Publications by authors named "Haruka Yokoyama"

13 Publications

  • Page 1 of 1

Different Effects of Polymorphic Flavin-Containing Monooxygenase 3 and Cytochrome P450 2A6 Activities on an Index of Arteriosclerosis as a Lifestyle-Related Disease in a General Population in Japan.

Curr Drug Metab 2020 ;21(14):1161-1164

Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan.

Background: The relationships between lifestyle-related diseases and polymorphic drug-metabolizing enzyme activities in the general population in Japan remain unclear.

Objective: In this study, the relationships between an index of arteriosclerosis and the phenotypic activities of flavin-containing monooxygenase 3 (FMO3) and cytochrome P450 (P450) 2A6 were analysed.

Methods: Subjects in a general population in Japan (age range 35-97 years, 640 men and 795 women, 12% were current smokers) who took part in a health check program were recruited.

Results: Subjects were divided into two groups using the median ankle-brachial pressure index (ABI) score. Subjects harbouring P450 2A6 wild-type allele had a significant age-adjusted odds ratio of 1.3 (95% CI, 1.0-1.6) of having a lower than median ABI score compared with subjects for mutant P450 2A6. For subjects with wild-type FMO3, the odds ratio of 0.89 was not significant. The proportions of P450 2A6 extensive metabolizers varied significantly across the inter-quartile ranges of the ABI scores (p = 0.008). Furthermore, the proportion of subjects with low ABI scores was also dependent on the phenotypic P450 2A6 activity (p = 0.025) as estimated from the P450 2A6 genotype. These results suggest that in a general population in Japan, the ABI score, as a risk index for arteriosclerosis, is associated with the predicted P450 2A6 phenotype but is not associated with FMO3 function.

Conclusion: The P450 2A6 wild-type allele may be a possible candidate biomarker for arteriosclerosis in a general population in Japan with a variety of dietary habits.
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http://dx.doi.org/10.2174/1389200221666201009140802DOI Listing
January 2020

Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation.

Nat Commun 2020 03 6;11(1):1222. Epub 2020 Mar 6.

Division of Cancer Cell Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, Japan.

Stable inheritance of DNA methylation is critical for maintaining differentiated phenotypes in multicellular organisms. We have recently identified dual mono-ubiquitylation of histone H3 (H3Ub2) by UHRF1 as an essential mechanism to recruit DNMT1 to chromatin. Here, we show that PCNA-associated factor 15 (PAF15) undergoes UHRF1-dependent dual mono-ubiquitylation (PAF15Ub2) on chromatin in a DNA replication-coupled manner. This event will, in turn, recruit DNMT1. During early S-phase, UHRF1 preferentially ubiquitylates PAF15, whereas H3Ub2 predominates during late S-phase. H3Ub2 is enhanced under PAF15 compromised conditions, suggesting that H3Ub2 serves as a backup for PAF15Ub2. In mouse ES cells, loss of PAF15Ub2 results in DNA hypomethylation at early replicating domains. Together, our results suggest that there are two distinct mechanisms underlying replication timing-dependent recruitment of DNMT1 through PAF15Ub2 and H3Ub2, both of which are prerequisite for high fidelity DNA methylation inheritance.
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http://dx.doi.org/10.1038/s41467-020-15006-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060239PMC
March 2020

Treatment strategy for brain metastases from esophageal cancer.

Tumori 2020 Apr 28;106(2):109-114. Epub 2019 Aug 28.

First Department of Surgery, Dokkyo Medical University, Mibu-machi, Tochigi, Japan.

Background: This study aimed to examine the treatment outcomes of patients with brain metastases from esophageal cancer. Brain metastases from esophageal cancer are rare and have a poorer prognosis than brain metastases from lung and breast cancer.

Methods: This study included patients who were diagnosed with and treated for esophageal cancer in our department and subsequently developed brain metastases between April 2010 and December 2014. We examined the differences in survival in patients based on receiving chemotherapy.

Results: In total, 8 patients (7 men and 1 woman) with a mean age of 65 years (range 51-73) were included. Seven presented with neurologic symptoms. Two were diagnosed via computed tomography (CT), 5 via magnetic resonance imaging, and 1 via positron emission tomography/CT. They were treated using whole-brain irradiation or with a gamma knife. In 5 patients, chemotherapy was administered after treatment of the brain metastases. The mean survival from the start of treatment was 358 days (range 31-1196).

Conclusion: The relatively successful local control of brain metastases in these patients indicates that long-term survival may be attainable via concomitant chemotherapy.
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http://dx.doi.org/10.1177/0300891619869518DOI Listing
April 2020

[A Case of Advanced Gastric Cancer with Multiple Bone Metastases, Virchow Lymph Node and Para-Aortic Lymph Node Metastases That Responded to Combined Modality Therapy and Underwent Conversion Surgery].

Gan To Kagaku Ryoho 2018 Oct;45(10):1453-1456

First Dept. of Surgery, Dokkyo Medical University.

A 41-year-old woman with type 3 advanced gastric cancer and Virchow lymph node, para-aortic lymph node, and multiple bone metastases was diagnosed with U-less cType 3 cT4aN3M1, cStage IV. We administered docetaxel, cisplatin, and S-1 (DCS)therapy for unresectable gastric cancer. After 11 courses of DCS, we confirmed that the distant lymph node metasta- ses were significantly reduced. We performed radiotherapy(30 Gy/10 Fr)on the thoracic lumber vertebrae. Because the patient was successfully downstaged, we performed total gastrectomy with Roux-en-Y reconstruction. The histopathological diagnosis was ypT3N2M0, ypStage III A. In this case, DCS therapy successfully treated gastric cancer with distant metastases, including multiple bone metastases.
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October 2018

F-Fluorodeoxyglucose positron emission tomography can be used to determine the indication for endoscopic resection of superficial esophageal cancer.

Cancer Med 2018 08 28;7(8):3604-3610. Epub 2018 Jun 28.

First Department of Surgery, Dokkyo Medical University, Mibu, Tochigi, Japan.

F-Fluorodeoxyglucose positron emission tomography (FDG-PET) is a useful imaging modality that reflects the tumor activity. However, FDG-PET is mainly used for advanced cancer, not superficial cancer. In this study, we investigated the relationship between the superficial tumor depth of esophageal cancer and the FDG uptake to determine the indications for endoscopic resection (ER). From 2009 to 2017, 444 patients with esophageal cancer underwent esophagectomy or endoscopic submucosal dissection (ESD), and 195 patients were pathologically diagnosed with superficial cancer. Among them, 146 patients were examined by FDG-PET before esophagectomy or ESD. In these 146 patients, the relationship between the pathological tumor depth and FDG uptake was analyzed. The mean maximum standardized uptake value in pT1a-EP/LPM tumors was 1.362 ± 0.890, that in pT1a-MM/pT1b-SM1 tumors was 2.453 ± 1.872, and that in pT1b-SM2/SM3 tumors was 4.265 ± 3.233 (P < .0001). Among 51 pT1a-EP/LPM tumors, 10 (19.6%) showed positive detection of FDG. For pT1a-MM/pT1b-SM1 and pT1b-SM2/SM3 tumors, the detection rate was 52.9% (18/34) and 82.0% (50/61), respectively. The detection rate of pT1a-EP/LPM was significantly lower than in the other two groups (P < .0001). Among 10 FDG-PET-positive lesions, only 1 had no apparent reason for PET positivity; however, 9 of 10 had a suitable reason for detectability by PET and inadequacy for ER. Negative detection of superficial esophageal squamous cell carcinoma by FDG-PET is useful to determine the indication for ER when the tumor depth cannot be diagnosed even after performing magnifying endoscopy with narrow band imaging and endoscopic ultrasonography. When FDG uptake is recognized, a therapeutic modality other than ER should be considered.
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http://dx.doi.org/10.1002/cam4.1628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089148PMC
August 2018

Epitope analysis of Japanese cedar pollen allergen Cry j2 with a human IgM class monoclonal antibody 404-117.

Hum Antibodies 2017 ;25(1-2):17-21

Tamagawa University, College of Agriculture, Machida, Tokyo, Japan.

Japanese cedar pollen allergen Cry j2 is a causal allergen of seasonal pollinosis in Japan. To analyze B cell epitopes of Cry j2, we established two human-mouse hybridomas secreting IgM class human monoclonal antibodies to Cry j2. A pin-peptide enzyme-linked immunosorbent assay with synthesized icosa peptides showed that 404-117 monoclonal antibody bound to peptides #11-13 with cry j2 amino acid sequence of 101F-L140. Detailed analysis with octa peptides and alanine substituted peptides indicated that an amino acid sequence of 118FKVD121 was an essential for antibody binding. When K119 (Asn) was substituted with alanine, 404-117 monoclonal antibody did not bind to the alanine substituted peptide. We concluded that the 118FKVD121 sequence might have a very important role in early recognition by Cry j2-specific B cells, which could act as antigen presenting cells.
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http://dx.doi.org/10.3233/HAB-160301DOI Listing
March 2017

Monaural Auditory Cue Affects the Process of Choosing the Initial Swing Leg in Gait Initiation.

J Mot Behav 2015 7;47(6):522-6. Epub 2015 Apr 7.

a College of Health and Human Sciences , Osaka Prefecture University , Habikino , Japan.

The authors investigated the effect of an auditory cue on the choice of the initial swing leg in gait initiation. Healthy humans initiated a gait in response to a monaural or binaural auditory cue. When the auditory cue was given in the ear ipsilateral to the preferred leg side, the participants consistently initiated their gait with the preferred leg. In the session in which the side of the monaural auditory cue was altered trial by trial randomly, the probability of initiating the gait with the nonpreferred leg increased when the auditory cue was given in the ear contralateral to the preferred leg side. The probability of choosing the nonpreferred leg did not increase significantly when the auditory cue was given in the ear contralateral to the preferred leg side in the session in which the auditory cue was constantly given in the ear contralateral to the preferred leg side. The reaction time of anticipatory postural adjustment was shortened, but the probability of choosing the nonpreferred leg was not significantly increased when the gait was initiated in response to a binaural auditory cue. An auditory cue in the ear contralateral to the preferred leg side weakens the preference for choosing the preferred leg as the initial swing leg in gait initiation when the side of the auditory cue is unpredictable.
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http://dx.doi.org/10.1080/00222895.2015.1020356DOI Listing
April 2016

Bimanual coordination of force enhances interhemispheric inhibition between the primary motor cortices.

Neuroreport 2014 Oct;25(15):1203-7

aCollege of Health and Human Sciences bGraduate School of Comprehensive Rehabilitation, Osaka Prefecture University, Habikino, Osaka, Japan.

The purpose of this study was to elucidate whether bimanual coordination of force affects interhemispheric inhibition (IHI) between the primary motor cortices (M1s). IHI with the index fingers isometrically abducted against a fixed plate (AAP task) was compared with IHI with the index fingers isometrically abducted against each other (AAF task). The index fingers were held stationary at the midline and activity levels of the first dorsal interosseous muscles were equalized between the tasks. The abduction force of each index finger was individually controlled during the AAP task, and bimanually coordinated during the AAF task. IHI during the AAF task was significantly higher than that during the AAP task. IHI between the M1s is related not only to the suppression of unwanted activity of the M1 contralateral to the active M1 but also to bimanual coordination of force.
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http://dx.doi.org/10.1097/WNR.0000000000000248DOI Listing
October 2014

Smooth pursuit eye movement preferentially facilitates motor-evoked potential elicited by anterior-posterior current in the brain.

Neuroreport 2014 Mar;25(5):279-83

College of Health and Human Sciences, Osaka Prefecture University, Habikino, Osaka Prefecture, Japan.

Neural interaction between the eye and hand movement centers must be a critical part of the mechanism underlying eye-hand coordination. One of the previous findings supporting this view is smooth pursuit eye movement-induced suppression of motor-evoked potential (MEP) in the hand muscles. The purpose of this study was to determine which descending volleys contributing to MEP are preferentially modulated by smooth pursuit eye movement. MEP in the first dorsal interosseous muscle was elicited by different directions of current in the brain during the steady-state phase of smooth pursuit eye movement. Smooth pursuit eye movement facilitated MEP elicited by anterior-posterior (AP) current, but this effect was not seen in MEP elicited by lateromedial or posterior-anterior current. Latency of MEP elicited by AP current was significantly longer than latencies of MEPs elicited by other directions of current, indicating that AP current in the brain predominantly elicited later I-waves. We conclude that smooth pursuit eye movement in the steady-state phase preferentially facilitates MEP predominantly elicited by later I-waves generated by AP current in the brain.
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http://dx.doi.org/10.1097/WNR.0000000000000075DOI Listing
March 2014

Beta4-galactosyltransferase-5 is a lactosylceramide synthase essential for mouse extra-embryonic development.

Glycobiology 2010 Oct 23;20(10):1311-22. Epub 2010 Jun 23.

Division of Transgenic Animal Science, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan.

Glycosphingolipids (GSLs) are important for various biological functions in the nervous system, the immune system, embryogenesis and in other tissues and processes. Lactosylceramide (LacCer), which is synthesized from glucosylceramide (GlcCer) by LacCer synthase, is a core structure of GSLs, including gangliosides. LacCer synthase was reported to be synthesized by the beta4-galactosyltransferase-6 (beta4GalT-6) gene in the rat brain. However, the existence of another LacCer synthase gene was shown in cultured cells lacking beta4GalT-6. Here, we report that LacCer synthase is mainly synthesized by the beta4GalT-5 gene during early mouse embryogenesis, and its disruption is embryonic lethal. beta4GalT-5-deficient embryos showed developmental retardation from E7.5 and died by E10.5 as reported previously. LacCer synthase activity was significantly reduced in beta4GalT-5-deficient embryos and extra-embryonic endoderm (XEN) cells derived from blastocysts, and it was recovered when beta4GalT-5 cDNA was introduced into beta4GalT-5-deficient XEN cells. The amounts of LacCer and GM3 ganglioside were drastically reduced, while GlcCer accumulated in the beta4GalT-5-deficient XEN cells. Hematoma and ectopically accumulated trophoblast giant cells were observed in the anti-mesometrial pole of the extra-embryonic tissues, although all three embryonic layers formed. beta4GalT-5-deficient embryos developed until E12.5 as chimeras with wild-type tetraploid cells, which formed the extra-embryonic membranes, indicating that extra-embryonic defects caused the early embryonic lethality. Our results suggest that beta4GalT-5 is essential for extra-embryonic development during early mouse embryogenesis.
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http://dx.doi.org/10.1093/glycob/cwq098DOI Listing
October 2010

Mutations in the helix termination motif of mouse type I IRS keratin genes impair the assembly of keratin intermediate filament.

Genomics 2007 Dec 24;90(6):703-11. Epub 2007 Oct 24.

Mammalian Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka, Japan.

Two classical mouse hair coat mutations, Rex (Re) and Rex wavy coat (Re(wc)), are linked to the type I inner root sheath (IRS) keratin genes of chromosome 11. An N-ethyl-N-nitrosourea-induced mutation, M100573, also maps close to the type I IRS keratin genes. In this study, we demonstrate that Re and M100573 mice bear mutations in the type I IRS gene Krt25; Re(wc) mice bear an additional mutation in the type I IRS gene Krt27. These three mutations are located in the helix termination motif of the 2B alpha-helical rod domain of a type I IRS keratin protein. Immunohistological analysis revealed abnormal foam-like immunoreactivity with an antibody raised to type II IRS keratin K71 in the IRS of Re/+ mice. These results suggest that the helix termination motif is essential for the proper assembly of types I and II IRS keratin protein complexes and the formation of keratin intermediate filaments.
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http://dx.doi.org/10.1016/j.ygeno.2007.07.013DOI Listing
December 2007

A novel dominant-negative mutation in Gdf5 generated by ENU mutagenesis impairs joint formation and causes osteoarthritis in mice.

Hum Mol Genet 2007 Oct 26;16(19):2366-75. Epub 2007 Jul 26.

Mouse Functional Genomics Research Group, RIKEN GSC, Tsukuba, Ibaraki, Japan.

Growth and differentiation factor 5 (GDF5) has been implicated in chondrogenesis and joint formation, and an association of GDF5 and osteoarthritis (OA) has been reported recently. However, the in vivo function of GDF5 remains mostly unclarified. Although various human GDF5 mutations and their phenotypic consequences have been described, only loss-of-function mutations that cause brachypodism (shortening and joint ankylosis of the digits) have been reported in mice. Here, we report a new Gdf5 allele derived from a large-scale N-ethyl-N-nitrosourea mutagenesis screen. This allele carries an amino acid substitution (W408R) in a highly conserved region of the active signaling domain of the GDF5 protein. The mutation is semi-dominant, showing brachypodism and ankylosis in heterozygotes and much more severe brachypodism, ankylosis of the knee joint and malformation with early-onset OA of the elbow joint in homozygotes. The mutant GDF5 protein is secreted and dimerizes normally, but inhibits the function of the wild-type GDF5 protein in a dominant-negative fashion. This study further highlights a critical role of GDF5 in joint formation and the development of OA, and this mouse should serve as a good model for OA.
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http://dx.doi.org/10.1093/hmg/ddm195DOI Listing
October 2007

A series of ENU-induced single-base substitutions in a long-range cis-element altering Sonic hedgehog expression in the developing mouse limb bud.

Genomics 2007 Feb 13;89(2):207-14. Epub 2006 Oct 13.

Mouse Functional Genomics Research Group, RIKEN GSC 3-1-1 Kouyadai, Tsukuba, Ibaraki 305-0074, Japan.

Mammal-fish-conserved-sequence 1 (MFCS1) is a highly conserved sequence that acts as a limb-specific cis-acting regulator of Sonic hedgehog (Shh) expression, residing 1 Mb away from the Shh coding sequence in mouse. Using gene-driven screening of an ENU-mutagenized mouse archive, we obtained mice with three new point mutations in MFCS1: M101116, M101117, and M101192. Phenotype analysis revealed that M101116 mice exhibit preaxial polydactyly and ectopic Shh expression at the anterior margin of the limb buds like a previously identified mutant, M100081. In contrast, M101117 and M101192 show no marked abnormalities in limb morphology. Furthermore, transgenic analysis revealed that the M101116 and M100081 sequences drive ectopic reporter gene expression at the anterior margin of the limb bud, in addition to the normal posterior expression. Such ectopic expression was not observed in the embryos carrying a reporter transgene driven by M101117. These results suggest that M101116 and M100081 affect the negative regulatory activity of MFCS1, which suppresses anterior Shh expression in developing limb buds. Thus, this study shows that gene-driven screening for ENU-induced mutations is an effective approach for exploring the function of conserved, noncoding sequences and potential cis-regulatory elements.
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http://dx.doi.org/10.1016/j.ygeno.2006.09.005DOI Listing
February 2007