parkinson's disease (PD), the task revealed deficits in movement preparation but not working memory. In contrast, patients with frontal cortical or cerebellar dysfunction had high error rates, suggesting impaired working memory. We show how neuronal activity may be explained by models of retinal and extra-retinal interaction in target selection and predictive control and thus aid understanding of underlying pathophysiology.
DNS Analysis on the Indirect Relationship between the Local Burning Velocity and the Flame Displacement Speed of Turbulent Premixed Flames  [PDF]
Kazuya Tsuboi, Eiji Tomita
Open Journal of Fluid Dynamics (OJFD) , 2014, DOI: 10.4236/ojfd.2014.43022
Abstract: The local burning velocity and the flame displacement speed are the dominant properties in the mechanism of turbulent premixed combustion. The flame displacement speed and the local burning velocity have been investigated separately, because the flame displacement speed can be used for the discussion of flame-turbulence interactions and the local burning velocity can be used for the discussion of the inner structure of turbulent premixed flames. In this study, to establish the basis for the discussion on the effects of turbulence on the inner structure of turbulent premixed flames, the indirect relationship between the flame displacement speed and the local burning velocity was investigated by the flame stretch, the flame curvature, and the tangential strain rate using DNS database with different density ratios. It was found that for the local tangential strain rate and the local flame curvature, the local burning velocity and the flame displacement speed had the opposite correlations in each density ratio case. Therefore, it is considered that the local burning velocity and the flame displacement speed have a negative correlation.
Factors Affecting the Health-Related Quality of Life of Community-Dwelling Elderly in Japan: A Focus on Spirituality  [PDF]
Minako Kobayashi, Eiji Marui
Health (Health) , 2017, DOI: 10.4236/health.2017.97080
This study aimed to explain factors affecting health-related quality of life among community-dwelling elderly individuals living in Japan. We conducted a questionnaire survey of 898 individuals at senior citizens clubs in a rural area near the Tokyo metropolitan area in 2015, and analyzed the responses of 715 who provided valid responses. The survey questions included basic attributes (e.g., age, economic affluence), state of health (e.g., whether s/he has heart disease or not), the Spirituality Rating Scale Related to Health in the Elderly (SP Health Scale, composed of, e.g., meaning and purpose of living, self-transcendence), the Abbreviated Lubben Social Network Scale, and the MOS 8-Item Short Form Health Survey (SF-8). Multiple regression analyses were performed using the physical component summary (PCS) and mental component summary (MCS) of the SF-8 as dependent variables and all others as independent variables. Factors associated with improved PCS were economic affluence and SP Health Scale (meaning and purpose of living), while the factors associated with reduced PCS were age and state of health (heart disease, gastrointestinal disease, osteoarthritis, lower back pain, knee pain, and eligible for long-term care). Meanwhile, factors associated with improved MCS were economic affluence, while those that were associated with reduced MCS were state of health (cancer and headache) and SP Health Scale (self-transcendence). These results suggest the need to understand spirituality in addition to the subjective economic situation, age, and medical condition of elderly individuals in order to improve their physical and mental health.
GWAM—An Institutional Model to Address Watershed Impacts from Urbanization: Field Validation  [PDF]
Thambirajah Saravanapavan, Eiji Yamaji
Journal of Water Resource and Protection (JWARP) , 2018, DOI: 10.4236/jwarp.2018.109053
Abstract: With the realization of the limitations to top-down and bottom-up watershed management approaches in addressing issues associated with urbanization, a conceptual framework for a hybrid approach that tries to effectively integrate the advantages of the two approaches while overcoming their respective limitations, grass root watershed management model (GWAM), was proposed and presented. This paper presents the details of implementation and validation of GWAM at Shawsheen River watershed in Massachusetts, USA. An investigation on the major components of GWAM, a common platform to conduct the management, a partnership of two major stakeholder groups from government and non-governmental organizations, and a facilitation mechanisms were carried out in detail to gain the needed understanding on structure, process and function of a successful GWAM. Also the decision making process in addressing three major urban watershed issues; flooding, habitat and aquatic life impairment, and bacterial impairment, were examined through a set of cyclic steps. Based on the lessons learned, GWAM was enhanced as a general hybrid model. The most important challenge in sustaining GWAM was to keep differently motivated stakeholders together. As revealed in the Shawsheen watershed, science should play a key role in keeping differently motivated stakeholders together by providing needed facts, understandings, data, and knowledge. When scientifically sound solutions are vetted through a process of public involvement that supports appropriate regulatory actions, the most effective environmental decisions can be made.
GWAM—An Institutional Model to Address Watershed Impacts from Urbanization: Conceptual Framework  [PDF]
Thambirajah Saravanapavan, Eiji Yamaji
Journal of Water Resource and Protection (JWARP) , 2018, DOI: 10.4236/jwarp.2018.109052
Abstract: The urbanization process exerts negative multidisciplinary impacts on the integrity of natural watershed conditions. These impacts are best analyzed and addressed with local inputs, as many of these are site specific and require consistent local monitoring along with appropriate policies and regulations from conventional governance in an interdisciplinary platform. With the realization of the limitations to top-down and bottom-up watershed management approaches in addressing issues associated with urbanization, a conceptual framework for a hybrid approach that tries to effectively integrate the advantages of the two approaches while overcoming their respective limitations, the Grass root Watershed Management model (GWAM), is presented in this paper. The model is to establish a self-sustaining and effective institutional forum that can be used in watersheds across geographical and political boundaries while accommodating the urbanization process. GWAM consists of three crucial components: a common platform, a partnership among major groups of stakeholders, and a facilitation mechanism to conduct the watershed management at local lever or grass-root level. With effective integration of the governmental agencies and institutes at the top with the local residents and non-governmental organizations at the bottom, the concept is that the hybrid approach can serve as a self-sustaining model in achieving effective management of urbanization impacts.
Detection of Learner’s Concentration in Distance Learning System with Multiple Biological Information  [PDF]
Kimario Nizetha Daniel, Eiji Kamioka
Journal of Computer and Communications (JCC) , 2017, DOI: 10.4236/jcc.2017.54001
Abstract: The trend of distance learning education has increased year by year because of the rapid advancement of information and communication technologies. Distance learning system can be regarded as one of ubiquitous computing applications since the learners can study anywhere even in mobile environments. However, the instructor cannot know if the learners comprehend the lecture or not since each learner is physically isolated. Therefore, a framework which detects the learners’ concentration condition is required. If a distance learning system obtains the information that many learners are not concentrated on the class due to the incomprehensible lecture style, the instructor can perceive it through the system and change the presentation strategy. This is a context-aware technology which is widely used for ubiquitous computing services. In this paper, an efficient distance learning system, which accurately detects learners’ concentration condition during a class, is proposed. The proposed system uses multiple biological information which are learners’ eye movement metrics, i.e. fixation counts, fixation rate, fixation duration and average saccade length obtained by an eye tracking system. The learners’ concentration condition is classified by using machine learning techniques. The proposed system has performed the detection accuracy of 90.7% when Multilayer Perceptron is used as a classifier. In addition, the effectiveness of the proposed eye metrics has been confirmed. Furthermore, it has been clarified that the fixation duration is the most important eye metric among the four metrics based on the investigation of evaluation experiment.
Collaborative Approach Using Psychophysiology and Psychophysics for Optimal Threshold Determination in HAS Service QoE Management  [PDF]
Phan Xuan Tan, Eiji Kamioka
Journal of Computer and Communications (JCC) , 2018, DOI: 10.4236/jcc.2018.68005
Abstract: In HTTP adaptive streaming (HAS) services, Quality of Experience (QoE) management has increasingly played an important role in guaranteeing the expected video quality perceived by the users with the minimal network resource. To achieve this, QoE must be automatically monitored and accurately controlled when it falls to a specific threshold. However, how to determine the QoE threshold with a scientific basis has not been carefully studied yet. In this paper, a new method to determine a QoE threshold based on biological information is proposed for a QoE management in HAS services. More concretely, the QoE threshold is determined by modeling the impact of the stimulus on the biological information obtained from the users who are watching videos. As the biological information, Skin Conductance and Heart Rate associated with Autonomic Nervous System (ANS) have been investigated. The evaluation results demonstrate that the QoE management by using the determined threshold can save more than 4.855% of the bandwidth consumption per control ensuring as high video quality as by using the fair threshold.
Sitagliptin is effective and safe as add-on to insulin in patients with absolute insulin deficiency: a case series
Eiji Kutoh
Journal of Medical Case Reports , 2011, DOI: 10.1186/1752-1947-5-117
Abstract: This report describes the efficacy of sitagliptin in three Japanese patients (a 91-year-old Japanese woman with type 1 diabetes, a 54-year-old Japanese man with type 2 diabetes and a 30-year-old Japanese man with features of both type 1 and type 2 diabetes) who had no detectable post-meal C-peptide levels. Although they were receiving intensive insulin therapy together with some oral hypoglycemic agents, their glycemic control remained poor. Sitagliptin was added to the ongoing therapeutic regimen to provide better glycemic control. Although these patients had mild hypoglycemia, effective reductions of hemoglobin A1c levels were observed without any adverse events in the liver and kidney during the following 24 weeks. Two of the patients were able to reduce their insulin doses, and one of the patients could discontinue one of the oral hypoglycemic agents. There was no weight gain or gastrointestinal complaints among the three patients. Post-meal C-peptide levels remained undetectable after sitagliptin treatment.This report demonstrates that sitagliptin is effective and safe as an add-on therapy to insulin in reducing blood glucose levels in patients who absolutely lack the capacity for endogenous insulin secretion. The improvement seen in glycemic control could not be due to enhanced endogenous insulin secretion, since post-meal C-peptide levels remained undetectable after sitagliptin treatment, but it could be a result of other factors (for example, suppression of glucagon levels). However, the glucagon-suppressive effect of sitagliptin is known to be rather weak and short-lived. Given this background, a novel hypothesis that the glycemic effects of this drug may be caused by mechanisms that are independent of the glucagon-like peptide 1 axis (extra-pancreatic effect) will be discussed.The incretin-based drugs glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidal peptidase 4 (DPP-4) inhibitors are a new class of drugs for the treatment of type 2 diabetes
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