Search

Abstract Background Although an increasing number of histone demethylases have been identified and biochemically characterized, their biological functions largely remain uncharacterized, particularly in the context of human diseases such as cancer. We investigated the role of KDM5B, a JmjC histone demethylase, in human carcinogenesis. Quantitative RT-PCR and microarray analyses were used to examine the expression profiles of histone demethylases in clinical tissue samples. We also examined the functional effects of KDM5B on the growth of cancer cell lines treated with small interfering RNAs (siRNAs). Downstream genes and signal cascades induced by KDM5B expression were identified from Affymetrix Gene Chip experiments, and validated by real-time PCR and reporter assays. Cell cycle-dependent characteristics of KDM5B were identified by immunofluorescence and FACS. Results Quantitative RT-PCR analysis confirmed that expression levels of KDM5B are significantly higher in human bladder cancer tissues than in their corresponding non-neoplastic bladder tissues (P < 0.0001). The expression profile analysis of clinical tissues also revealed up-regulation of KDM5B in various kinds of malignancies. Transfection of KDM5B-specific siRNA into various bladder and lung cancer cell lines significantly suppressed the proliferation of cancer cells and increased the number of cells in sub-G1 phase. Microarray expression analysis indicated that E2F1 and E2F2 are downstream genes in the KDM5B pathway. Conclusions Inhibition of KDM5B may affect apoptosis and reduce growth of cancer cells. Further studies will explore the pan-cancer therapeutic potential of KDM5B inhibition.

Purpose: The aim of this study was to investigate the relationship between the hammering sound level and the presence of postoperative subsidence., Methods: The last five hammering sounds during the final-size broaching procedure and during the real stem insertion were recorded and analysed in 95 patients who were operated on by one of seven surgeons using two implants (Trident cup, Accolade II, Stryker; G7 cup, Taperloc Complete Microplasty Stem, Zimmer Biomet). The maximum peak was semi-automatically identified and analysed to determine the maximum C-weighted sound pressure level (LCpeak) of each of the five hammering sounds and the equivalent continuous A-weighted sound pressure (LAeq) of the entire five-sound hammering procedure., Results: Among the 95 hips, 25 (26.3%) had ≥ 3 mm of postoperative subsidence. Therefore, 125 of 475 hammering sounds (LCpeak) and 25 of 95 hammering procedures (LAeq) in both the broaching procedure and stem insertion procedure were associated with postoperative subsidence. The hammering sound level in both the broaching and stem insertion procedures were significantly weaker in patients with postoperative subsidence than in those without subsidence. Among the seven surgeons, there was intra-surgeon and inter-surgeon heterogeneity with large variance regarding the sound levels. With univariate and multivariate analyses, the hammering sound level was independently associated with postoperative subsidence in the two models., Conclusion: A weak hammering sound level was associated with postoperative subsidence in THA with a cementless stem. An objective evaluation of the hammering procedure might be useful to decrease the incidence of postoperative subsidence., Competing Interests: Declarations. Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Ethics Committee of Juntendo University Faculty of Medicine (E21-0340, 18-March-2022). Consent to participate: Informed consent was obtained from all individual participants included in the study. Consent to publish: The authors affirm that human research participants provided informed consent for publication. Competing interests: Yasuhiro Homma has received payments for speakers bureau/paid presentations from Zimmer Biomet and B.braun Aesclup, research support from B.braun Aesclup and is a consultant to Zimmer Biomet, Kyocera and Teijin, a correspoinding member of International Orthopaedics, a member of the board of subspecialities (Hip arthroplasty), an executive committee member of Asia pacific orthopaedic association and Asia pacific hip society. Tomonori Baba has received royalties and payments for speakers bureau/paid presentations from Zimmer Biomet. Muneaki Ishijima has received payments for speakers bureau/paid presentations from Asahi Kasei Corporation, Astellas Pharma Inc., Amgen K.K., ALCARE Co., Ltd., EA Pharma Co.,Ltd., Viatris Inc., Eisai Co., Ltd., ONO PHARMACEUTICAL CO., LTD., KAKEN PHARMACEUTICAL CO.,LTD., SHIONOGI & CO., LTD., DAIICHI SANKYO COMPANY, LIMITED, Taisho Pharmaceutical Co., Ltd, Mitsubishi Tanabe Pharma Corporation, CHUGAI PHARMACEUTICAL CO., LTD., TEIJIN LIMITED, Eli Lilly Japan K.K., Japan Medical Dynamic Marketing, INC., Nippon Zoki Pharmaceutical Co., Ltd., HISAMITSU PHARMACEUTICAL CO.,INC. and Pfizer Japan Inc., research support from Suntory Wellness Ltd., Stryker Japan K.K, Japan Medical Dynamic Marketing, INC., HISAMITSU PHARMACEUTICAL CO.,INC., Olympus Terumo Biomaterials Corp.,NIHON MATHYS K.K., CellSource Co., Ltd, CHUGAI PHARMACEUTICAL CO., LTD., Zimmer Biomet G.K. OHTA’S ISAN Co., Ltd., Taisho Pharmaceutical Co., Ltd and Aimedic MMT CO., LTD and is an editorial/governing board member of Osteoarthritis and Cartilage, Osteoarthritis and Cartilage Open and Journal of Joint Surgery and Research, a board member/committee appointments for a society of Osteoarthritis Research Society International., (© 2024. The Author(s) under exclusive licence to SICOT aisbl.)

Background: Although hearing loss in orthopaedic surgeons from exposure to hammering sounds have been previously reported, there are no reports on the noise environment during total hip arthroplasty (THA) in Japan. The aim of this study was to investigate the sound level generated by cementless THA in Japan, and to discuss the broader sound environment within this space., Methods: 94 cementless THAs (94 patients with informed consent) performed by four surgeons were included. The equivalent continuous A-weighted sound levels (LAeq) in a series of 1086 continuous hammering maneuvers without pause and the maximum C-weighted sound levels (LCpeak) in 17,210 hammering sounds were investigated., Results: Among the hammering sounds analysed in terms of LAeq, the sound pressure level associated with some procedures did result in non-scrubbed personnel being exposed to the 8-h sound levels exceeding the LAeq threshold (85 dB), while most procedures exceeded this threshold for scrubbed personnel. For scrubbed personnel, the maximum number of operations that could be safely attended per day were 16.1 and 1.6 operations under average and worst-case scenario conditions, respectively. For LCpeak, no sound was found to be above the threshold (135 dB) for either non-scrubbed or scrubbed personnel., Conclusions: Although average sound levels in a standard operating theatre during cementless THA did not exceed recommended thresholds among non-scrubbed medical practitioners, our data are not sufficient to conclude that the sound environment is safe for scrubbed personnel close to the sound source. Further investigation is needed regarding sound exposure and the occurrence of hearing impairment in surgeons who perform total hip arthroplasties., Competing Interests: Conflict of interest The authors report grants or contracts, royalties or licenses, consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Suntory Wellness Ltd., Stryker Japan K.K, Japan Medical Dynamic Marketing, INC., HISAMITSU PHARMACEUTICAL CO.,INC., Olympus Terumo Biomaterials Corp., NIHON MATHYS K.K., CellSource Co., Ltd, CHUGAI PHARMACEUTICAL CO., LTD., Zimmer Biomet, OHTA’S ISAN Co., Ltd., Taisho Pharmaceutical Co., Ltd, Aimedic MMT CO., LTD., Innomed, BodyCad, Ortho Development, United Ortho, Asahi Kasei Corporation, Astellas Pharma Inc., Amgen K.K., ALCARE Co., Ltd., EA Pharma Co.,Ltd., Viatris Inc., Eisai Co., Ltd., ONO PHARMACEUTICAL CO., LTD., KAKEN PHARMACEUTICAL CO.,LTD., SHIONOGI & CO., LTD., DAIICHI SANKYO COMPANY, LIMITED, Mitsubishi Tanabe Pharma Corporation, TEIJIN LIMITED, Eli Lilly Japan K.K., Nippon Zoki Pharmaceutical Co., Ltd., Pfizer Japan Inc. and B. braun Aesclup. The authors have leadership or fiduciary role in American Academy of Orthopaedic Surgeons, American Association of Hip and Knee Surgeons, Anterior Hip Foundation, Osteoarthritis and Cartilage, Osteoarthritis and Cartilage Open, Journal of Joint Surgery and Research, International Orthopaedics, Osteoarthritis Research Society International, International society of orthopaedic surgery and traumatology and Asia pacific orthopaedic association. The authors have stock or stock options of Johnson & Johnson, Procter & Gamble and Zimmer Biomet., (Copyright © 2025 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Amyloid fibril formation is associated with various amyloidoses, including neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Despite the numerous studies on the inhibition of amyloid formation, the prevention and treatment of a majority of amyloid-related disorders are still challenging. In this study, we investigated the effects of various plant extracts on amyloid formation of α-synuclein. We found that the extracts from Eucalyptus gunnii are able to inhibit amyloid formation, and to disaggregate preformed fibrils, in vitro. The extract itself did not lead to cell damage. In the extract, miquelianin, which is a glycosylated form of quercetin and has been detected in the plasma and the brain, was identified and assessed to have a moderate inhibitory activity, compared to the effects of ellagic acid and quercetin, which are strong inhibitors for amyloid formation. The properties of miquelianin provide insights into the mechanisms controlling the assembly of α-synuclein in the brain., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

We have recently discovered that the so-called subcortical maternal complex (SCMC) proteins composing of cytoplasmic lattices are destabilized in Uhrf1 knockout murine fully grown oocytes (FGOs). Here we report that human UHRF1 interacts with human NLRP5 and OOEP, which are core components of the SCMC. Moreover, NLRP5 and OOEP interact with DPPA3, which is an essential factor for exporting UHRF1 from the nucleus to the cytoplasm in oocytes. We identify that NLRP5, not OOEP, stabilizes UHRF1 protein in the cytoplasm utilizing specifically engineered cell lines mimicking UHRF1 status in oocytes and preimplantation embryos. Further, UHRF1 is destabilized both in the cytoplasm and nucleus of Nlrp5 knockout murine FGOs. Since pathogenic variants of the SCMC components frequently cause multilocus imprinting disturbance and UHRF1 is essential for maintaining CpG methylation of imprinting control regions during preimplantation development, our results suggest possible pathogenesis behind the disease, which has been a long-standing mystery., (© The Author(s) 2024. Published by Oxford University Press.)

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, a rare autosomal recessive disorder, manifests with hypoglobulinemia and chromosomal instability accompanied by DNA hypomethylation. Pathological variants in the DNMT3B , ZBTB24 , CDCA7 , or HELLS genes underlie its etiology. Activated lymphocytes from patients often display distinctive multiradial chromosomes fused via pericentromeric regions. Recent studies have provided deeper insights into how pathological variants in ICF-related proteins cause DNA hypomethylation and chromosome instability. However, the understanding of the molecular pathogenesis underlying immunodeficiency is still in its nascent stages. In the past half-decade, the roles of CDCA7, HELLS, and ZBTB24 in classical non-homologous end joining during double-strand DNA break repair and immunoglobulin class-switch recombination (CSR) have been unveiled. Nevertheless, given the decreased all classes of immunoglobulins in most patients, CSR deficiency alone cannot fully account for the immunodeficiency. The latest finding showing dysregulation of immunoglobulin signaling may provide a clue to understanding the immunodeficiency mechanism. While less common, a subgroup of patients exhibits T-cell abnormalities alongside B-cell anomalies, including reduced regulatory T-cells and increased effector memory T- and follicular helper T-cells. The dysregulation of immunoglobulin signaling in B-cells, the imbalance in T-cell subsets, and/or satellite RNA-mediated activation of innate immune response potentially explain autoimmune manifestations in a subset of patients. These findings emphasize the pivotal roles of ICF-related proteins in both B- and T-cell functions. ICF syndrome studies have illuminated many fundamental mechanisms. Further investigations will certainly continue to unveil additional mechanisms and their interplay., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Unoki.)

Complex congenital chromosome abnormalities are rare but often cause severe symptoms. However, the structures and biological impacts of such abnormalities have seldomly been analyzed at the molecular level. Previously, we reported a Japanese female patient with severe developmental defects. The patient had an extra dicentric chromosome 21 (chr21) consisting of two partial chr21 copies fused together within their long arms along with two centromeres and many copy number changes. In this study, we performed whole-genome, transcriptional, and DNA methylation analyses, coupled with novel bioinformatic approaches, to reveal the complex structure of the extra chromosome and its transcriptional and epigenetic changes. Long-read sequencing accurately identified the structures of junctions related to the copy number changes in extra chr21 and suggested the mechanism of the structural changes. Our transcriptome analysis showed the overexpression of genes in extra chr21. Additionally, an allele-specific DNA methylation analysis of the long-read sequencing data suggested that the centromeric region of extra chr21 was hypermethylated, a property associated with the inactivation of one centromere in the extra chromosome. Our comprehensive analysis provides insights into the molecular mechanism underlying the generation of the extra chromosome and its pathogenic roles., (© 2023. The Author(s).)

Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is a protein essential for the maintenance of DNA methylation in somatic cells. However, UHRF1 is predominantly localized in the cytoplasm of mouse oocytes and preimplantation embryos, where it may play a role unrelated to the nuclear function. We herein report that oocyte-specific Uhrf1 KO results in impaired chromosome segregation, abnormal cleavage division, and preimplantation lethality of derived embryos. Our nuclear transfer experiment showed that the phenotype is attributable to cytoplasmic rather than nuclear defects of the zygotes. A proteomic analysis of KO oocytes revealed the down-regulation of proteins associated with microtubules including tubulins, which occurred independently of transcriptomic changes. Intriguingly, cytoplasmic lattices were disorganized, and mitochondria, endoplasmic reticulum, and components of the subcortical maternal complex were mislocalized. Thus, maternal UHRF1 regulates the proper cytoplasmic architecture and function of oocytes and preimplantation embryos, likely through a mechanism unrelated to DNA methylation., (© 2023 Uemura et al.)

Immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is in most cases caused by mutations in either DNA methyltransferase (DNMT)3B, zinc finger and BTB domain containing 24, cell division cycle associated 7 or helicase lymphoid-specific. However, the causative genes of a few ICF patients remain unknown. We, herein, identified ubiquitin-like with plant homeodomain and really interesting new gene finger domains 1 (UHRF1) as a novel causative gene of one such patient with atypical symptoms. This patient is a compound heterozygote for two previously unreported mutations in UHRF1: c.886C > T (p.R296W) and c.1852C > T (p.R618X). The R618X mutation plausibly caused nonsense-mediated decay, while the R296W mutation changed the higher order structure of UHRF1, which is indispensable for the maintenance of CG methylation along with DNMT1. Genome-wide methylation analysis revealed that the patient had a centromeric/pericentromeric hypomethylation, which is the main ICF signature, but also had a distinctive hypomethylation pattern compared to patients with the other ICF syndrome subtypes. Structural and biochemical analyses revealed that the R296W mutation disrupted the protein conformation and strengthened the binding affinity of UHRF1 with its partner LIG1 and reduced ubiquitylation activity of UHRF1 towards its ubiquitylation substrates, histone H3 and proliferating cell nuclear antigen -associated factor 15 (PAF15). We confirmed that the R296W mutation causes hypomethylation at pericentromeric repeats by generating the HEK293 cell lines that mimic the patient's UHRF1 molecular context. Since proper interactions of the UHRF1 with LIG1, PAF15 and histone H3 are essential for the maintenance of CG methylation, the mutation could disturb the maintenance process. Evidence for the importance of the UHRF1 conformation for CG methylation in humans is, herein, provided for the first time and deepens our understanding of its role in regulation of CG methylation., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)