Publications by authors named "Yuki Yamaguchi"

139 Publications

Three human RNA polymerases interact with TFIIH via a common RPB6 subunit.

Nucleic Acids Res 2021 Jul 16. Epub 2021 Jul 16.

Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.

In eukaryotes, three RNA polymerases (RNAPs) play essential roles in the synthesis of various types of RNA: namely, RNAPI for rRNA; RNAPII for mRNA and most snRNAs; and RNAPIII for tRNA and other small RNAs. All three RNAPs possess a short flexible tail derived from their common subunit RPB6. However, the function of this shared N-terminal tail (NTT) is not clear. Here we show that NTT interacts with the PH domain (PH-D) of the p62 subunit of the general transcription/repair factor TFIIH, and present the structures of RPB6 unbound and bound to PH-D by nuclear magnetic resonance (NMR). Using available cryo-EM structures, we modelled the activated elongation complex of RNAPII bound to TFIIH. We also provide evidence that the recruitment of TFIIH to transcription sites through the p62-RPB6 interaction is a common mechanism for transcription-coupled nucleotide excision repair (TC-NER) of RNAPI- and RNAPII-transcribed genes. Moreover, point mutations in the RPB6 NTT cause a significant reduction in transcription of RNAPI-, RNAPII- and RNAPIII-transcribed genes. These and other results show that the p62-RPB6 interaction plays multiple roles in transcription, TC-NER, and cell proliferation, suggesting that TFIIH is engaged in all RNAP systems.
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http://dx.doi.org/10.1093/nar/gkab612DOI Listing
July 2021

Broadened bioactivity and enhanced durability of two structurally distinct metal-organic frameworks containing Zn ions and thiabendazole.

Dalton Trans 2021 Jun;50(21):7176-7180

College of Science, Department of Chemistry, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo, 171-8501, Japan.

Novel metal-organic frameworks (MOFs) based on thiabendazole (TBZ) were developed. The two structurally distinct TBZ-MOFs synthesized in this study exhibited enhanced durability and a broader biocidal spectrum than either individual bioactive species (i.e., Zn2+ and TBZ). The characteristics of each TBZ-MOF are related to the coordination modes among the Zn2+ ions and ligand donors. The difference in water solubility between the two TBZ-MOFs due to the structural design allows for the controlled release of the desired bioactive component.
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http://dx.doi.org/10.1039/d1dt00733eDOI Listing
June 2021

Exploiting ubiquitin ligase cereblon as a target for small-molecule compounds in medicine and chemical biology.

Cell Chem Biol 2021 Jul 24;28(7):987-999. Epub 2021 May 24.

Department of Chemical Biology, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku 160-8402, Japan. Electronic address:

Cereblon (CRBN), originally identified as a gene associated with intellectual disability, was identified as primary target of thalidomide. Accumulating evidence has shown that CRBN is a substrate receptor of Cullin Ring E3 ubiquitin ligase 4 (CRL4) containing DDB1, CUL4, and RBX1, which recognizes specific neosubstrates in the presence of thalidomide or its analogs and induces their ubiquitination and proteasomal degradation. A set of small-molecule, CRBN-binding drugs are known as molecular glue degraders because these compounds promote the interaction between CRBN and its neosubstrates. Moreover, CRBN-based proteolysis-targeting chimeras, heterobifunctional molecules hijacking CRBN and inducing degradation of proteins of interest, have emerged as a promising modality in drug development and are being actively investigated. Meanwhile, the original functions and regulations of CRBN are still largely elusive. In this review, we describe key findings surrounding CRBN since its discovery and then discuss a few unanswered issues.
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http://dx.doi.org/10.1016/j.chembiol.2021.04.012DOI Listing
July 2021

Comparison of electrochemical impedance spectra for electrolyte-supported solid oxide fuel cells (SOFCs) and protonic ceramic fuel cells (PCFCs).

Sci Rep 2021 May 19;11(1):10622. Epub 2021 May 19.

Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai, Miyagi, 980-8577 , Japan.

Protonic ceramic fuel cells (PCFCs) are expected to achieve high power generation efficiency at intermediate temperature around 400-600 °C. In the present work, the distribution of relaxation times (DRT) analysis was investigated in order to deconvolute the anode and cathode polarization resistances for PCFCs supported on yttria-doped barium cerate (BCY) electrolyte in comparison with solid oxide fuel cells (SOFCs) supported on scandia-stabilized zirconia (ScSZ) electrolyte. Four DRT peaks were detected from the impedance spectra measured at 700 °C excluding the gas diffusion process for ScSZ and BCY. The DRT peaks at 5 × 10-1 × 10 Hz and 1 × 10-2 × 10 Hz were related to the hydrogen oxidation reaction at the anode and the oxygen reduction reaction at the cathode, respectively, for both cells. The DRT peak at 2 × 10-1 × 10 Hz depended on the hydrogen concentration at the anode for ScSZ, while it was dependent on the oxygen concentration at the cathode for BCY. Compared to ScSZ, steam was produced at the opposite electrode in the case of BCY, which enhanced the cathode polarization resistance for PCFCs.
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http://dx.doi.org/10.1038/s41598-021-90211-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134428PMC
May 2021

Comparison of the inhibitory effects of azole antifungals on cytochrome P450 3A4 genetic variants.

Drug Metab Pharmacokinet 2021 Jun 22;38:100384. Epub 2021 Jan 22.

Division of Clinical Pharmacokinetics, Keio University Faculty of Pharmacy, Shibakoen, Minato-ku, Tokyo, 105-8512, Japan. Electronic address:

Cytochrome P450 (CYP) 3A4 is one of the major drug-metabolizing enzymes. Genetic variants of CYP3A4 with altered activity are one of the factors responsible for interindividual differences in drug metabolism. Azole antifungals inhibit CYP3A4 to cause clinically significant drug-drug interactions. In the present quantitative study, we investigated the inhibitory effects of three azole antifungals (ketoconazole, voriconazole, and fluconazole) on testosterone metabolism by recombinant CYP3A4 genetic variants (CYP3A4.1 (WT), CYP3A4.2, CYP3A4.7, CYP3A4.16, and CYP3A4.18) and compared them with those previously reported for itraconazole. The inhibition constants (K) of ketoconazole, voriconazole, and fluconazole for rCYP3A4.1 were 3.6 nM, 3.2 μM, and 16.1 μM, respectively. The K values of these azoles for rCYP3A4.16 were 13.9-, 13.6-, and 6.2-fold higher than those for rCYP3A4.1, respectively, whereas the K value of itraconazole for rCYP3A4.16 was 0.54-fold of that for rCYP3A4.1. The other genetic variants had similar effects on the K values of the three azoles, whereas a very different pattern was seen for itraconazole. In conclusion, itraconazole has unique characteristics that are distinct from those shared by the other azole anti-fungal drugs ketoconazole, voriconazole, and fluconazole with regard to the influence of genetic variations on the inhibition of CYP3A4.
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http://dx.doi.org/10.1016/j.dmpk.2021.100384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144059PMC
June 2021

Telomere shortening in head and neck cancer: association between DNA demethylation and survival.

J Cancer 2021 22;12(8):2165-2172. Epub 2021 Feb 22.

Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan.

A growing body of evidence indicates that telomere dysfunction is a biological marker of progression in several types of cancer. However, the association between head and neck squamous cell carcinoma (HNSCC) and telomere length (TL) remains unknown. We measured the absolute TL levels in a well-characterised dataset of 211 tumoral vs normal tissues obtained from the same patients by quantitative polymerase chain reaction assay. Normalised TL levels were significantly lower in tumour samples than in normal tissue ( < 0.001) and there was a positive correlation between tumour tissue and normal mucosal tissue (R = 0.176, < 0.001). We were able to distinguish two classes, one with a tumour/normal TL ratio ≤ 0.3 (38.4%), which showed clear telomere erosion, and the other with a tumour/normal TL ratio > 0.3 (61.6%), in which the TL was slightly shorter or longer than that in normal tissue. Notably, the tumour/normal TL ratio was correlated with the likelihood of disease recurrence ( = 0.002), the 5-hydroxymethylcytosine level ( = 0.043), and expression of the ten-eleven translocation () gene ( = 0.043). Our findings show that TL shortening and subsequent low levels of 5-hydroxymethylcytosine and expression may contribute to development of HNSCC.
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http://dx.doi.org/10.7150/jca.54760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974875PMC
February 2021

GEX1 Is a Nuclear Membrane Protein of Gametes Required for Nuclear Fusion During Reproduction.

Front Plant Sci 2020 12;11:548032. Epub 2020 Oct 12.

Kihara Institute for Biological Research, Yokohama City University, Yokohama, Japan.

During the life cycle of flowering plants, nuclear fusion, or karyogamy, occurs three times: once during female gametogenesis, when the two polar nuclei fuse in the central cell, and twice during double fertilization. In , nuclear fusion events during sexual reproduction proceed without the breakdown of the nuclear envelope, indicating that nuclear membrane fusion is essential for the completion of this process. gamete expressed 1 (GEX1) is a membrane protein that is conserved among plant species. GEX1 shares homology with the yeast karyogamy protein Kar5, which is primarily expressed in the nuclear membrane. The GEX1 family represents a putative karyogamy factor. Herein, we show that GEX1 is required for the nuclear fusion events in reproduction. GEX1-deficient mature female gametophytes were found to contain two unfused polar nuclei in close proximity within the central cell. Electron microscopy showed that the outer membrane of the polar nuclei was connected via the endoplasmic reticulum, whereas the inner membrane remained unfused. These results indicate that GEX1 is involved in polar nuclear membrane fusion following the fusion of the outer nuclear membrane. Furthermore, sperm nuclear fusion events were defective in the fertilized egg and central cell following plasmogamy in the fertilization of female gametophytes by pollen. An analysis of GEX1 localization in the female gametophyte using a transgenic line expressing GFP-tagged GEX1 driven by the promoter showed that GEX1 is a nuclear membrane protein in the egg and central cell. Time-lapse live-cell imaging showed that in developing female gametophytes, the nuclear GFP-GEX1 signal was first detectable in the central cell shortly before the polar nuclei came in close contact, and then in the egg cell. Thus, we suggest that the GEX1-family proteins are nuclear membrane proteins involved in karyogamy in the reproduction of eukaryotes including flowering plants.
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http://dx.doi.org/10.3389/fpls.2020.548032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586128PMC
October 2020

Long interspersed nuclear element 1 hypomethylation has novel prognostic value and potential utility in liquid biopsy for oral cavity cancer.

Biomark Res 2020 23;8:53. Epub 2020 Oct 23.

Department of Otorhinolaryngology /Head and Neck Surgery, 1-20-1 Handayama, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192 Japan.

Background: New biomarkers are urgently needed to improve personalized treatment approaches for head and neck squamous cell carcinoma (HNSCC). Global DNA hypomethylation has wide-ranging functions in multistep carcinogenesis, and the hypomethylation of long interspersed nucleotide element-1 (LINE-1) is related to increased retrotransposon activity and induced genome instability. However, little information is available regarding LINE-1 hypomethylation and its prognostic implications in HNSCC.

Methods: In this study, we analyzed LINE-1 hypomethylation levels in a well-characterized dataset of 317 primary HNSCC tissues and 225 matched pairs of normal mucosa tissues, along with five oral cavity cancer (OCC) circulating tumor DNA (ctDNA) samples using quantitative real-time methylation and unmethylation PCR. The analysis was performed according to various clinical characteristics and prognostic implications.

Results: The results demonstrated that LINE-1 hypomethylation levels were significantly higher in the HNSCC tissues than in corresponding normal tissues from the same individuals ( < 0.001). Univariate analysis revealed that high levels of LINE-1 hypomethylation were correlated with poor disease-free survival (DFS; log-rank test,  = 0.038), whereas multivariate analysis demonstrated that they were significant independent prognostic factor for DFS (hazard ratio: 2.10, 95% confidence interval: 1.02-4.36;  = 0.045). Moreover, samples with high LINE-1 hypomethylation levels exhibited the greatest decrease in 5-hydroxymethylcytosine (5-hmC) levels and increase in tumor-suppressor gene methylation index ( = 0.006 and  < 0.001, respectively). Further, ctDNA studies also showed that LINE-1 hypomethylation had high predictive ability in OCC.

Conclusions: LINE-1 hypomethylation is associated with a higher risk of early OCC relapse, and is hence, a potential predictive biomarker for OCC. Furthermore, 5-hmC levels also exhibited predictive potential in OCC, based on their inverse correlation with LINE-1 hypomethylation levels. LINE-1 hypomethylation analysis, therefore, has applications in determining patient prognosis and real-time surveillance of disease recurrence, and could serve as an alternative method for OCC screening.

Supplementary Information: accompanies this paper at 10.1186/s40364-020-00235-y.
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http://dx.doi.org/10.1186/s40364-020-00235-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585304PMC
October 2020

G Protein-Coupled Receptor Genes, PTGDR1, PTGDR2, and PTGIR, Are Candidate Epigenetic Biomarkers and Predictors for Treated Patients with HPV-Associated Oropharyngeal Cancer.

Microorganisms 2020 Sep 29;8(10). Epub 2020 Sep 29.

Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.

Differences in the biology of human papillomavirus (HPV)-associated oropharyngeal cancers (OPCs) and HPV-negative OPCs may have implications in patient management. Early detection is imperative to reduce HPV-associated OPC mortality. Circulating tumor DNA (ctDNA) can potentially serve as a biomarker for monitoring clinically relevant cancer-related genetic and epigenetic modifications. We analyzed the methylation status of 24 G protein-coupled receptor (GPCR) genes in verification (85 OPC primary samples) and validation (8 OPC ctDNA samples) studies using quantitative methylation-specific polymerase chain reaction (Q-MSP). The Q-MSP-based verification study with 85 OPC primary samples revealed the GPCR genes that were significantly associated with recurrence in high methylation groups (≥14 methylated genes) with OPC and HPV-associated OPC ( < 0.001). In the Kaplan-Meier estimate and multivariate Cox proportional hazard analyses, 13 GPCR genes were significantly related to increased recurrence in the methylation group. Furthermore, the validation study on ctDNA showed that three of these genes (Prostaglandin D2 receptor 1: , Prostaglandin D2 receptor 2: , and Prostaglandin I2 Receptor: ) had a prediction performance as emerging biomarkers. We characterized the relationship between the methylation status of GPCR genes and outcomes in HPV-associated OPC. Our results highlight the potential utility of ctDNA methylation-based detection for the clinical management of HPV-associated OPC.
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http://dx.doi.org/10.3390/microorganisms8101504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601742PMC
September 2020

ARID2 is a pomalidomide-dependent CRL4 substrate in multiple myeloma cells.

Nat Chem Biol 2020 11 21;16(11):1208-1217. Epub 2020 Sep 21.

Department of Chemical Biology, Tokyo Medical University, Shinjuku, Japan.

The immunomodulatory drug (IMiD) thalidomide and its derivatives lenalidomide and pomalidomide are therapeutic agents used in the treatment of multiple myeloma. Although pomalidomide offers considerable clinical benefits to patients with lenalidomide-resistant multiple myeloma, the molecular mechanisms underlying its superior efficacy remain unclear. Here we show that ARID2, a component of the polybromo-associated BAF (PBAF) chromatin-remodeling complex, is a pomalidomide-induced neosubstrate of CRL4. BRD7, another subunit of PBAF, is critical for pomalidomide-induced ARID2 degradation. ARID2 is involved in transcriptional regulation of pomalidomide target genes including MYC. Pomalidomide is more effective than lenalidomide in degrading ARID2 and is capable of inhibiting MYC expression and proliferation in lenalidomide-resistant cell lines. Notably, ARID2 expression is associated with a poor prognosis and is higher in chemoresistant minimal residual disease (MRD) populations, and in patients with relapsed/refractory multiple myeloma. These findings suggest that ARID2 is a promising target for overcoming lenalidomide resistance in patients with multiple myeloma.
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http://dx.doi.org/10.1038/s41589-020-0645-3DOI Listing
November 2020

Risk Factors for Skin Toxicities Associated with Bendamustine-Based Chemotherapy in Patients with Non-Hodgkin Lymphoma.

Biol Pharm Bull 2020 Oct 14;43(10):1577-1582. Epub 2020 Aug 14.

Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences.

Bendamustine plays an especially important role as a treatment for non-Hodgkin lymphoma (NHL). However, patients administered bendamustine alone or in combination with rituximab (BR) may experience drug-associated skin toxicities that can profoundly impact their health-related QOL through both physical discomfort and psychological distress. Moreover, worsening skin symptoms may lead to dose reduction or termination in the management of cancer chemotherapy. We retrospectively investigated patient backgrounds and pretreatment characteristics from medical records of NHL patients treated with bendamustine alone or BR therapy and identified predictive factors for skin toxicities at the start of chemotherapy. Patients were eligible for the study if they were 20 years older, diagnosed with NHL, and received bendamustine alone or BR therapy at the Department of Hematology, Kobe City Medical Center General Hospital, between April 1, 2011, and March 31, 2018. This study included 95 patients with newly diagnosed or refractory or relapsed NHL. Multivariate stepwise logistic regression analysis with backward selection revealed that baseline non-prior chemotherapy (odds ratio (OR), 15.72; 95% confidence interval (CI), 4.24-83.13, p < 0.001) was a significant factor influencing the occurrence of skin toxicity. Our results demonstrated that non-prior chemotherapy was a significant risk factor for skin toxicities in patients with NHL receiving bendamustine alone or BR therapy. No patient experience serious side effects of grade 3 or higher and that bendamustine is very useful as a first-line treatment.
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http://dx.doi.org/10.1248/bpb.b20-00428DOI Listing
October 2020

Evaluation of Synthesized Ester or Amide Coumarin Derivatives on Aromatase Inhibitory Activity.

Biol Pharm Bull 2020 ;43(8):1179-1187

School of Pharmaceutical Sciences, Health Sciences University of Hokkaido.

Aromatase inhibitors are effective for the treatment of diseases such as breast cancer, which has led to an increase in their demand. However, only a limited number of aromatase inhibitor drugs are currently being marketed. In addition, considering the important aspect of drug resistance, the development of newer drug types is required. We have been developing inhibitors with backbone structures that differ from existing aromatase inhibitors. In this regard, we previously reported that diethylaminocoumarin dimers and thiazolyl coumarin derivatives possess strong aromatase inhibiting capabilities. In this study, we further examined the structure-activity relationships of coumarin derivatives synthesized from thiazolyl coumarin derivatives and their aromatase inhibiting capabilities. Consequently, amide coumarin N-benzhydryl-7-(diethylamino)-2-oxo-2H-chromene-3-carboxamide (IC values 4.5 µM) is inhibitor of aromatase. This inhibitor was found to be comparable aromatase inhibitory activity to the 1st generation aromatase inhibitor aminoglutethimide (3.2 µM). Substitution of the amide group on the amide coumarin derivative affects the aromatase inhibiting activity. Our findings suggest that the structure of each substituent changes the orientation of the compound in the active site of aromatase, thus creating a difference in their activities.
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http://dx.doi.org/10.1248/bpb.b20-00035DOI Listing
May 2021

Risk Factors for Febrile Neutropenia Induced by Docetaxel Chemotherapy in Patients with Non-small Cell Lung Cancer.

Biol Pharm Bull 2020 Aug 21;43(8):1235-1240. Epub 2020 May 21.

Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences.

We retrospectively obtained data of patient background and pretreatment characteristics from medical records and identified the predictive factors of febrile neutropenia (FN) in patients with non-small cell lung cancer (NSCLC) treated with docetaxel alone or in combination with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab. Patients were eligible for inclusion in the study if they were 20 years or older, diagnosed with NSCLC, and received docetaxel monotherapy alone or in combination with bevacizumab at the Department of Respiratory Medicine, Kobe City Medical Center General Hospital, between July 1, 2011, and March 31, 2018. Eighty-one patients with recurrent or advanced NSCLC were included. Multivariate stepwise logistic regression analysis with backward selection revealed that lower baseline Eastern Cooperative Oncology Group performance status (ECOG-PS) scores of 1 and 2 (odds ratio (OR), 5.098; 95% confidence interval (CI), 1.045-24.879, p = 0.021) and baseline platelet count below 18.8 × 10/µL (OR, 3.861; 95% CI, 1.211-12.311, p = 0.022) were significant factors influencing the FN occurrence rate. Our results demonstrated that ECOG-PS 1-2 and lower baseline platelet count were significant risk factors of FN in patients with NSCLC receiving docetaxel-based chemotherapy. Moreover, the combination of anti-VEGF antibodies and docetaxel might be associated with increased FN frequency. Despite the limitations of this study including its retrospective design, single-center site, and small sample size, baseline ECOG-PS score and platelet count may be regarded as important indices to identify patients for prophylactic granulocyte-colony stimulating factor (G-CSF) treatment before docetaxel-based chemotherapy.
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http://dx.doi.org/10.1248/bpb.b20-00266DOI Listing
August 2020

Electrical conductance measurement of Hg-mediated DNA duplex in buffered aqueous solution.

Nucleosides Nucleotides Nucleic Acids 2020 28;39(8):1083-1087. Epub 2020 Apr 28.

Faculty of Pharmaceutical Science, Tokushima Bunri University, Tokushima, Tokushima, Japan.

Electrical properties of metal-mediated DNA duplexes (metallo-DNA) have been of particular interest because of their potential applications in DNA-based nanoelectronics. We prepared Hg-mediated DNA duplex with NH anchors and measured the electrical conductance of single-molecule metallo-DNA via scanning tunneling microscopy-based break junction method in the buffered solution. Three conductance values were observed that may correspond to different conformations of the metallo-DNA molecule bridged over metallic electrodes.
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http://dx.doi.org/10.1080/15257770.2020.1755044DOI Listing
January 2021

Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide.

Sci Rep 2020 03 4;10(1):4012. Epub 2020 Mar 4.

School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, 226-8501, Japan.

Pomalidomide, a derivative of thalidomide, is an effective treatment for multiple myeloma. The drug exerts its effects through CRBN, a component of the E3 ubiquitin ligase complex CRL4. To search for novel factors involved in the anti-cancer activity of pomalidomide, we performed a genome-wide shRNA library screen and identified 445 genes as those affecting pomalidomide sensitivity. Genes encoding components of the ubiquitin-proteasome pathway, such as subunits of the CRL4 complex, the COP9 signalosome, and the 26S proteasome, were among the pomalidomide-affecting genes. Karyopherin beta 1 (KPNB1) was identified as a novel pomalidomide-affecting gene. KPNB1 was required for the nuclear import of CRBN and for the CRBN-directed, pomalidomide-dependent degradation of a clinically relevant substrate, the transcription factor Aiolos. By contrast, the cytoplasmic translation factor GSPT1 was degraded following treatment with the thalidomide derivative CC-885 only when CRBN was present in the cytoplasm, indicating that subcellular distribution of CRBN is critical for the efficacy of thalidomide-based medications.
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http://dx.doi.org/10.1038/s41598-020-61027-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055313PMC
March 2020

The role of Mediator and Little Elongation Complex in transcription termination.

Nat Commun 2020 02 26;11(1):1063. Epub 2020 Feb 26.

Department of Biochemistry, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.

Mediator is a coregulatory complex that regulates transcription of Pol II-dependent genes. Previously, we showed that human Mediator subunit MED26 plays a role in the recruitment of Super Elongation Complex (SEC) or Little Elongation Complex (LEC) to regulate the expression of certain genes. MED26 plays a role in recruiting SEC to protein-coding genes including c-myc and LEC to small nuclear RNA (snRNA) genes. However, how MED26 engages SEC or LEC to regulate distinct genes is unclear. Here, we provide evidence that MED26 recruits LEC to modulate transcription termination of non-polyadenylated transcripts including snRNAs and mRNAs encoding replication-dependent histone (RDH) at Cajal bodies. Our findings indicate that LEC recruited by MED26 promotes efficient transcription termination by Pol II through interaction with CBC-ARS2 and NELF/DSIF, and promotes 3' end processing by enhancing recruitment of Integrator or Heat Labile Factor to snRNA or RDH genes, respectively.
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http://dx.doi.org/10.1038/s41467-020-14849-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044329PMC
February 2020

Neuropeptide receptor genes GHSR and NMUR1 are candidate epigenetic biomarkers and predictors for surgically treated patients with oropharyngeal cancer.

Sci Rep 2020 01 23;10(1):1007. Epub 2020 Jan 23.

Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan.

Pathological staging and histological grading systems are useful, but imperfect, predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). Aberrant promoter methylation is the main type of epigenetic modification that plays a role in the inactivation of tumor suppressor genes. To identify new potential prognostic markers, we investigated the promoter methylation status of five neuropeptide receptor genes. The methylation status of the target genes was compared with clinical characteristics in 278 cases; 72 hypopharyngeal cancers, 54 laryngeal cancers, 75 oropharyngeal cancers, and 77 oral cavity cancers were studied. We found that the NTSR1, NTSR2, GHSR, MLNR, and NMUR1 promoters were methylated in 47.8%, 46.8%, 54.3%, 39.2%, and 43.5% of the samples, respectively. GHSR and NMUR1 promoter methylation independently predicted recurrence in HNSCC. In patients with oropharyngeal cancer (n = 75), GHSR and NMUR1 promoter methylation significantly correlates with survival in surgically treated patients. We classified our patients as having a low, intermediate, or high-risk of death based on three factors: HPV status, and GHSR and NMUR1 promoter methylation. The disease-free survival (DFS) rates were 87.1%, 42.7%, and 17.0%, respectively. Combined data analysis of the methylation status of ten-eleven translocation (TET) family genes indicated a trend toward greater methylation indices as the number of TET methylation events increased. In the current study, we presented the relationship between the methylation status of the GHSR and NMUR1 genes and recurrence in HNSCC, specifically in risk classification of oropharyngeal carcinomas cases with HPV status.
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http://dx.doi.org/10.1038/s41598-020-57920-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978330PMC
January 2020

Prostanoid receptor genes confer poor prognosis in head and neck squamous cell carcinoma via epigenetic inactivation.

J Transl Med 2020 01 21;18(1):31. Epub 2020 Jan 21.

Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Shizuoka, 431-3192, Japan.

Background: Chronic inflammation is a risk factor for head and neck squamous cell carcinoma (HNSCC) and other diseases. Prostanoid receptors are clearly involved in the development of many types of cancer. However, their role is not simple and is poorly understood in HNSCC.

Methods: Methylation profiles of prostanoid receptor family genes were generated for tumour samples obtained from 274 patients with HNSCC, including 69 hypopharynx, 51 larynx, 79 oral cavity, and 75 oropharynx tumour samples, by quantitative methylation-specific PCR. Promoter methylation was then evaluated with respect to various clinical characteristics and patient survival.

Results: The mean number of methylated genes per sample was 2.05 ± 2.59 (range 0 to 9). Promoters of PTGDR1, PTGDR2, PTGER1, PTGER2, PTGER3, PTGER4, PTGFR, PTGIR, and TBXA2R were methylated in 43.8%, 18.2%, 25.5%, 17.5%, 41.2%, 8.0%, 19.3%, 20.4%, and 11.3% of the samples, respectively. Methylation indices for prostanoid receptor family genes tended to be higher as the number of TET methylation events increased. Patients with 5-9 methylated genes had a significantly lower survival rate than that of patients with 0-4 methylated genes (log-rank test, P= 0.007). In multivariate analyses, PTGDR1 methylation was most highly correlated with recurrence in patients with hypopharyngeal cancer (P = 0.014). A similar correlation was observed for PTGER4 in patients with laryngeal cancer (P = 0.046). Methylation of the PTGIR and TBXA2R promoters was positively correlated with recurrence in oropharyngeal cancer (P = 0.028 and P = 0.006, respectively). Moreover, Patients with 5-9 methylated genes were extremely lower of 5hmC levels (P = 0.035) and was correlated with increasing expression of DNMT3A and DNMT3B (P < 0.05 and P < 0.05, respectively).

Conclusion: We characterised the relationship between the methylation status of prostanoid receptor genes and recurrence in HNSCC. These results provide new perspectives for the development of molecular targeted treatment approaches.
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http://dx.doi.org/10.1186/s12967-020-02214-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977280PMC
January 2020

Nanocomposite electrodes for high current density over 3 A cm in solid oxide electrolysis cells.

Nat Commun 2019 11 28;10(1):5432. Epub 2019 Nov 28.

Inorganic Functional Materials Research Institute, Department of Materials and Chemistry, National Institute of Advanced Industrial Science and Technology (AIST), 2266-98 Anagahora, Shimo-shidami, Moriyama-ku, Nagoya, Aichi, 463-8560, Japan.

Solid oxide electrolysis cells can theoretically achieve high energy-conversion efficiency, but current density must be further increased to improve the hydrogen production rate, which is essential to realize widespread application. Here, we report a structure technology for solid oxide electrolysis cells to achieve a current density higher than 3 A cm, which exceeds that of state-of-the-art electrolyzers. Bimodal-structured nanocomposite oxygen electrodes are developed where nanometer-scale SmSrCoO and CeSmO are highly dispersed and where submicrometer-scale particles form conductive networks with broad pore channels. Such structure is realized by fabricating the electrode structure from the raw powder material stage using spray pyrolysis. The solid oxide electrolysis cells with the nanocomposite electrodes exhibit high current density in steam electrolysis operation (e.g., at 1.3 V), reaching 3.13 A cm at 750 °C and 4.08 A cm at 800 °C, corresponding to a hydrogen production rate of 1.31 and 1.71 L h cm respectively.
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http://dx.doi.org/10.1038/s41467-019-13426-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883038PMC
November 2019

Nrf2 activation in osteoblasts suppresses osteoclastogenesis via inhibiting IL-6 expression.

Bone Rep 2019 Dec 1;11:100228. Epub 2019 Nov 1.

Department of Orthodontics, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa pref., 230-8501, Japan.

Bone destructive diseases such as periodontitis and rheumatoid arthritis are caused by excessive activation of osteoclasts. Osteoclastogenesis is regulated by Receptor activator of nuclear factor kappa-β ligand (RANKL) produced by osteoclastogenesis supporting cells such as osteoblast and osteocyte. Previously, we reported that NF-E2-related factor-2 (Nrf2) activation in osteoclast precursors inhibited osteoclastogenesis and bone destruction via induction of anti-oxidation and thereby attenuated intracellular ROS signaling. However, it still remains unknown whether Nrf2 activation in cells other than osteoclasts give any negative influence on supporting property for osteoclastogenesis. Here we discovered that Nrf2 activation in osteoblasts suppresses indirectly osteoclastogenesis via inhibiting the expression of interleukin-6 (IL-6) which promotes osteoclastogenesis. In this study, 5-aminolevulinic acid hydrochloride (ALA) and sodium ferrous citrate (SFC) was used as the Nrf2 activator. experiments, using osteoblast cell line, MC3T3-E1, revealed that the expression of IL-6 was increased by LPS stimulation, but decreased after ALA/SFC treatment in mRNA and protein levels. Furthermore, RANKL expression was augmented by LPS, which was blocked by ALA/SFC treatment. Neutralizing antibody against IL-6 confirmed that LPS-mediated RANKL augmentation was dependent on IL-6 induction. experiments with LPS-mediated bone destruction in mice, confirmed that augmented IL-6 expression in osteoblasts by immunochemical analysis. ALA/SFC treatment attenuated LPS-mediated IL-6 upregulation. These results suggest that Nrf2 activation in osteoblasts suppress IL-6 and inflammatory bone destruction. The Nrf2 activator acts not only on osteoclasts but also on osteoblasts, in other word, Nrf2 activation indirectly suppresses osteoclastogenesis. In conclusion, the Nrf2 activator exhibits dual inhibitory effects via direct action on osteoclast and indirect action on osteoclast supporting cells.
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http://dx.doi.org/10.1016/j.bonr.2019.100228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861591PMC
December 2019

Evaluation of adverse events focusing on infection associated with infliximab originator and biosimilar using a spontaneous reporting system database.

J Pharm Health Care Sci 2019 7;5:21. Epub 2019 Oct 7.

Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094 Japan.

Background: Infliximab (IFX) has changed the management of many life-threatening immune-mediated diseases. The high cost of IFX and its patent expiry have led to pharmaceutical companies developing a biosimilar; however, its safety profile remains unknown in the real world. The purpose of this study was to clarify the adverse events associated with IFX originator and its biosimilar using the Japanese Adverse Drug Event Report (JADER) database.

Methods: Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between the third quarter of 2014 and the fourth quarter of 2018. We calculated the reporting odds ratio and 95% confidence interval for each adverse event.

Results: We obtained 2771 reports of adverse events associated with IFX originator and 402 reports with IFX biosimilar. Signals were detected for pneumonia, interstitial lung disease, tuberculosis, and sepsis with both IFX originator and its biosimilar, whereas there was no signal for infection with the biosimilar.

Conclusions: The strength of the association between IFX originator and its biosimilar with adverse events is partly different, but reports were quite limited for the biosimilar compared with originator. It is recommended that research be continued in order to accumulate a wide variety of information, and that newly reported data be placed in the multifaceted viewpoints for improvement of care levels.
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http://dx.doi.org/10.1186/s40780-019-0149-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781388PMC
October 2019

p63 is a cereblon substrate involved in thalidomide teratogenicity.

Nat Chem Biol 2019 11 7;15(11):1077-1084. Epub 2019 Oct 7.

Department of Nanoparticle Translational Research, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.

Cereblon (CRBN) is a primary target of thalidomide and mediates its multiple pharmacological activities, including teratogenic and antimyeloma activities. CRBN functions as a substrate receptor of the E3 ubiquitin ligase CRL4, whose substrate specificity is modulated by thalidomide and its analogs. Although a number of CRL4 substrates have recently been identified, the substrate involved in thalidomide teratogenicity is unclear. Here we show that p63 isoforms are thalidomide-dependent CRL4 neosubstrates that are responsible, at least in part, for its teratogenic effects. The p53 family member p63 is associated with multiple developmental processes. ∆Np63α is essential for limb development, while TAp63α is important for cochlea development and hearing. Using a zebrafish model, we demonstrate that thalidomide exerts its teratogenic effects on pectoral fins and otic vesicles by inducing the degradation of ∆Np63α and TAp63α, respectively. These results may contribute to the invention of new thalidomide analogs lacking teratogenic activity.
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http://dx.doi.org/10.1038/s41589-019-0366-7DOI Listing
November 2019

The Fab portion of immunoglobulin G contributes to its binding to Fcγ receptor III.

Sci Rep 2019 08 16;9(1):11957. Epub 2019 Aug 16.

Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki, 444-8787, Japan.

Most cells active in the immune system express receptors for antibodies which mediate a variety of defensive mechanisms. These receptors interact with the Fc portion of the antibody and are therefore collectively called Fc receptors. Here, using high-speed atomic force microscopy, we observe interactions of human, humanized, and mouse/human-chimeric immunoglobulin G1 (IgG1) antibodies and their cognate Fc receptor, FcγRIIIa. Our results demonstrate that not only Fc but also Fab positively contributes to the interaction with the receptor. Furthermore, hydrogen/deuterium exchange mass spectrometric analysis reveals that the Fab portion of IgG1 is directly involved in its interaction with FcγRIIIa, in addition to the canonical Fc-mediated interaction. By targeting the previously unidentified receptor-interaction sites in IgG-Fab, our findings could inspire therapeutic antibody engineering.
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http://dx.doi.org/10.1038/s41598-019-48323-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697678PMC
August 2019

Cereblon Control of Zebrafish Brain Size by Regulation of Neural Stem Cell Proliferation.

iScience 2019 May 9;15:95-108. Epub 2019 Apr 9.

Department of Nanoparticle Translational Research, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan. Electronic address:

Thalidomide is a teratogen that causes multiple malformations in the developing baby through its interaction with cereblon (CRBN), a substrate receptor subunit of the CRL4 E3 ubiquitin ligase complex. CRBN was originally reported as a gene associated with autosomal recessive non-syndromic mild mental retardation. However, the function of CRBN during brain development remains largely unknown. Here we demonstrate that CRBN promotes brain development by facilitating the proliferation of neural stem cells (NSCs). Knockdown of CRBN in zebrafish embryos impaired brain development and led to small brains, as did treatment with thalidomide. By contrast, overexpression of CRBN resulted in enlarged brains, leading to the expansion of NSC regions and increased cell proliferation in the early brain field and an expanded expression of brain region-specific genes and neural and glial marker genes. These results demonstrate that CRBN functions in the determination of brain size by regulating the proliferation of NSCs during development.
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http://dx.doi.org/10.1016/j.isci.2019.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501120PMC
May 2019

TLP-mediated global transcriptional repression after double-strand DNA breaks slows down DNA repair and induces apoptosis.

Sci Rep 2019 03 19;9(1):4868. Epub 2019 Mar 19.

School of Life Science and Technology, Tokyo Institute of Technology, 4259 Nagatsuta, Yokohama, 226-8501, Japan.

Transcription and DNA damage repair act in a coordinated manner. Recent studies have shown that double-strand DNA breaks (DSBs) are repaired in a transcription-coupled manner. Active transcription results in a faster recruitment of DSB repair factors and expedites DNA repair. On the other hand, transcription is repressed by DNA damage through multiple mechanisms. We previously reported that TLP, a TATA box-binding protein (TBP) family member that functions as a transcriptional regulator, is also involved in DNA damage-induced apoptosis. However, the mechanism by which TLP affects DNA damage response was largely unknown. Here we show that TLP-mediated global transcriptional repression after DSBs is crucial for apoptosis induction by DNA-damaging agents such as etoposide and doxorubicin. Compared to control cells, TLP-knockdown cells were resistant to etoposide-induced apoptosis and exhibited an elevated level of global transcription after etoposide exposure. DSBs were efficiently removed in transcriptionally hyperactive TLP-knockdown cells. However, forced transcriptional shutdown using transcriptional inhibitors α-amanitin and 5,6-dichloro-1-ß-D-ribofuranosylbenzimidazole (DRB) slowed down DSB repair and resensitized TLP-knockdown cells to etoposide. Taken together, these results indicate that TLP is a critical determinant as to how cells respond to DSBs and triggers apoptosis to cells that have sustained DNA damage.
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http://dx.doi.org/10.1038/s41598-019-41057-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425004PMC
March 2019

Characteristics of mitral valve leaflet length in patients with pectus excavatum: A single center cross-sectional study.

PLoS One 2019 11;14(2):e0212165. Epub 2019 Feb 11.

Department of Clinical Laboratory, National Hospital Organization Yokohama Medical Center, Yokohama, Kanagawa, Japan.

The mitral valve morphology in patients with pectus excavatum (PE) has not been fully investigated. Thirty-five patients with PE, 46 normal controls, and patients with hypertrophic cardiomyopathy (HCM) who underwent 2 leaflet length measurements of Carpentier classification P2 and A2 using a transthoracic echocardiography were retrospectively investigated. The coaptation lengths and depths, papillary muscle tethering length, and mitral annular diameters were also measured. The P2 and A2 lengths were separately compared between 2 groups: older than 16 years and 16 years or younger. Furthermore, the correlations between actual P2 or A2 lengths and Haller computed tomography index, an index of chest deformity, were investigated in patients with PE exclusively. Among subjects older than 16 years, patients with PE had significantly shorter P2, longer A2, shorter copatation depth, and longer papillary muscle tethering length compared with normal controls. Similarly, patients with PE had significantly shorter P2 and shorter coaptation depth even compared with patients with HCM, while no significant difference was found in A2 length and papillary muscle tethering length. The same tendency was noted between 4 normal controls and 7 age- and sex-matched patients with PE ≤ 16 years old. No significant difference regarding A2/P2 ratio was found between patients with PE older and younger than 16 years. No significant correlation between the Haller computed tomography index and actual mitral leaflet lengths in patients with PE older than 16 years was noted; the same was observed for A2/P2 in all patients with PE. In conclusion, the characteristic features of the shorter posterior mitral leaflet, the longer anterior mitral leaflet, the shorter coaptation depth, and the longer papillary muscle tethering length in patients with PE was demonstrated. This finding might provide a clue regarding the etiology of mitral valve prolapse in PE at its possible earliest form.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212165PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370242PMC
November 2019

Nutritional supplementation with myo-inositol in growing mice specifically augments mandibular endochondral growth.

Bone 2019 04 22;121:181-190. Epub 2019 Jan 22.

Department of Orthodontics, Tsurumi University School of Dental Medicine, Yokohama, Japan.

Introduction: The purpose of this study was to examine growth-promoting effects of myo-inositol nutritional supplementation on the mandible in experimental animals.

Methods: Mice were fed on diets that contained various concentration of myo-inositol for 3 to 12 weeks. The length of the mandible, maxilla, and femur were measured on μCT images. The mandible and tibia were examined histologically and immunohistochemically. The effects of myo-inositol on cell proliferation and chondrocytic differentiation were examined using ATDC5 cells.

Results: Myo-inositol supplementation had no effects on body weight, length, and maxilla and femur lengths. However, the length of mandible and the thickness of the mandibular condylar cartilage (MCC) were increased by myo-inositol supplement. Microarray analysis revealed that Pik3cd was highly expressed in MCC as compared to that in the cartilage of the tibial growth plate, which was confirmed by real-time RT-PCR and immunohistochemistry. ATDC5 cells also highly expressed Pik3CD. Myoinositol induced increases in cell proliferation and chondrocytic differentiation in ATDC5 cells. The addition of a PIK3CD inhibitor blocked the induction of cell proliferation by myo-inositol in ATDC5 cells.

Conclusions: Nutritional supplementation with myo-inositol in growing mice augmented mandibular endochondral growth without any systemic effects. The specific promotion of mandibular growth by myoinositol is primarily dependent on the specific intensive expression of PIK3CD in the MCC.
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http://dx.doi.org/10.1016/j.bone.2019.01.020DOI Listing
April 2019

Evaluation of medication-related osteonecrosis of the jaw using the Japanese Adverse Drug Event Report database.

Ther Clin Risk Manag 2019 24;15:59-64. Epub 2018 Dec 24.

Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka 569-1094, Japan,

Background: Bisphosphonates (BPs) and denosumab are widely used to treat osteoporosis and complications associated with bone metastases. However, medication-related osteonecrosis of the jaw (MRONJ) is a serious problem.

Objective: The objective of this study was to evaluate the frequency, outcome, and characteristics of patients with drug-induced MRONJ.

Methods: Retrospective pharmacovigilance disproportionality analysis was conducted using the Japanese Adverse Drug Event Report (JADER) database from the Pharmaceuticals and Medical Devices Agency. Adverse event reports submitted to JADER between 2004 and 2017 were analyzed, and the reporting odds ratio (ROR) was calculated.

Results: Among the BPs that cause MRONJ, zoledronate was the most common; therefore, we compared the characteristics of cases of MRONJ induced by zoledronate with those induced by denosumab. Among the 3,875 (68.1% women) cases of MRONJ, zoledronate-related MRONJ accounted for 1,283 (56.0% women) and denosumab-related MRONJ accounted for 322 (55.3% women). MRONJ was more frequent after 70 years of age regardless of the use of either zoledronate or denosumab; onset occurred after 1 year from the denosumab treatment, but it is unknown when onset occurred after zoledronate treatment. The outcomes for MRONJ were poor, with 406 reports on zoledronate (31.6%) and 152 reports on denosumab (47.2%) demonstrating nonrecovery. Zoledronate (ROR: 319.3, 95% CI: 296.0-344.4) had the highest ROR among BP agents. Denosumab had a high ROR (ROR: 155.2, 95% CI: 136.5-176.3). Zoledronate and denosumab were used in similar patient backgrounds, and their use resulted in a similar frequency of MRONJ.

Conclusion: The findings of this comprehensive evaluation of MRONJ using the JADER database will be helpful for prescribing medications to elderly patients.
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http://dx.doi.org/10.2147/TCRM.S176620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307679PMC
December 2018

Application of high-performance magnetic nanobeads to biological sensing devices.

Anal Bioanal Chem 2019 Mar 9;411(9):1825-1837. Epub 2019 Jan 9.

Department of Nanoparticle Translational Research, Tokyo Medical University, 6-2-2 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.

Nanomaterials have extensive applications in the life sciences and in clinical diagnosis. We have developed magnetic nanoparticles with high dispersibility and extremely low nonspecific binding to biomolecules and have demonstrated their application in chemical biology (e.g., for the screening of drug receptor proteins). Recently, the excellent properties of nanobeads have made possible the development of novel rapid immunoassay systems and high-precision technologies for exosome detection. For immunoassays, we developed a technology to encapsulate a fluorescent substance in magnetic nanobeads. The fluorescent nanobeads allow the rapid detection of a specific antigen in solution or in tissue specimens. Exosomes, which are released into the blood, are expected to become markers for several diseases, including cancer, but techniques for measuring the absolute quantity of exosomes in biological fluids are lacking. By integrating magnetic nanobead technology with an optical disc system, we developed a novel method for precisely quantifying exosomes in human serum with high sensitivity and high linearity without requiring enrichment procedures. This review focuses on the properties of our magnetic nanobeads, the development of novel biosensors using these nanobeads, and their broad practical applications. Graphical abstract ᅟ.
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http://dx.doi.org/10.1007/s00216-018-1548-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453870PMC
March 2019

Author's response.

Am J Orthod Dentofacial Orthop 2018 10;154(4):461-462

Yokohama, Japan.

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http://dx.doi.org/10.1016/j.ajodo.2018.07.003DOI Listing
October 2018
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