115 results on '"Niino, M."'
Search Results
2. Design of a Concentration Solar Thermoelectric Generator
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Li, Peng, Cai, Lanlan, Zhai, Pengcheng, Tang, Xinfeng, Zhang, Qingjie, and Niino, M.
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- 2010
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3. Approach for Compensation System of Asbestos-Related Lung Cancer
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Nishina, Y, primary, Niino, M, primary, and Higashi, T, primary
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- 2019
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4. Bubble mode of flow of a gas-liquid mixture in a vertical pipe
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Niino, M., Kashinskii, O. N., and Odnoral, V. P.
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- 1978
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5. Relationship between Barkhof criteria and the clinical features of multiple sclerosis in northern Japan
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Nakamura, M., Houzen, H., Niino, M., Tanaka, K., Sasaki, H., Nakamura, M., Houzen, H., Niino, M., Tanaka, K., and Sasaki, H.
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Background and Objective: We previously reported that the prevalence of MS in Tokachi Province of Hokkaido has increased from 8.6 to 13.1 per 100,000 individuals between 2001 and 2006. Here, we studied the frequency of MS patients who fulfill the Barkhof criteria and identified their common features. Subjects: All 47 subjects in our previous study, who fulfilled Poser's criteria, were included in this study. Results: Of these, 33 satisfied the Barkhof criteria. In 2006, 9.2 per 100,000 MS patients fulfilled the Barkhof criteria; the percentage of patients who fulfilled these criteria was significantly higher among patients born after 1960 than among those born before 1960 (84.3% and 40.0%, respectively). The proportion of patients with conventional MS (C-MS) who fulfilled the Barkhof criteria was higher than that of patients with opticospinal MS (OS-MS) who fulfilled these criteria (93.9% and 71.4%, respectively). Longitudinally extensive spinal cord lesions (LESCLs) were not associated with the brain lesions defined in the Barkhof criteria (Barkhof brain lesions). Conclusion: In Tokachi Province, the increased percentage of MS patients who fulfill the Barkhof criteria was associated with increased C-MS incidence and increase in the proportion of C-MS patients with Barkhof brain lesions among people born after 1960.
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- 2009
6. Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor
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Yoshikawa, S, primary, Kukimoto-Niino, M, additional, Parker, L, additional, Handa, N, additional, Terada, T, additional, Fujimoto, T, additional, Terazawa, Y, additional, Wakiyama, M, additional, Sato, M, additional, Sano, S, additional, Kobayashi, T, additional, Tanaka, T, additional, Chen, L, additional, Liu, Z-J, additional, Wang, B-C, additional, Shirouzu, M, additional, Kawa, S, additional, Semba, K, additional, Yamamoto, T, additional, and Yokoyama, S, additional
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- 2012
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7. Crystal structure of a predicted phosphoribosyltransferase (TT1426) from Thermus thermophilus HB8 at 2.01 A resolution
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Kukimoto-Niino, M., primary
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- 2005
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8. Interaction of surfactant with polymer gel binding isotherm and swelling ratio
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Shirahama, K., primary, Sato, S., additional, Niino, M., additional, and Takisawa, N., additional
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- 1996
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9. Design of a Concentration Solar Thermoelectric Generator.
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Peng Li, Lanlan Cai, Pengcheng Zhai, Xinfeng Tang, Qingjie Zhang, and Niino, M.
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SOLAR thermal energy ,THERMOELECTRIC generator design & construction ,SOLAR radiation ,THERMOELECTRIC materials ,FINITE element method ,ENERGY conversion ,TEMPERATURE inversions ,THERMOELECTRIC cooling - Abstract
Thermoelectric technology can be another direct way to convert solar radiation into electricity, using the Seebeck effect. Herein, a prototype concentration solar thermoelectric generator (CTG) and a discrete numerical model for the evaluation of the whole system are presented. The model takes into account the temperature dependence of the thermoelectric material properties by dividing the thermoelectric leg into finite elements and is proved to be more accurate for calculation of the conversion efficiency of the thermoelectric modules when large temperature gradients occur in the CTG system. Based on the best available properties of various bulk thermoelectric materials reported in the literature, the best possible performance of the CTG system is predicted, and the CTG system design, including the selection of the concentration ratio and the cooling method for different thermoelectric materials, are discussed in detail. [ABSTRACT FROM AUTHOR]
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- 2010
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10. Life prediction of CIP formed thrust chamber
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Niino, M., primary, Kumakawa, A., additional, Hirano, T., additional, Sumiyoshi, K., additional, and Watanabe, R., additional
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- 1986
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11. APOE epsilon variation in multiple sclerosis susceptibility and disease severity: some answers
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Reinhold Schmidt, Beata Zakrzewska-Pniewska, W. E. R. Ollier, Alastair Compston, Rita Cittadella, Helena Schmidt, Jonathan L. Haines, Stephen Sawcer, Richard M. Burwick, S. J. M. Weatherby, Hubert Kwieciński, Patricia P. Ramsay, Christian Enzinger, Lisa F. Barcellos, Masaaki Niino, Nikos Evangelou, Jacqueline Palace, Chris H. Polman, Seiji Kikuchi, Franz Fazekas, Aldo Quattrone, J. Zwemmer, Peter Høgh, Margaret A. Pericak-Vance, Jan Hillert, Bernard M. J. Uitdehaag, Stephen L. Hauser, Maria Edite Rio, Giovanni Savettieri, Silke Schmidt, Mónica Santos, Patrícia Maciel, Jorge R. Oksenberg, C. P. Hawkins, Thomas Masterman, [et al.], Universidade do Minho, Burwick, RM, Ramsay, PP, Haines, JL, Hauser, SL, Oksenberg, JR, Pericak-Vance, MA, Schmidt, S, Compston, A, Sawcer, S, Cittadella,R, Savettieri,G, Quattrone,A, Polman,CH, Uitdehaag, BM, Zwemmer, JN, Hawkins,CP, Ollier, WE, Weatherby, S, Enzinger, C, Fazekas, F, Schmidt, H, Schmidt, R, Hillert, J, Masterman, T, Hogh, P, Niino, M, Kikuchi,S, Maciel, P, Santos, M, Rio, ME, Kwiecinski, H, Zakrzewska-Pniewska, B, Evangelou, N, Palace, J, and Barcellos, LF.
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Apolipoprotein E ,Oncology ,Risk ,medicine.medical_specialty ,Pathology ,Multiple Sclerosis ,Genotype ,Apolipoprotein E2 ,Apolipoprotein E4 ,Polymorphism, Single Nucleotide ,Severity of Illness Index ,Linkage Disequilibrium ,Primary progressive ,Central nervous system disease ,03 medical and health sciences ,0302 clinical medicine ,Apolipoproteins E ,Disease severity ,Polymorphism (computer science) ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,10. No inequality ,Alleles ,030304 developmental biology ,0303 health sciences ,Expanded Disability Status Scale ,Polymorphism, Genetic ,Science & Technology ,business.industry ,Multiple sclerosis ,medicine.disease ,3. Good health ,Pedigree ,Phenotype ,Case-Control Studies ,Settore MED/26 - Neurologia ,Neurology (clinical) ,business ,Multiple Sclerosis, APOE, disease severity, meta-analysis ,030217 neurology & neurosurgery - Abstract
Background: Previous studies have examined the role of APOE variation in multiple sclerosis (MS), but have lacked the statistical power to detect modest genetic influences on risk and disease severity. The meta- and pooled analyses presented here utilize the largest collection, to date, of MS cases, controls, and families genotyped for the APOE epsilon polymorphism. Methods: Studies of MS and APOE were identified by searches of PubMed, Biosis, Web of Science, Cochrane Review, and Embase. When possible, authors were contacted for individual genotype data. Meta-analyses of MS case-control data and family-based analyses were performed to assess the association of APOE epsilon genotype with disease risk. Pooled analyses of MS cases were also performed to assess the influence of APOE epsilon genotype on disease severity. Results: A total of 22 studies (3,299 MS cases and 2,532 controls) were available for meta-analysis. No effect of e2 or e4 status on MS risk was observed (summary OR 1.14, 95% CI 0.96–1.34 and OR 0.89, 95% CI 0.78–1.01). Results obtained from analyses of APOE genotypes in 1,279 MS families were also negative ( p = 0.61). Finally, results from pooled analyses of 4,048 MS cases also argue strongly that APOE epsilon status does not distinguish a relapsing-remitting from primary progressive disease course, or influence disease severity, as measured by the Expanded Disability Status Scale and disease duration. Conclusion: Overall, these findings do not support a role for APOE in multiple sclerosis, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.
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- 2006
12. Interleukin-6 Immunology in Macrophage Activation Syndrome Related to Neuroimmunological Diseases.
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Nomura T, Niino M, Odani T, Naganuma R, Amino I, Miyazaki Y, Akimoto S, Tanei ZI, Kimura T, Minami N, and Kikuchi S
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Macrophage activation syndrome (MAS) involves an excessive amount of acute inflammatory responses to inflammatory cytokines, particularly interleukin-6 (IL-6). IL-6 is also strongly associated with the pathophysiology of certain neuroimmunological diseases. However, there have so far been few reports of MAS being accompanied by neuroimmunological diseases. We herein report two cases of MAS comorbid with myasthenia gravis or neuromyelitis optica spectrum disorders, IL-6 related neuroimmunological diseases. Standard immunosuppressive therapies could not stabilize the symptoms in our cases until antibodies against the IL-6 receptor were administered. This finding suggests that it is important to consider the underlying pathophysiology of MAS in relation to these neuroimmunological diseases when treating affected patients.
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- 2024
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13. RhoG facilitates a conformational transition in the guanine nucleotide exchange factor complex DOCK5/ELMO1 to an open state.
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Kukimoto-Niino M, Katsura K, Ishizuka-Katsura Y, Mishima-Tsumagari C, Yonemochi M, Inoue M, Nakagawa R, Kaushik R, Zhang KYJ, and Shirouzu M
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- Humans, GTPase-Activating Proteins metabolism, GTPase-Activating Proteins chemistry, GTPase-Activating Proteins genetics, Protein Binding, Protein Conformation, rho GTP-Binding Proteins metabolism, rho GTP-Binding Proteins chemistry, Adaptor Proteins, Signal Transducing metabolism, Adaptor Proteins, Signal Transducing chemistry, Guanine Nucleotide Exchange Factors metabolism, Guanine Nucleotide Exchange Factors chemistry, rac1 GTP-Binding Protein metabolism, rac1 GTP-Binding Protein chemistry
- Abstract
The dedicator of cytokinesis (DOCK)/engulfment and cell motility (ELMO) complex serves as a guanine nucleotide exchange factor (GEF) for the GTPase Rac. RhoG, another GTPase, activates the ELMO-DOCK-Rac pathway during engulfment and migration. Recent cryo-EM structures of the DOCK2/ELMO1 and DOCK2/ELMO1/Rac1 complexes have identified closed and open conformations that are key to understanding the autoinhibition mechanism. Nevertheless, the structural details of RhoG-mediated activation of the DOCK/ELMO complex remain elusive. Herein, we present cryo-EM structures of DOCK5/ELMO1 alone and in complex with RhoG and Rac1. The DOCK5/ELMO1 structure exhibits a closed conformation similar to that of DOCK2/ELMO1, suggesting a shared regulatory mechanism of the autoinhibitory state across DOCK-A/B subfamilies (DOCK1-5). Conversely, the RhoG/DOCK5/ELMO1/Rac1 complex adopts an open conformation that differs from that of the DOCK2/ELMO1/Rac1 complex, with RhoG binding to both ELMO1 and DOCK5. The alignment of the DOCK5 phosphatidylinositol (3,4,5)-trisphosphate binding site with the RhoG C-terminal lipidation site suggests simultaneous binding of RhoG and DOCK5/ELMO1 to the plasma membrane. Structural comparison of the apo and RhoG-bound states revealed that RhoG facilitates a closed-to-open state conformational change of DOCK5/ELMO1. Biochemical and surface plasmon resonance (SPR) assays confirm that RhoG enhances the Rac GEF activity of DOCK5/ELMO1 and increases its binding affinity for Rac1. Further analysis of structural variability underscored the conformational flexibility of the DOCK5/ELMO1/Rac1 complex core, potentially facilitating the proximity of the DOCK5 GEF domain to the plasma membrane. These findings elucidate the structural mechanism underlying the RhoG-induced allosteric activation and membrane binding of the DOCK/ELMO complex., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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14. Autism Spectrum Disorder- and/or Intellectual Disability-Associated Semaphorin-5A Exploits the Mechanism by Which Dock5 Signalosome Molecules Control Cell Shape.
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Okabe M, Sato T, Takahashi M, Honjo A, Okawa M, Ishida M, Kukimoto-Niino M, Shirouzu M, Miyamoto Y, and Yamauchi J
- Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes autism, Asperger's syndrome, and pervasive developmental disorder. Individuals with ASD may exhibit difficulties in social interactions, communication challenges, repetitive behaviors, and restricted interests. While genetic mutations in individuals with ASD can either activate or inactivate the activities of the gene product, impacting neuronal morphogenesis and causing symptoms, the underlying mechanism remains to be fully established. Herein, for the first time, we report that genetically conserved Rac1 guanine-nucleotide exchange factor (GEF) Dock5 signalosome molecules control process elongation in the N1E-115 cell line, a model line capable of achieving neuronal morphological changes. The increased elongation phenotypes observed in ASD and intellectual disability (ID)-associated Semaphorin-5A (Sema5A) Arg676-to-Cys [p.R676C] were also mediated by Dock5 signalosome molecules. Indeed, knockdown of Dock5 using clustered regularly interspaced short palindromic repeat (CRISPR)/CasRx-based guide(g)RNA specifically recovered the mutated Sema5A-induced increase in process elongation in cells. Knockdown of Elmo2, an adaptor molecule of Dock5, also exhibited similar recovery. Comparable results were obtained when transfecting the interaction region of Dock5 with Elmo2. The activation of c-Jun N-terminal kinase (JNK), one of the primary signal transduction molecules underlying process elongation, was ameliorated by either their knockdown or transfection. These results suggest that the Dock5 signalosome comprises abnormal signaling involved in the process elongation induced by ASD- and ID-associated Sema5A. These molecules could be added to the list of potential therapeutic target molecules for abnormal neuronal morphogenesis in ASD at the molecular and cellular levels.
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- 2024
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15. A macrocyclic kinase inhibitor overcomes triple resistant mutations in EGFR-positive lung cancer.
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Suzuki M, Uchibori K, Oh-Hara T, Nomura Y, Suzuki R, Takemoto A, Araki M, Matsumoto S, Sagae Y, Kukimoto-Niino M, Kawase Y, Shirouzu M, Okuno Y, Nishio M, Fujita N, and Katayama R
- Abstract
Brigatinib-based therapy was effective against osimertinib-resistant EGFR C797S mutants and is undergoing clinical studies. However, tumor relapse suggests additional resistance mutations might emerge. Here, we first demonstrated the binding mode of brigatinib to the EGFR-T790M/C797S mutant by crystal structure analysis and predicted brigatinib-resistant mutations through a cell-based assay including N-ethyl-N-nitrosourea (ENU) mutagenesis. We found that clinically reported L718 and G796 compound mutations appeared, consistent with their proximity to the binding site of brigatinib, and brigatinib-resistant quadruple mutants such as EGFR-activating mutation/T790M/C797S/L718M were resistant to all the clinically available EGFR-TKIs. BI-4020, a fourth-generation EGFR inhibitor with a macrocyclic structure, overcomes the quadruple and major EGFR-activating mutants but not the minor mutants, such as L747P or S768I. Molecular dynamics simulation revealed the binding mode and affinity between BI-4020 and EGFR mutants. This study identified potential therapeutic strategies using the new-generation macrocyclic EGFR inhibitor to overcome the emerging ultimate resistance mutants., (© 2024. The Author(s).)
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- 2024
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16. Literature Review of Studies Using the National Database of the Health Insurance Claims of Japan (NDB): Limitations and Strategies in Using the NDB for Research.
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Suto M, Iba A, Sugiyama T, Kodama T, Takegami M, Taguchi R, Niino M, Koizumi R, Kashiwagi K, Imai K, Ihana-Sugiyama N, Ichinose Y, Takehara K, and Iso H
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The use of the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) for research has increased over time. Researchers need to understand the characteristics of the data to generate quality-assured evidence from the NDB. In this review, we mapped and characterized the limitations and related strategies using the NDB for research based on the descriptions of published NDB studies. To find studies that used Japanese healthcare claims data, we searched MEDLINE, EMBASE, and Ichushi-Web up to June 2023. Additionally, we hand-searched the NDB data publication list from the Ministry of Health, Labour and Welfare (2017-2023). We abstracted data based on the NDB data type, research themes, age of the study sample or population, targeted disease, and the limitations and strategies in the NDB studies. Ultimately, 267 studies were included. Overall, the most common research theme was describing and estimating the prescriptions and treatment patterns (125 studies, 46.8%). There was a variation in the frequency of themes according to the type of NDB data. We identified the following categories of limitations: (1) lack of information on confounders/covariates, outcomes, and other clinical content, (2) limitations regarding patients not included in the NDB, (3) misclassification of data, (4) lack of unique identifiers and register of beneficiaries, and (5) others. Although the included studies noted several limitations of using the NDB for research, they also provided some strategies to address them. Organizing the limitations of NDB in research and the related strategies across research fields can help support high-quality NDB studies., Competing Interests: None, (Copyright © Japan Medical Association.)
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- 2024
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17. A small molecule iCDM-34 identified by in silico screening suppresses HBV DNA through activation of aryl hydrocarbon receptor.
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Furutani Y, Hirano Y, Toguchi M, Higuchi S, Qin XY, Yanaka K, Sato-Shiozaki Y, Takahashi N, Sakai M, Kongpracha P, Suzuki T, Dohmae N, Kukimoto-Niino M, Shirouzu M, Nagamori S, Suzuki H, Kobayashi K, Masaki T, Koyama H, Sekiba K, Otsuka M, Koike K, Kohara M, Kojima S, Kakeya H, and Matsuura T
- Abstract
IFN-alpha have been reported to suppress hepatitis B virus (HBV) cccDNA via APOBEC3 cytidine deaminase activity through interferon signaling. To develop a novel anti-HBV drug for a functional cure, we performed in silico screening of the binding compounds fitting the steric structure of the IFN-alpha-binding pocket in IFNAR2. We identified 37 compounds and named them in silico cccDNA modulator (iCDM)-1-37. We found that iCDM-34, a new small molecule with a pyrazole moiety, showed anti-HCV and anti-HBV activities. We measured the anti-HBV activity of iCDM-34 dependent on or independent of entecavir (ETV). iCDM-34 suppressed HBV DNA, pgRNA, HBsAg, and HBeAg, and also clearly exhibited additive inhibitory effects on the suppression of HBV DNA with ETV. We confirmed metabolic stability of iCDM-34 was stable in human liver microsomal fraction. Furthermore, anti-HBV activity in human hepatocyte-chimeric mice revealed that iCDM-34 was not effective as a single reagent, but when combined with ETV, it suppressed HBV DNA compared to ETV alone. Phosphoproteome and Western blotting analysis showed that iCDM-34 did not activate IFN-signaling. The transcriptome analysis of interferon-stimulated genes revealed no increase in expression, whereas downstream factors of aryl hydrocarbon receptor (AhR) showed increased levels of the expression. CDK1/2 and phospho-SAMHD1 levels decreased under iCDM-34 treatment. In addition, AhR knockdown inhibited anti-HCV activity of iCDM-34 in HCV replicon cells. These results suggest that iCDM-34 decreases the phosphorylation of SAMHD1 through CDK1/2, and suppresses HCV replicon RNA, HBV DNA, and pgRNA formation., (© 2023. The Author(s).)
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- 2023
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18. RhoG-Binding Domain of Elmo1 Ameliorates Excessive Process Elongation Induced by Autism Spectrum Disorder-Associated Sema5A.
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Okabe M, Miyamoto Y, Ikoma Y, Takahashi M, Shirai R, Kukimoto-Niino M, Shirouzu M, and Yamauchi J
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Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes autism, Asperger's syndrome, and pervasive developmental disorder. ASD is characterized by poor interpersonal relationships and strong attachment. The correlations between activated or inactivated gene products, which occur as a result of genetic mutations affecting neurons in ASD patients, and ASD symptoms are now of critical concern. Here, for the first time, we describe the process in which that the respective ASD-associated mutations (Arg676-to-Cys [R676C] and Ser951-to-Cys [S951C]) of semaphorin-5A (Sema5A) localize Sema5A proteins themselves around the plasma membrane in the N1E-115 cell line, a model line that can achieve neuronal morphological differentiation. The expression of each mutated construct resulted in the promotion of excessive elongation of neurite-like processes with increased differentiation protein markers; R676C was more effective than S951C. The differentiated phenotypes were very partially neutralized by an antibody, against Plexin-B3 as the specific Sema5A receptor, suggesting that the effects of Sema5A act in an autocrine manner. R676C greatly increased the activation of c-Jun N-terminal kinase (JNK), one of the signaling molecules underlying process elongation. In contrast, the blocking of JNK signaling, by a chemical JNK inhibitor or an inhibitory construct of the interaction of RhoG with Elmo1 as JNK upstream signaling molecules, recovered the excessive process elongation. These results suggest that ASD-associated mutations of Sema5A, acting through the JNK signaling cascade, lead to excessive differentiated phenotypes, and the inhibition of JNK signaling recovers them, revealing possible therapeutic targets for recovering the potential molecular and cellular phenotypes underlying certain ASD symptoms.
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- 2023
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19. Nursing support for breathlessness in patients with cancer: a scoping review.
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Kako J, Morikawa M, Kobayashi M, Kanno Y, Kajiwara K, Nakano K, Matsuda Y, Shimizu Y, Hori M, Niino M, Suzuki M, and Shimazu T
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- Humans, Adolescent, Adult, Dyspnea etiology, Dyspnea therapy, Palliative Care methods, Physical Therapy Modalities, Walking, Neoplasms complications
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Objective: To identify nursing support provided for the relief of breathlessness in patients with cancer., Design: A scoping review following a standard framework proposed by Arksey and O'Malley., Study Selection: Electronic databases (PubMed, CINAHL, CENTRAL and Ichushi-Web of the Japan Medical Abstract Society Databases) were searched from inception to 31 January 2022. Studies reporting on patients with cancer (aged ≥18 years), intervention for relief from breathlessness, nursing support and quantitatively assessed breathlessness using a scale were included., Results: Overall, 2629 articles were screened, and 27 were finally included. Results of the qualitative thematic analysis were categorised into 12 nursing support components: fan therapy, nurse-led intervention, multidisciplinary intervention, psychoeducational programme, breathing technique, walking therapy, inspiratory muscle training, respiratory rehabilitation, yoga, acupuncture, guided imagery and abdominal massage., Conclusions: We identified 12 components of nursing support for breathlessness in patients with cancer. The study results may be useful to understand the actual state of nursing support provided for breathlessness in patients with terminal cancer and to consider possible support that can be implemented., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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20. Studies of Health Insurance Claims Data in Japan: A Scoping Review.
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Suto M, Sugiyama T, Imai K, Furuno T, Hosozawa M, Ichinose Y, Ihana-Sugiyama N, Kodama T, Koizumi R, Shimizu-Motohashi Y, Murata S, Nakamura Y, Niino M, Sato M, Taguchi R, Takegami M, Tanaka M, Tsutsumimoto K, Usuda K, Takehara K, and Iso H
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Background: Health insurance claims data are used in various research fields; however, an overview on how they are used in healthcare research is scarce in Japan. Therefore, we conducted a scoping review to systematically map the relevant studies using Japanese claims data., Methods: MEDLINE, EMBASE, and Ichushi-Web were searched up to April 2021 for studies using Japanese healthcare claims data. We abstracted the data on study characteristics and summarized target diseases and research themes by the types of claims database. Moreover, we described the results of studies that aimed to compare health insurance claims data with other data sources narratively., Results: A total of 1,493 studies were included. Overall, the most common disease classifications were "Diseases of the circulatory system" (18.8%, n = 281), "Endocrine, nutritional, and metabolic diseases" (11.5%, n = 171; mostly diabetes), and "Neoplasms" (10.9%, n = 162), and the most common research themes were "medical treatment status" (30.0%, n = 448), "intervention effect" (29.9%, n = 447), and "clinical epidemiology, course of diseases" (27.9%, n = 417). Frequent diseases and themes varied by type of claims databases. A total of 19 studies aimed to assess the validity of the claims-based definition, and 21 aimed to compare the results of claims data with other data sources. Most studies that assessed the validity of claims data compared to medical records were hospital-based, with a small number of institutions., Conclusions: Claims data are used in various research areas and will increasingly provide important evidence for healthcare policy in Japan. It is important to use previous claims database studies and share information on methodology among researchers, including validation studies, while informing policymakers about the applicability of claims data for healthcare planning and management., Competing Interests: None, (Copyright © Japan Medical Association.)
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- 2023
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21. Smoking and younger age at onset in anti-acetylcholine receptor antibody-positive myasthenia gravis.
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Miyazaki Y, Sakushima K, Niino M, Takahashi E, Oiwa K, Naganuma R, Amino I, Akimoto S, Minami N, Yabe I, and Kikuchi S
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- Male, Humans, Female, Age of Onset, Cross-Sectional Studies, Retrospective Studies, Receptors, Cholinergic, Autoantibodies, Smoking adverse effects, Myasthenia Gravis epidemiology, Myasthenia Gravis etiology, Thymus Neoplasms complications
- Abstract
Smoking is a known risk factor for the development and progression of several autoimmune diseases. Previous studies have pointed out the association of smoking with the development and worsening of symptoms in myasthenia gravis (MG), but further investigation is necessary to confirm this association. Smoking history was investigated in a cross-sectional study of 139 patients with anti-acetylcholine receptor antibody-positive MG, and the association of smoking history with the age at the onset of MG was analyzed. Patients who had been smoking at the onset of MG were significantly younger compared with those who had never smoked or had quit before the onset of MG. A linear regression analysis adjusting for sex and the presence/absence of thymoma showed a significant association between smoking at onset and younger age at onset (regression coefficient -9.05; 95% confidence interval, -17.6, -0.51; p = 0.039). Among patients with smoking exposure within 10 years prior to or at the onset of MG, women were significantly younger at the onset of MG compared with men. Our results suggest that smoking is an independent risk factor for the earlier development of anti-acetylcholine receptor antibody-positive MG and further support the putative link between smoking and MG.
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- 2023
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22. Immunotherapy for ocular myasthenia gravis: an observational study in Japan.
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Narita T, Nakane S, Nagaishi A, Minami N, Niino M, Kawaguchi N, Murai H, Kira JI, Shimizu J, Iwasa K, Yoshikawa H, Hatanaka Y, Sonoo M, Shimizu Y, and Matsuo H
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Background: Treatment for ocular myasthenia gravis (OMG) has not yet been well established. Few reports have been published on the clinical practice and outcomes of OMG., Objectives: We investigated treatment of OMG and its outcomes in Japan.We investigated treatment of OMG and its outcomes in Japan., Design: We performed a retrospective cross-sectional survey of OMG patients from eight hospitals in Japan., Methods: Clinical information, including sex, age at onset, initial symptoms, autoantibodies, clinical course, treatment history, complications, and outcomes, was obtained. In addition, we recorded the total number of patients with MG and OMG separately., Results: In total, 135 patients with OMG (67 men, 68 women) were included. Treatment of OMG was not simple and involved various immunotherapeutic strategies. Eight patients went into remission spontaneously without immunotherapy. A total of 117 patients showed improvements after treatment, whereas 10 patients showed refractory responses to treatment. Overall outcomes were good; however, symptoms persisted in 60.7% of patients even after treatment. Among 90 patients who received immunotherapy, only two showed a refractory response. Meanwhile, for 45 patients who did not receive immunotherapy, 8 were refractory. Thus, the rate of refractory disease in the group with immunotherapy was significantly lower ( p = 0.001, u-test) than in the group without immunotherapy. The proportion of generalized MG patients among all MG cases was low in medical centers where immunotherapy for OMG was frequently performed., Conclusion: Although the overall prognosis for patients with OMG was good, symptoms remained in more than half of the patients. Immunotherapy, including corticosteroids, may be beneficial for patients with OMG., Plain Language Summary: Is immunosuppressive therapy beneficial for myasthenia gravis patients with ocular symptoms only? Patients with ocular myasthenia gravis (OMG) have only eye symptoms for more than 2 years. Whether this condition is an initial stage of the disease before eventually progressing to generalized myasthenia gravis (gMG) is still uncertain. Different from gMG, OMG is not life-threatening. But eye symptoms often cause troublesome problems in life. Doctors have treated OMG patients similarly to patients with gMG. There is no standard clinical practice for OMG. In this study, we examined how patients with OMG were treated at eight different specialist centers in Japan. In 135 patients with OMG, 8 patients became symptom free without treatment, 117 patients showed improvements after treatment, whereas 10 patients did not get well. Overall outcomes were good, but symptoms remained in 60.7% of patients even after treatment. Among 90 patients who received one or more immunotherapies, only 2 did not get well. Meanwhile, for 45 patients who did not receive immunotherapy, 8 remained ill. We found that treatment of OMG was not simple and often needed multiple immunotherapies. Administering immunotherapy, including corticosteroids, may be beneficial for patients with OMG., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2023.)
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- 2023
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23. Targeting Ras-binding domain of ELMO1 by computational nanobody design.
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Tam C, Kukimoto-Niino M, Miyata-Yabuki Y, Tsuda K, Mishima-Tsumagari C, Ihara K, Inoue M, Yonemochi M, Hanada K, Matsumoto T, Shirouzu M, and Zhang KYJ
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Molecular Dynamics Simulation, rho GTP-Binding Proteins genetics, rho GTP-Binding Proteins metabolism
- Abstract
The control of cell movement through manipulation of cytoskeletal structure has therapeutic prospects notably in the development of novel anti-metastatic drugs. In this study, we determine the structure of Ras-binding domain (RBD) of ELMO1, a protein involved in cytoskeletal regulation, both alone and in complex with the activator RhoG and verify its targetability through computational nanobody design. Using our dock-and-design approach optimized with native-like initial pose selection, we obtain Nb01, a detectable binder from scratch in the first-round design. An affinity maturation step guided by structure-activity relationship at the interface generates 23 Nb01 sequence variants and 17 of them show enhanced binding to ELMO1-RBD and are modeled to form major spatial overlaps with RhoG. The best binder, Nb29, inhibited ELMO1-RBD/RhoG interaction. Molecular dynamics simulation of the flexibility of CDR2 and CDR3 of Nb29 reveal the design of stabilizing mutations at the CDR-framework junctions potentially confers the affinity enhancement., (© 2023. The Author(s).)
- Published
- 2023
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24. Structural Insight into TNIK Inhibition.
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Kukimoto-Niino M, Shirouzu M, and Yamada T
- Subjects
- Humans, Wnt Proteins metabolism, Protein Serine-Threonine Kinases, Wnt Signaling Pathway, beta Catenin metabolism, Colorectal Neoplasms pathology
- Abstract
TRAF2- and NCK-interacting kinase (TNIK) has emerged as a promising therapeutic target for colorectal cancer because of its essential role in regulating the Wnt/β-catenin signaling pathway. Colorectal cancers contain many mutations in the Wnt/β-catenin signaling pathway genes upstream of TNIK, such as the adenomatous polyposis coli ( APC ) tumor suppressor gene. TNIK is a regulatory component of the transcriptional complex composed of β-catenin and T-cell factor 4 (TCF4). Inhibition of TNIK is expected to block the aberrant Wnt/β-catenin signaling caused by colorectal cancer mutations. Here we present structural insights into TNIK inhibitors targeting the ATP-binding site. We will discuss the effects of the binding of different chemical scaffolds of nanomolar inhibitors on the structure and function of TNIK.
- Published
- 2022
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25. Nursing support for symptoms in patients with cancer and caregiver burdens: a scoping review protocol.
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Kako J, Kobayashi M, Kanno Y, Kajiwara K, Nakano K, Morikawa M, Matsuda Y, Shimizu Y, Hori M, Niino M, Suzuki M, and Shimazu T
- Subjects
- Caregiver Burden, Caregivers, Humans, Research Design, Systematic Reviews as Topic, Neoplasms, Nutrition Therapy
- Abstract
Introduction: Terminally ill patients with cancer experience a variety of symptoms, and their families experience certain caregiver burdens. Most studies on this topic have focused on the symptoms experienced by patients with cancer. There is little established evidence to show how nursing support affects these symptoms and burdens. Nurses provide support by extrapolating their clinical experience, practical knowledge and insights gained from the treatment phase of patients with cancer, regardless of the existence or degree of evidence. This study presents a scoping review protocol with the aim of categorising the feasibility of nursing support from the initial to the terminal phases in the trajectory of cancer care., Method and Analysis: This review will be guided by Arksey and O'Malley's five-stage scoping review framework and Levac's extension. Our research project team will focus on the pain, dyspnoea, nausea and vomiting, constipation, delirium, fatigue and skin disorders experienced by patients with cancer as well as the burdens experienced by caregivers of such patients. All available published articles from database inception to 31 January 2022 will be systematically searched using the following electrical databases: PubMed, CINAHL, CENTRAL in the Cochrane Library and Ichushi-Web of the Japan Medical Abstract Society databases. In addition, we will assess relevant studies from the reference list and manually search each key journal. The formula creation phase of the literature search involves working with a librarian to identify relevant keywords. At least two reviewers will independently screen and review articles and extract data using a data chart form. Results will be mapped according to study design and analysed for adaptation in the field of terminal cancer., Ethics and Dissemination: This review does not require ethical approval as it is a secondary analysis of pre-existing, published data. The findings will be disseminated through peer-reviewed publications and conference presentations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
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26. B-cell depletion therapy for multiple sclerosis.
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Miyazaki Y and Niino M
- Subjects
- B-Lymphocytes, Central Nervous System, Cytokines, Humans, Lymphocyte Depletion, Multiple Sclerosis drug therapy
- Abstract
Since the initial observation of increased immunoglobulin concentrations in the cerebrospinal fluid of multiple sclerosis (MS) patients in the 1940s, B cells have been considered to participate in the pathology of MS through the production of autoantibodies reactive against central nervous system antigens. However, it is now recognized that B cells contribute to MS relapses via antibody-independent activities, including the presentation of antigens to T cells and the release of pro-inflammatory cytokines. In addition, the recent identification of B cell-rich follicle-like structures in the meninges of progressive MS patients suggests that the pathogenic roles of B cells also exist at the progressive phase of this disease. Recently, large-scale clinical trials have demonstrated the efficacy of B-cell depletion therapy using anti-CD20 antibodies in relapsing as well as primary progressive MS. B-cell depletion therapy has become an essential treatment option for MS based on its unique benefit to risk balance in relapsing MS, and because it is the only drug that has been shown to be effective in primary progressive MS to date.
- Published
- 2022
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27. Association of Smoking and Generalized Manifestations of Myasthenia Gravis.
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Miyazaki Y, Niino M, Sakushima K, Takahashi E, Naganuma R, Amino I, Akimoto S, Minami N, Yabe I, and Kikuchi S
- Subjects
- Activities of Daily Living, Cross-Sectional Studies, Humans, Retrospective Studies, Smoking adverse effects, Smoking epidemiology, Myasthenia Gravis complications, Myasthenia Gravis diagnosis, Myasthenia Gravis epidemiology, Thymus Neoplasms complications
- Abstract
Objective Smoking is a known risk factor for the development and progression of autoimmune diseases. Previous studies in ocular myasthenia gravis (MG) patients showed that smoking is associated with the severity of symptoms and progression to generalized MG. However, whether smoking affects MG symptoms in patients with a broader clinical spectrum of presentations is unknown. Therefore, in this study, the associations of smoking with the clinical characteristics of MG were analyzed in a cohort of patients including those with generalized, seronegative, and thymoma-associated MG. Methods The smoking history was investigated in a cross-sectional study of 187 patients with MG followed in a referral hospital for neurology. The association of smoking with MG-activities of daily living score at survey, the presence of generalized manifestations, and the age of onset was assessed using multiple regression models. Results Neither current nor prior smoking habit was associated with the MG-activities of daily living score at survey. However, smoking exposure after MG onset was significantly associated with the presence of generalized manifestations during the disease course (odds ratio, 3.57; 95% confidence interval, 1.04, 12.3). The smoking history before or at onset of MG was not associated with the age of onset. Conclusion Smoking exposure after the onset is associated with generalized manifestations of MG in our cohort of patients with a broad clinical spectrum of presentations.
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- 2022
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28. Elucidation of Chemical Interactions between Crude Drugs Using Quantitative Thin-Layer Chromatography Analysis.
- Author
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Oshima N, Saito M, Niino M, Hiraishi Y, Ueki K, Okoshi K, Hakamatsuka T, and Hada N
- Subjects
- Phytochemicals analysis, Plant Extracts analysis, Plant Roots chemistry, Chromatography, Thin Layer methods, Complex Mixtures analysis, Complex Mixtures metabolism, Drug Interactions, Drugs, Chinese Herbal chemistry, Medicine, Kampo, Phytochemicals metabolism, Plant Extracts metabolism
- Abstract
To elucidate the interactions between crude drugs in Kampo medicines (traditional Japanese medicines), it is important to determine the content of the constituents in a cost-effective and simple manner. In this study, we quantified the constituents in crude drug extracts using thin-layer chromatography (TLC), an inexpensive and simple analytical method, to elucidate the chemical interactions between crude drugs. We focused on five crude drugs, for which quantitative high-performance liquid chromatography (HPLC) methods are stipulated in the Japanese Pharmacopoeia XVIII (JP XVIII) and compared the analytical data of HPLC and TLC, confirming that the TLC results corresponded with the HPLC data and satisfied the criteria of JP XVIII. ( Z )-ligustilide, a major constituent in Japanese Angelica Root, for which a method of quantification has not been stipulated in JP XVIII, was also quantitatively analyzed using HPLC and TLC. Furthermore, Japanese Angelica Root was combined with 26 crude drugs to observe the variation in the ( Z )-ligustilide content from each combination by TLC. The results revealed that combinations with Phellodendron Bark, Citrus Unshiu Peel, Scutellaria Root, Coptis Rhizome, Gardenia Fruit, and Peony Root increased the ( Z )-ligustilide content. Quantifying the constituents in crude drug extracts using the inexpensive and simple TLC method can contribute to elucidating interactions between crude drugs in Kampo medicines, as proposed by the herbal-pair theory.
- Published
- 2022
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29. Age-specific incidence rate of immunoproliferative disease and multiple myeloma in the world.
- Author
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Niino M and Okuyama A
- Subjects
- Age Factors, Humans, Incidence, Multiple Myeloma epidemiology
- Published
- 2021
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30. Direct homophilic interaction of LAMP2A with the two-domain architecture revealed by site-directed photo-crosslinks and steric hindrances in mammalian cells.
- Author
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Terasawa K, Kato Y, Ikami Y, Sakamoto K, Ohtake K, Kusano S, Tomabechi Y, Kukimoto-Niino M, Shirouzu M, Guan JL, Kobayashi T, Iwata T, Watabe T, Yokoyama S, and Hara-Yokoyama M
- Subjects
- Animals, Fibroblasts metabolism, Lysosomal-Associated Membrane Protein 2 metabolism, Lysosomal Membrane Proteins metabolism, Lysosomes metabolism, Mammals metabolism, Mice, Autophagy genetics, Molecular Chaperones metabolism
- Abstract
LAMP1 (lysosomal-associated membrane protein 1) and LAMP2 are the most abundant protein components of lysosome membranes. Both LAMPs have common structures consisting of a large lumenal domain composed of two domains (N-domain and C-domain, which are membrane-distal and -proximal, respectively), both with the β-prism fold, a transmembrane domain, and a short cytoplasmic tail. LAMP2 is involved in various aspects of autophagy, and reportedly forms high-molecular weight complexes at the lysosomal membrane. We previously showed that LAMP2 molecules coimmunoprecipitated with each other, but whether the homophilic interaction is direct or indirect has remained to be elucidated. In the present study, we demonstrated the direct homophilic interaction of mouse LAMP2A molecules, using expanded genetic code technologies that generate photo-crosslinking and/or steric hindrance at specified interfaces. Specifically, the results suggested that LAMP2A molecules assemble by facing each other with one side of the β-prism (defined as side A) of the C-domains. The N-domain truncation, which increased the coimmunoprecipitation of LAMP2A molecules in our previous study, permitted the nonspecific involvement of both sides of the β-prism (side A and side B). Thus, the presence of the N-domain restricts the LAMP2A interactions to side A-specific. The truncation of LAMP2A impaired the recruitment of GAPDH (a CMA-substrate) fused to the HaloTag protein to the surface of late endosomes/lysosomes (LE/Lys) and affected a process that generates LE/Lys. The present study revealed that the homophilic interaction of LAMP2A is direct, and the side A-specific, homophilic interaction of LAMP2A is required for the functional aspects of LAMP2A. Abbreviations: Aloc-Lys: N
ε -allyloxycarbonyl-l-lysine; CMA: chaperone-mediated autophagy; FFE: free-flow electrophoresis; GAPDH-HT: glyceraldehyde-3-phosphate dehydrogenase fused to HaloTag protein; LAMP1: lysosomal-associated membrane protein 1; LAMP2A: lysosomal-associated membrane protein 2A; LBPA: lysobisphosphatidic acid; LE/Lys: late endosome/lysosomes; MEFs: mouse embryonic fibroblasts; p Bpa: p -benzoyl- l-phenylalanine.- Published
- 2021
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31. Age-specific lip, oral cavity and pharynx cancer incidence rate in the world.
- Author
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Saito E and Niino M
- Subjects
- Age Factors, Humans, Incidence, Lip, Pharyngeal Neoplasms epidemiology
- Published
- 2021
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- View/download PDF
32. Cryo-EM structure of the human ELMO1-DOCK5-Rac1 complex.
- Author
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Kukimoto-Niino M, Katsura K, Kaushik R, Ehara H, Yokoyama T, Uchikubo-Kamo T, Nakagawa R, Mishima-Tsumagari C, Yonemochi M, Ikeda M, Hanada K, Zhang KYJ, and Shirouzu M
- Abstract
The dedicator of cytokinesis (DOCK) family of guanine nucleotide exchange factors (GEFs) promotes cell motility, phagocytosis, and cancer metastasis through activation of Rho guanosine triphosphatases. Engulfment and cell motility (ELMO) proteins are binding partners of DOCK and regulate Rac activation. Here, we report the cryo-electron microscopy structure of the active ELMO1-DOCK5 complex bound to Rac1 at 3.8-Å resolution. The C-terminal region of ELMO1, including the pleckstrin homology (PH) domain, aids in the binding of the catalytic DOCK homology region 2 (DHR-2) domain of DOCK5 to Rac1 in its nucleotide-free state. A complex α-helical scaffold between ELMO1 and DOCK5 stabilizes the binding of Rac1. Mutagenesis studies revealed that the PH domain of ELMO1 enhances the GEF activity of DOCK5 through specific interactions with Rac1. The structure provides insights into how ELMO modulates the biochemical activity of DOCK and how Rac selectivity is achieved by ELMO., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
- Published
- 2021
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- View/download PDF
33. Reduced efficacy of a Src kinase inhibitor in crowded protein solution.
- Author
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Kasahara K, Re S, Nawrocki G, Oshima H, Mishima-Tsumagari C, Miyata-Yabuki Y, Kukimoto-Niino M, Yu I, Shirouzu M, Feig M, and Sugita Y
- Subjects
- Animals, Binding Sites, CSK Tyrosine-Protein Kinase drug effects, CSK Tyrosine-Protein Kinase metabolism, Computational Biology, Models, Molecular, Proteins chemistry, Pyrazoles pharmacology, Pyrimidines pharmacology, src-Family Kinases chemistry, Protein Kinase Inhibitors pharmacology, Proteins metabolism, src-Family Kinases drug effects, src-Family Kinases metabolism
- Abstract
The inside of a cell is highly crowded with proteins and other biomolecules. How proteins express their specific functions together with many off-target proteins in crowded cellular environments is largely unknown. Here, we investigate an inhibitor binding with c-Src kinase using atomistic molecular dynamics (MD) simulations in dilute as well as crowded protein solution. The populations of the inhibitor, 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1), in bulk solution and on the surface of c-Src kinase are reduced as the concentration of crowder bovine serum albumins (BSAs) increases. This observation is consistent with the reduced PP1 inhibitor efficacy in experimental c-Src kinase assays in addition with BSAs. The crowded environment changes the major binding pathway of PP1 toward c-Src kinase compared to that in dilute solution. This change is explained based on the population shift mechanism of local conformations near the inhibitor binding site in c-Src kinase.
- Published
- 2021
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34. Age-specific skin cancer incidence rate in the world.
- Author
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Niino M and Matsuda T
- Subjects
- Age Factors, Humans, Incidence, Registries, Skin Neoplasms epidemiology
- Published
- 2021
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- View/download PDF
35. Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer.
- Author
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Mizuta H, Okada K, Araki M, Adachi J, Takemoto A, Kutkowska J, Maruyama K, Yanagitani N, Oh-Hara T, Watanabe K, Tamai K, Friboulet L, Katayama K, Ma B, Sasakura Y, Sagae Y, Kukimoto-Niino M, Shirouzu M, Takagi S, Simizu S, Nishio M, Okuno Y, Fujita N, and Katayama R
- Subjects
- Aminopyridines, Animals, Apoptosis physiology, Benzamides therapeutic use, Carbazoles therapeutic use, Cell Line, Cell Survival physiology, Crizotinib therapeutic use, Drug Resistance, Neoplasm genetics, Humans, Immunoblotting, Indazoles therapeutic use, Lactams, Lung Neoplasms drug therapy, Lung Neoplasms enzymology, Mice, Mice, Inbred BALB C, Molecular Dynamics Simulation, Neoplasm Recurrence, Local, Piperidines therapeutic use, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Pyrazoles, Receptor Protein-Tyrosine Kinases genetics, Receptor Protein-Tyrosine Kinases metabolism, Aniline Compounds therapeutic use, Enzyme Inhibitors therapeutic use, Lactams, Macrocyclic therapeutic use, Pyrazines therapeutic use
- Abstract
ALK gene rearrangement was observed in 3%-5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI-resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.
- Published
- 2021
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36. A conserved PI(4,5)P2-binding domain is critical for immune regulatory function of DOCK8.
- Author
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Sakurai T, Kukimoto-Niino M, Kunimura K, Yamane N, Sakata D, Aihara R, Yasuda T, Yokoyama S, Shirouzu M, Fukui Y, and Uruno T
- Subjects
- Amino Acid Sequence, Binding Sites, Humans, Models, Molecular, PDZ Domains, Protein Binding, Protein Conformation, Structure-Activity Relationship, Guanine Nucleotide Exchange Factors chemistry, Guanine Nucleotide Exchange Factors metabolism, Immunomodulation, Phosphatidylinositol 4,5-Diphosphate chemistry, Phosphatidylinositol 4,5-Diphosphate metabolism, Protein Interaction Domains and Motifs
- Abstract
DOCK8 is a Cdc42-specific guanine-nucleotide exchange factor that is essential for development and functions of various subsets of leukocytes in innate and acquired immune responses. Although DOCK8 plays a critical role in spatial control of Cdc42 activity during interstitial leukocyte migration, the mechanism remains unclear. We show that the DOCK homology region (DHR)-1 domain of DOCK8 binds specifically to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and is required for its recruitment to the plasma membrane. Structural and biochemical analyses reveal that DOCK8 DHR-1 domain consists of a C2 domain-like core with loops creating the upper surface pocket, where three basic residues are located for stereospecific recognition of phosphoinositides. Substitution of the two basic residues, K576 and R581, with alanine abolished PI(4,5)P2 binding in vitro, ablated the ability of DOCK8 to activate Cdc42 and support leukocyte migration in three-dimensional collagen gels. Dendritic cells carrying the mutation exhibited defective interstitial migration in vivo. Thus, our study uncovers a critical role of DOCK8 in coupling PI(4,5)P2 signaling with Cdc42 activation for immune regulation., (© 2021 Sakurai et al.)
- Published
- 2021
- Full Text
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37. Age-specific incidence rates of gallbladder cancer in the world.
- Author
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Saito E and Niino M
- Published
- 2021
- Full Text
- View/download PDF
38. HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data.
- Author
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Watanabe M, Nakamura Y, Sato S, Niino M, Fukaura H, Tanaka M, Ochi H, Kanda T, Takeshita Y, Yokota T, Nishida Y, Matsui M, Nagayama S, Kusunoki S, Miyamoto K, Mizuno M, Kawachi I, Saji E, Ohashi T, Shimohama S, Hisahara S, Nishiyama K, Iizuka T, Nakatsuji Y, Okuno T, Ochi K, Suzumura A, Yamamoto K, Kawano Y, Tsuji S, Hirata M, Sakate R, Kimura T, Shimizu Y, Nagaishi A, Okada K, Hayashi F, Sakoda A, Masaki K, Shinoda K, Isobe N, Matsushita T, and Kira JI
- Subjects
- Adult, Case-Control Studies, Female, Genotype, Humans, Japan epidemiology, Male, Middle Aged, Multiple Sclerosis epidemiology, Multiple Sclerosis genetics, Multiple Sclerosis immunology, Neuromyelitis Optica epidemiology, Neuromyelitis Optica genetics, Neuromyelitis Optica immunology, Phenotype, Biological Specimen Banks, Genetic Association Studies, HLA-DP beta-Chains genetics, HLA-DRB1 Chains genetics, Multiple Sclerosis pathology, Neuromyelitis Optica pathology
- Abstract
HLA genotype-clinical phenotype correlations are not established for multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We studied HLA-DRB1/DPB1 genotype-phenotype correlations in 528 MS and 165 NMOSD cases using Japan MS/NMOSD Biobank materials. HLA-DRB1*04:05, DRB1*15:01 and DPB1*03:01 correlated with MS susceptibility and DRB1*01:01, DRB1*09:01, DRB1*13:02 and DPB1*04:01 were protective against MS. HLA-DRB1*15:01 was associated with increased optic neuritis and cerebellar involvement and worsened visual and pyramidal functional scale (FS) scores, resulting in higher progression index values. HLA-DRB1*04:05 was associated with younger onset age, high visual FS scores, and a high tendency to develop optic neuritis. HLA-DPB1*03:01 increased brainstem and cerebellar FS scores. By contrast, HLA-DRB1*01:01 decreased spinal cord involvement and sensory FS scores, HLA-DRB1*09:01 decreased annualized relapse rate, brainstem involvement and bowel and bladder FS scores, and HLA-DRB1*13:02 decreased spinal cord and brainstem involvement. In NMOSD, HLA-DRB1*08:02 and DPB1*05:01 were associated with susceptibility and DRB1*09:01 was protective. Multivariable analysis revealed old onset age, long disease duration, and many relapses as independent disability risks in both MS and NMOSD, and HLA-DRB1*15:01 as an independent risk only in MS. Therefore, both susceptibility and protective alleles can influence the clinical manifestations in MS, while such genotype-phenotype correlations are unclear in NMOSD.
- Published
- 2021
- Full Text
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39. Age-specific corpus uteri cancer incidence rate in the world.
- Author
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Niino M and Matsuda T
- Published
- 2020
- Full Text
- View/download PDF
40. Progressive Multifocal Leukoencephalopathy during Tocilizumab Treatment for Rheumatoid Arthritis.
- Author
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Anada M, Tohyama M, Oda Y, Kamoshima Y, Amino I, Nakano F, Miyazaki Y, Akimoto S, Minami N, Kikuchi S, Terae S, and Niino M
- Subjects
- Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Female, Humans, Leukoencephalopathy, Progressive Multifocal diagnosis, Magnetic Resonance Imaging, Methotrexate therapeutic use, Middle Aged, Receptors, Interleukin-6 antagonists & inhibitors, Antibodies, Monoclonal, Humanized adverse effects, Arthritis, Rheumatoid drug therapy, Leukoencephalopathy, Progressive Multifocal chemically induced
- Abstract
A 61-year-old woman was diagnosed with rheumatoid arthritis 12 years ago and received multiple treatment regimens before achieving symptomatic stability with methotrexate plus tocilizumab, a humanized monoclonal antibody against the IL-6 receptor, about 2 years prior to the current presentation. Sixteen months after tocilizumab initiation, she exhibited dysarthria and disorientation; five months later, she was hospitalized with movement difficulties. Her neurological symptoms deteriorated thereafter, accompanied by enlarged cerebral white matter lesions on magnetic resonance imaging. A biopsy of the right frontal lesion confirmed progressive multifocal leukoencephalopathy (PML). While several therapeutic monoclonal antibodies have been linked to PML, this is the first case associated with tocilizumab.
- Published
- 2020
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- View/download PDF
41. Contribution of cortical lesions to cognitive impairment in Japanese patients with multiple sclerosis.
- Author
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Shinoda K, Matsushita T, Nakamura Y, Masaki K, Sakai S, Nomiyama H, Togao O, Hiwatashi A, Niino M, Isobe N, and Kira JI
- Subjects
- Adult, Asian People, Cerebral Cortex pathology, Cognitive Dysfunction diagnostic imaging, Female, HLA-DRB1 Chains genetics, Humans, Imaging, Three-Dimensional, Logistic Models, Magnetic Resonance Imaging methods, Male, Neuropsychological Tests, Cerebral Cortex diagnostic imaging, Cognitive Dysfunction genetics, Cognitive Dysfunction pathology, Multiple Sclerosis pathology, Multiple Sclerosis psychology
- Abstract
Cortical lesions (CLs) have a low prevalence and are associated with physical disabilities in Japanese patients with multiple sclerosis (MS). However, the contribution of CLs to cognitive impairment remains unclear in Asian MS. Sixty-one prospectively enrolled MS patients underwent three-dimensional double inversion recovery MR imaging, the Brief Repeatable Battery of Neuropsychological Tests (BRB-N), the Apathy Scale (AS), the Fatigue Questionnaire (FQ), and the Hospital Anxiety and Depression Scale (HADS) within a 1-week period. The cognitive impairment index (CII) score was calculated to measure patients' overall cognitive impairment. MS patients with CLs had poorer scores than those without CLs in most BRB-N tests, but scored comparably in the FQ, AS, and HADS. The number of CLs correlated negatively with all BRB-N test scores and positively with total CII scores. Leukocortical lesions were more extensively associated with cognitive dysfunction in various domains than intracortical lesions. Stepwise multiple regression analysis revealed that potential confounding factors for the highest quartile of CII score were the number of CLs (odds ratio 2.38, p = 0.0070) and the Expanded Disability Severity Scale score (odds ratio 2.13, p = 0.0003). Our results demonstrate that the presence and number of CLs are robustly associated with cognitive dysfunction in Asian MS patients.
- Published
- 2020
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42. International comparison of skin cancers incidence by detailed sites.
- Author
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Niino M and Matsuda T
- Published
- 2019
- Full Text
- View/download PDF
43. International comparison of urinary tract cancers incidence by detailed sites.
- Author
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Matsuda T and Niino M
- Published
- 2019
- Full Text
- View/download PDF
44. Incidence rates of liver cancer in the world from the Cancer Incidence in Five Continents XI.
- Author
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Niino M and Matsuda T
- Published
- 2019
- Full Text
- View/download PDF
45. Granzyme A Stimulates pDCs to Promote Adaptive Immunity via Induction of Type I IFN.
- Author
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Shimizu K, Yamasaki S, Sakurai M, Yumoto N, Ikeda M, Mishima-Tsumagari C, Kukimoto-Niino M, Watanabe T, Kawamura M, Shirouzu M, and Fujii SI
- Subjects
- Animals, CD8-Positive T-Lymphocytes cytology, Dendritic Cells cytology, Granzymes genetics, Granzymes immunology, Mice, Mice, Knockout, Myeloid Differentiation Factor 88 genetics, Myeloid Differentiation Factor 88 immunology, Plasma Cells cytology, Toll-Like Receptor 9 genetics, Toll-Like Receptor 9 immunology, CD8-Positive T-Lymphocytes immunology, Dendritic Cells immunology, Granzymes pharmacology, Immunity, Cellular drug effects, Plasma Cells immunology
- Abstract
Granzyme A (GzmA), together with perforin, are well-known for their cytotoxic activity against tumor or virus-infected cells. In addition to this cytotoxic function, GzmA stimulates several immune cell types and induces inflammation in the absence of perforin, however, its effect on the dendritic cell (DC) is unknown. In the current study, we showed that recombinant GzmA induced the phenotypic maturation of plasmacytoid DCs (pDCs) and conventional DCs (cDCs), but not their apoptosis. Particularly, GzmA made pDCs more functional, thus leading to production of type I interferon (IFN) via the TLR9-MyD88 pathway. We also demonstrated that GzmA binds TLR9 and co-localizes with it in endosomes. When co-administered with antigen, GzmA acted as a powerful adjuvant for eliciting antigen-specific cytotoxic CD8
+ T lymphocytes (CTLs) that protected mice from tumor challenge. The induction of CTL was completely abolished in XCR1+ DC-depleted mice, whereas it was reduced to less than half in pDC-depleted or IFN-α/β receptor knockout mice. Thus, CTL cross-priming was dependent on XCR1+ cDC and also type I IFN, which was produced by GzmA-activated pDCs. These results indicate that GzmA -stimulated pDCs enhance the cross-priming activity of cDCs in situ . We also showed that the adjuvant effect of GzmA is superior to CpG-ODN and LPS. Our findings highlight the ability of GzmA to bridge innate and adaptive immune responses via pDC help and suggest that GzmA may be useful as a vaccine adjuvant.- Published
- 2019
- Full Text
- View/download PDF
46. Structural Basis for the Dual Substrate Specificity of DOCK7 Guanine Nucleotide Exchange Factor.
- Author
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Kukimoto-Niino M, Tsuda K, Ihara K, Mishima-Tsumagari C, Honda K, Ohsawa N, and Shirouzu M
- Subjects
- Crystallization, Crystallography, X-Ray, Humans, Molecular Conformation, Molecular Dynamics Simulation, Mutagenesis, GTPase-Activating Proteins chemistry, Guanine Nucleotide Exchange Factors chemistry, Substrate Specificity, cdc42 GTP-Binding Protein chemistry, rac1 GTP-Binding Protein chemistry
- Abstract
The Dedicator Of CytoKinesis (DOCK) family of atypical guanine nucleotide exchange factors activates the Rho family GTPases Rac and/or Cdc42 through DOCK homology region 2 (DHR-2). Previous structural analyses of the DHR-2 domains of DOCK2 and DOCK9 have shown that they preferentially bind Rac1 and Cdc42, respectively; however, the molecular mechanism by which DHR-2 distinguishes between these GTPases is unclear. Here we report the crystal structure of the Cdc42-bound form of the DOCK7 DHR-2 domain showing dual specificity for Rac1 and Cdc42. The structure revealed increased substrate tolerance of DOCK7 at the interfaces with switch 1 and residue 56 of Cdc42. Furthermore, molecular dynamics simulations showed a closed-to-open conformational change in the DOCK7 DHR-2 domain between the Cdc42- and Rac1-bound states by lobe B displacement. Our results suggest that lobe B acts as a sensor for identifying different switch 1 conformations and explain how DOCK7 recognizes both Rac1 and Cdc42., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
47. Testis cancer incidence rates in the world from the Cancer Incidence in Five Continents XI.
- Author
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Niino M and Matsuda T
- Published
- 2019
- Full Text
- View/download PDF
48. Bladder cancer incidence rates in the world from the Cancer Incidence in Five Continents XI.
- Author
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Matsuda T and Niino M
- Published
- 2018
- Full Text
- View/download PDF
49. Disease Exacerbation after the Cessation of Fingolimod Treatment in Japanese Patients with Multiple Sclerosis.
- Author
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Sato K, Niino M, Kawashima A, Yamada M, Miyazaki Y, and Fukazawa T
- Subjects
- Adult, Contrast Media, Dimethyl Fumarate therapeutic use, Disease Progression, Drug Substitution, Female, Gadolinium, Humans, Magnetic Resonance Imaging methods, Male, Middle Aged, Multiple Sclerosis diagnostic imaging, Withholding Treatment, Fingolimod Hydrochloride therapeutic use, Immunosuppressive Agents therapeutic use, Multiple Sclerosis drug therapy
- Abstract
Objective In Japan, following the launch of dimethyl fumarate (DMF) after fingolimod as a disease-modifying drug in multiple sclerosis (MS), some patients switched from fingolimod to DMF. The aim of this study was to determine the follow-up status of MS patients who switched to DMF after fingolimod cessation. Methods Clinical and magnetic resonance imaging (MRI) data in 19 patients with MS who switched to DMF were collected for at least for 6 months after fingolimod cessation. Results Ten patients (52.6%) experienced clinical or MRI exacerbation after fingolimod cessation. The peripheral blood lymphocyte counts at the time of fingolimod cessation in those with disease exacerbation were significantly lower than in those without exacerbation. The patients with disease exacerbation were further classified into three groups based on MRI findings: those with some new T2-weighted lesions with or without gadolinium (Gd) enhancement (group I), those with more new and/or enlarged T2-weighted lesions with Gd enhancement compared to pre-fingolimod induction (group II), and those with multifocal tumefactive demyelinating lesions. In group II, the clinical disease activity, which was similar to that at fingolimod initiation in group I, was higher than the clinical disease activity observed before fingolimod initiation. Conversely, group III exhibited unexpected new MRI findings that were not evident before fingolimod initiation. Conclusion Cessation of fingolimod might precipitate rebound or reactivation of clinical disease in patients with MS, and careful follow-up is necessary for patients who discontinue fingolimod.
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- 2018
- Full Text
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50. Structural Basis for the Inhibition of Cyclin G-Associated Kinase by Gefitinib.
- Author
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Ohbayashi N, Murayama K, Kato-Murayama M, Kukimoto-Niino M, Uejima T, Matsuda T, Ohsawa N, Yokoyoma S, Nojima H, and Shirouzu M
- Abstract
Gefitinib is the molecular target drug for advanced non-small-cell lung cancer. The primary target of gefitinib is the positive mutation of epidermal growth factor receptor, but it also inhibits cyclin G-associated kinase (GAK). To reveal the molecular bases of GAK and gefitinib binding, structure analyses were conducted and determined two forms of the gefitinib-bound nanobody⋅GAK kinase domain complex structures. The first form, GAK_1, has one gefitinib at the ATP binding pocket, whereas the second form, GAK_2, binds one each in the ATP binding site and a novel binding site adjacent to the activation segment C-terminal helix, a unique element of the Numb-associated kinase family. In the novel binding site, gefitinib binds in the hydrophobic groove around the activation segment, disrupting the conserved hydrogen bonds for the catalytic activity. These structures suggest possibilities for the development of selective GAK inhibitors for viral infections, such as the hepatitis C virus.
- Published
- 2018
- Full Text
- View/download PDF
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