Publications by authors named "Shotaro Suzuki"

55 Publications

Temporal variability of Cs concentrations in coastal sediments off Fukushima.

Sci Total Environ 2022 Mar 18;831:154670. Epub 2022 Mar 18.

Institute of Environmental Radioactivity, Fukushima University, Fukushima, Japan.

Large amounts of radiocesium were released into marine environments following the Fukushima Daiichi Nuclear Power Plant accident in March 2011. Released radiocesium influenced not only marine environment but also marine biota in Fukushima. Since marine biota as fisheries products is important for Japanese market, it is important to assess the distribution of radiocesium in coastal environment off Fukushima for safety concerns of radioactive contamination. Radiocesium concentrations in sediments are important for understanding fishing ground conditions and for proving the safety of fisheries products in Fukushima. In this study, monthly monitoring data collected from May 2011 to March 2020 were analyzed to describe the temporal variability of Cs concentrations in coastal sediments off Fukushima (total of 3647 samples from eight lines at depths of 7-125 m off Fukushima, and three sites in Matsukawa-ura Lagoon). The Cs concentration in sediment showed a decreasing trend, but our nonlinear model fitting suggested that this rate of decrease had slowed down. Additionally, Cs concentrations were up to 4.08 times greater in shallow sampling sites (7, 10, 20 m depth) following heavy rainfall events (before five months vs. after five months), such as typhoons. These observations were consistent with increasing input from particulate Cs fluxes from rivers and increasing dissolved Cs concentrations in seawater. Finally, our numerical modeling suggested that riverine Cs input could maintain Cs concentrations in coastal sediment. These results indicate that riverine Cs input following heavy rainfall events is the main factor for maintaining Cs concentrations in coastal sediments near the Fukushima Daiichi Nuclear Power Plant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.scitotenv.2022.154670DOI Listing
March 2022

Extramedullary haematopoiesis within hepatic sinusoids of a patient with primary myelofibrosis.

Br J Haematol 2022 03 18;196(5):1130. Epub 2021 Nov 18.

Division of Haematology, Department of Internal Medicine, Chiba Rosai Hospital, Ichihara, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.17923DOI Listing
March 2022

Factors controlling dissolved Cs activities in coastal waters on the eastern and western sides of Honshu, Japan.

Sci Total Environ 2022 Feb 27;806(Pt 3):151216. Epub 2021 Oct 27.

Fukushima Prefectural Fisheries and Marine Science Research Center, Iwaki, Fukushima 970-0316, Japan.

The distributions of dissolved Cs in river, nearshore, and offshore waters on the east and west coasts of the Japanese island of Honshu were studied in 2018-2021, 7-10 years after the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident. On the east side along the north western North Pacific (Fukushima Prefecture), estuarine processes, including desorption from riverine particles and dissolution into pore water from riverine particles that had settled to the seafloor, contributed to the maintenance of high dissolved Cs activities in nearshore and offshore waters. A survey and mass-balance calculation in a semi-enclosed estuarine area, the Matsukawa-ura, in the northern part of Fukushima, provided convincing evidence that rivers contributed to the influx of Cs to coastal waters. In contrast, the extremely low activities of dissolved and particulate Cs in the Tedori River of Ishikawa Prefecture on the western side of Japan along the Japan Sea suggested that inputs of riverine Cs made a negligible contribution to the increase of dissolved Cs activities in the nearshore and offshore waters. The relatively high dissolved Cs activities observed in the offshore waters of the Japan Sea were due to movement of FDNPP-derived Cs into the Japan Sea via the Tsushima Warm Current. Mechanisms controlling the distributions of Cs activities in coastal waters of the eastern and western sides of Japan therefore differ.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.scitotenv.2021.151216DOI Listing
February 2022

COVID-19 and adult-onset Still's disease as part of hyperferritinemic syndromes.

Mod Rheumatol Case Rep 2022 01;6(1):101-105

Division of Rheumatology and Allergology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.

The coronavirus disease (COVID-19) is known to cause hyperferritinemia and haemophagocytic lymphohistiocytosis. Including this laboratory parameter, symptoms similar to COVID-19 have been observed in adult-onset Still's disease (AOSD), catastrophic antiphospholipid syndrome, macrophage activation syndrome, and septic shock, which has led to the proposal of a concept called 'hyperferritinemic syndromes'. High levels of some clinical markers in both COVID-19 and AOSD make them difficult to differentiate. While the efficacy of ciclesonide had been expected for mild pneumonia with COVID-19, the efficacy of tocilizumab (TCZ), which is a known treatment for AOSD, was not established. We report the first known occurrence of COVID-19 diagnosed in March 2020, preceded by the diagnosis of AOSD in April 2019. The patient was given prednisolone and TCZ, which led to remission. With the dyspnea and ground-glass appearance on chest computed tomography, PCR test revealed COVID-19 infection. Ciclesonide was started on Day 7 of the disease onset, which led to improved inflammatory markers. We infer that while TCZ is theoretically useful for COVID-19 due to its inhibition of interleukin 6. AOSD and COVID-19 may be differentiated by levels of ferritin, and appropriate treatment must be allocated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/mrcr/rxab032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500156PMC
January 2022

Oral Ulcers Associated with Scrub Typhus.

Intern Med 2021 Dec 12;60(23):3841-3842. Epub 2021 Jun 12.

Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.7037-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8710392PMC
December 2021

Altered replication stress response due to CARD14 mutations promotes recombination-induced revertant mosaicism.

Am J Hum Genet 2021 06 17;108(6):1026-1039. Epub 2021 May 17.

Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan; Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan. Electronic address:

Revertant mosaicism, or "natural gene therapy," refers to the spontaneous in vivo reversion of an inherited mutation in a somatic cell. Only approximately 50 human genetic disorders exhibit revertant mosaicism, implicating a distinctive role played by mutant proteins in somatic correction of a pathogenic germline mutation. However, the process by which mutant proteins induce somatic genetic reversion in these diseases remains unknown. Here we show that heterozygous pathogenic CARD14 mutations causing autoinflammatory skin diseases, including psoriasis and pityriasis rubra pilaris, are repaired mainly via homologous recombination. Rather than altering the DNA damage response to exogenous stimuli, such as X-irradiation or etoposide treatment, mutant CARD14 increased DNA double-strand breaks under conditions of replication stress. Furthermore, mutant CARD14 suppressed new origin firings without promoting crossover events in the replication stress state. Together, these results suggest that mutant CARD14 alters the replication stress response and preferentially drives break-induced replication (BIR), which is generally suppressed in eukaryotes. Our results highlight the involvement of BIR in reversion events, thus revealing a previously undescribed role of BIR that could potentially be exploited to develop therapeutics for currently intractable genetic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2021.04.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206392PMC
June 2021

Arthritis and enthesitis during dupilumab therapy completely remitted by celecoxib.

J Dermatol 2021 Jun 28;48(6):e279-e280. Epub 2021 Mar 28.

Department of Dermatology, St Marianna University School of Medicine, Kawasaki, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.15872DOI Listing
June 2021

Back to normal; serological testing for COVID-19 diagnosis unveils missed infections.

J Med Virol 2021 07 25;93(7):4549-4552. Epub 2021 Mar 25.

Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.

Background: The gold standard for coronavirus disease (COVID-19) diagnosis has been the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA by nucleic acid amplification testing (NAAT). On the other hand, serological testing for COVID-19 may offer advantages in detecting possibly overlooked infections by NAAT.

Methods: To evaluate seroconversion of NAAT-negative pneumonia patients, immunoglobulin M (IgM) and IgG targeting the spike protein of SARS-CoV-2 were semiquantified by an immunofluorescence assay. Seroconversion was confirmed by another serological method, targeting the nucleocapsid protein.

Results: Eight suspected but unconfirmed COVID-19 pneumonia patients (median age, 39 years; range, 21-55) were included. The median period between symptom onset and NAAT sample collection was 6 days (2-27 days). None of them had tested positive for SARS-CoV-2 by NAAT. In contrast, all eight patients revealed seropositivity with the two serological methods, indicating actual seroconversion against SARS-CoV-2. The median period between onset and blood sampling was 26.5 days (7-51 days).

Conclusion: Eight patients with COVID-19 pneumonia, initially tested negative for SARS-CoV-2 by NAAT, were finally confirmed of the diagnosis by serological testing. To cover the whole spectrum of this heterogenous infectious disease, serology testing should be implemented to the multitiered diagnostic algorithm for COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmv.26949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250857PMC
July 2021

The fission yeast gmn2 gene encodes an ERD1 homologue of Saccharomyces cerevisiae required for protein glycosylation and retention of luminal endoplasmic reticulum proteins.

J Gen Appl Microbiol 2021 Jun 3;67(2):67-76. Epub 2021 Feb 3.

Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University.

The gmn2 mutant of Schizosaccharomyces pombe has previously been shown to exhibit defects in protein glycosylation of N-linked oligosaccharides (Ballou, L. and Ballou, CE., Proc. Natl. Acad. Sci. USA, 92, 2790-2794 (1995)). Like most glycosylation-defective mutants, the S. pombe gmn2 mutant was found to be sensitive to hygromycin B, an aminoglycoside antibiotic. As a result of complementation analysis, the gmn2 gene was found to be a single open reading frame that encodes a polypeptide of 373 amino acids consisting of multiple membrane-spanning regions. The Gmn2 protein shares sequence similarity with Kluyveromyces lactis and Saccharomyces cerevisiae Erd1 proteins, which are required for retention of luminal endoplasmic reticulum (ER) proteins. Although disruption of the gmn2 gene is not lethal, the secreted glycoprotein showed a significant glycosylation defect with destabilization of the glycosyltransferase responsible for N-glycan elongation. It was also shown that a significant amount of BiP was missorted to the cell surface according to ADEL receptor destabilization. Fluorescent microscopy revealed that the functional Gmn2-EGFP fusion protein is mainly localized in the Golgi membrane. These results indicate that the Gmn2 protein is required for protein glycosylation and for retention of ER-resident proteins in S. pombe cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2323/jgam.2020.07.002DOI Listing
June 2021

Rheumatoid arthritis relapse in patients with other iatrogenic immunodeficiency-associated lymphoproliferative disorders and its treatment.

Mod Rheumatol 2021 Nov 1;31(6):1087-1093. Epub 2021 Mar 1.

Division of Rheumatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.

Objectives: Rheumatoid arthritis (RA) in patients undergoing immunosuppressive therapy (IS) is sometimes involved with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPD). We aimed to clarify the effects of LPD treatment on RA and the current status of RA treatment options after LPD onset and subsequent IS withdrawal.

Methods: We retrospectively analyzed data of patients who had RA with LPD and examined the relationship between LPD course and RA treatment as well as that between RA relapse and LPD treatment.

Results: LPD patients were categorized into two groups: patients who regressed spontaneously ( = 19) and those who needed chemotherapy ( = 12). The chemotherapy group had significantly less RA relapse than the spontaneous regression group ( = .041). RA almost relapsed early in the spontaneous regression group and needed treatment for RA. Chemotherapy with rituximab prevented long-term RA relapse, and RA did not relapse for long even after rituximab monotherapy. The total dose of rituximab in monotherapy correlated with the time to RA relapse. Six patients with RA relapse received biologics and had no LPD relapse for more than 1 year.

Conclusions: Rituximab in chemotherapy for LPD may help prevent RA relapse with LPD. Large-scale studies are required in the future for verification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14397595.2021.1879367DOI Listing
November 2021

Symmetrical acral keratoderma: A waxing and waning scaly pigmented skin lesions on the acral extremities.

J Dermatol 2021 Apr 19;48(4):e151-e152. Epub 2020 Dec 19.

Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.15732DOI Listing
April 2021

Effects of growth hormone and cortisol administration on plasma insulin-like growth factor binding proteins in juveniles of three subspecies of masu salmon (Oncorhynchus masou).

Comp Biochem Physiol A Mol Integr Physiol 2021 01 11;251:110821. Epub 2020 Oct 11.

Graduate School of Environmental Science, Hokkaido University, Kita 10, Nishi 5, Kita-ku, Sapporo, Hokkaido 060-0810, Japan; Faculty of Fisheries Sciences, Hokkaido University, 3-1-1 Minato, Hakodate, Hokkaido 041-8611, Japan. Electronic address:

In this study, we examined the effects of porcine growth hormone (GH) and cortisol on plasma insulin-like growth factor binding proteins (IGFBPs) in juveniles of three subspecies of Oncorhynchus masou (masu, amago, and Biwa salmon). Ligand blotting using digoxigenin-labeled human IGF-I was used to detect and semi-quantify three major circulating IGFBP bands at 41, 28, and 22 kDa, corresponding to IGFBP-2b, -1a, and -1b, respectively. GH increased plasma IGFBP-2b concentration in masu and Biwa salmon but suppressed it in amago salmon. Plasma IGFBP-2b levels were increased by cortisol in the three subspecies. Cortisol induced plasma IGFBP-1a in the three subspecies, whereas GH had a suppressive effect in masu and Biwa salmon. Sham and cortisol injections increased plasma IGFBP-1b levels after 1 day in masu and amago salmon, suggesting that IGFBP-1b is induced following exposure to stressors via cortisol. Increased IGFBP-1b levels were restored to basal levels when co-injected with GH in Biwa salmon, and the same trend was seen in masu and amago salmon. However, the suppressive effect of GH disappeared 2 days after injection in the three subspecies. Despite some differences among subspecies, the findings suggest that cortisol is a primary inducer of plasma IGFBP-1b; however, GH counteracts it in the short term. Therefore, GH has the potential to modulate the degree of increase in circulating IGFBP-1b levels during acute stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cbpa.2020.110821DOI Listing
January 2021

Suspended Particle-Water Interactions Increase Dissolved Cs Activities in the Nearshore Seawater during Typhoon Hagibis.

Environ Sci Technol 2020 09 19;54(17):10678-10687. Epub 2020 Aug 19.

Institute of Environmental Radioactivity, Fukushima University, Fukushima, Fukushima 960-1296, Japan.

Distributions of Cs in dissolved and particulate phases of the downstream reaches of seven rivers and adjacent nearshore and offshore waters as far as ∼60 km south of the Fukushima Dai-ichi nuclear power plant (FDNPP) were studied during the high-river-flow period (June-September 2019) and during the period of October 2019 after typhoon Hagibis. Dissolved Cs activities in nearshore water were higher than those in rivers and offshore waters, and this distribution was more intensified after the typhoon, indicating the desorption of Cs from riverine suspended particles in addition to the ongoing release of contaminated water from the FDNPP and re-entry of radiocesium via submarine groundwater discharge. This scenario is also supported by the reduction of distribution coefficient () from a geometric mean value of 5.5 × 10 L/kg in rivers to 9.8 × 10 L/kg in nearshore water. The occupation of desorbed Cs to the dissolved activity of this nuclide in nearshore water was estimated to be 0.7%-20% (median: 9.7%) during the high-river-flow period, increasing to 1.4%-66% (32.3%) after the typhoon, suggesting that the desorption during the flood period such as typhoons further contributes to the increase in dissolved Cs levels in nearshore water.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.est.0c03254DOI Listing
September 2020

Speckled lentiginous nevus in a patient with Hermansky-Pudlak syndrome type 1.

J Dermatol 2020 Jan 17;47(1):e20-e21. Epub 2019 Oct 17.

Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.15121DOI Listing
January 2020

A Case of Malignant Melanoma Arising in Nagashima-type Palmoplantar Keratosis.

Acta Derm Venereol 2019 Dec;99(13):1311-1312

Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, 0608638 Sapporo, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2340/00015555-3326DOI Listing
December 2019

Cultured Epidermal Autografts from Clinically Revertant Skin as a Potential Wound Treatment for Recessive Dystrophic Epidermolysis Bullosa.

J Invest Dermatol 2019 10 2;139(10):2115-2124.e11. Epub 2019 May 2.

Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Inherited skin disorders have been reported recently to have sporadic normal-looking areas, where a portion of the keratinocytes have recovered from causative gene mutations (revertant mosaicism). We observed a case of recessive dystrophic epidermolysis bullosa treated with cultured epidermal autografts (CEAs), whose CEA-grafted site remained epithelized for 16 years. We proved that the CEA product and the grafted area included cells with revertant mosaicism. Based on these findings, we conducted an investigator-initiated clinical trial of CEAs from clinically revertant skin for recessive dystrophic epidermolysis bullosa. The donor sites were analyzed by genetic analysis, immunofluorescence, electron microscopy, and quantification of the reverted mRNA with deep sequencing. The primary endpoint was the ulcer epithelization rate per patient at 4 weeks after the last CEA application. Three patients with recessive dystrophic epidermolysis bullosa with 8 ulcers were enrolled, and the epithelization rate for each patient at the primary endpoint was 87.7%, 100%, and 57.0%, respectively. The clinical effects were found to persist for at least 76 weeks after CEA transplantation. One of the three patients had apparent revertant mosaicism in the donor skin and in the post-transplanted area. CEAs from clinically normal skin are a potentially well-tolerated treatment for recessive dystrophic epidermolysis bullosa.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2019.03.1155DOI Listing
October 2019

Fracture Prevention with Zoledronate in Older Women with Osteopenia.

N Engl J Med 2019 03;380(13):1287

Tokyo Kita Medical Center, Tokyo, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMc1900923DOI Listing
March 2019

Somatic recombination underlies frequent revertant mosaicism in loricrin keratoderma.

Life Sci Alliance 2019 02 4;2(1). Epub 2019 Feb 4.

Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Revertant mosaicism is a phenomenon in which pathogenic mutations are rescued by somatic events, representing a form of natural gene therapy. Here, we report on the first evidence for revertant mosaicism in loricrin keratoderma (LK), an autosomal dominant form of ichthyosis caused by mutations in on 1q21.3. We identified two unrelated LK families exhibiting dozens of previously unreported white spots, which increased in both number and size with age. Biopsies of these spots revealed that they had normal histology and that causal mutations were lost. Notably, dense single nucleotide polymorphism mapping identified independent copy-neutral loss-of-heterozygosity events on chromosome 1q extending from regions centromeric to to the telomere in all investigated spots, suggesting that somatic recombination represents a common reversion mechanism in LK. Furthermore, we demonstrated that reversion of mutations confers a growth advantage to cells in vitro, but the clinically limited size of revertant spots suggests the existence of mechanisms constraining revertant clone expansion. Nevertheless, the identification of revertant mosaicism in LK might pave the way for revertant therapy for this intractable disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.26508/lsa.201800284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362306PMC
February 2019

Pacritinib in Patients With Myelofibrosis.

JAMA Oncol 2018 12;4(12):1786-1787

Jyoban Hospital of Tokiwa Foundation, Fukushima, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2018.4830DOI Listing
December 2018

Compound heterozygous missense mutations p.Leu207Pro and p.Tyr544Cys in TGM1 cause a severe form of lamellar ichthyosis.

J Dermatol 2018 Dec 10;45(12):1463-1467. Epub 2018 Oct 10.

Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

TGM1 is the most common gene responsible for lamellar ichthyosis. Previous studies have suggested that patients with lamellar ichthyosis carrying two missense mutations in TGM1 show significantly less severe phenotypes than those with at least one truncating mutation in TGM1. Here, we report a patient with severe lamellar ichthyosis who was compound heterozygous for TGM1 missense mutations, including a novel one. A 22-year-old Japanese man presented with large, dark brown, plate-like scales on the extremities and small adherent scales on the face and trunk. His other clinical findings included ectropion, hair loss, hypohidrosis, hyperthermia in summer, palmoplantar keratoderma and constriction of the fingers. Dermoscopy revealed accentuated sulci cutis with numerous large keratotic plugs in the cristae cutis. Histologically, orthohyperkeratosis and mild acanthosis were noted. Electron microscopy showed reduced cornified envelope thickness and numerous lipid droplets in the stratum corneum. Mutation analysis revealed the patient to be compound heterozygous for missense mutations, c.620T>C (p.Leu207Pro) and c.1631A>G (p.Tyr544Cys), in TGM1. Furthermore, we showed that TGM1 enzymatic activity was largely absent in his epidermis. These findings led us to diagnose him as having lamellar ichthyosis. This study has two important notions. First, even two missense mutations in TGM1 can cause severe lamellar ichthyosis. Second, this is the first report of dermoscopic findings of lamellar ichthyosis, implicating the obstruction of sweat glands by keratotic plugs in the pathogenesis of hypohidrosis in the disease. In conclusion, this study provides further insights into genotype-phenotype correlations and pathogenesis in lamellar ichthyosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.14675DOI Listing
December 2018

Potential role of extracellular vesicle-mediated antigen presentation in Helicobacter pylori hypersensitivity during eradication therapy.

J Allergy Clin Immunol 2018 08 11;142(2):672-676.e12. Epub 2018 Apr 11.

Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2018.02.046DOI Listing
August 2018

Chromosomal inversions as a hidden disease-modifying factor for somatic recombination phenotypes.

JCI Insight 2018 03 22;3(6). Epub 2018 Mar 22.

Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Heterozygous chromosomal inversions suppress recombination. Therefore, they may potentially influence recombination-associated phenotypes of human diseases, but no studies have verified this hypothesis. Here, we describe a 35-year-old man with severe congenital ichthyosis. Mutation analysis revealed a heterozygous splice-site mutation, c.1374-2A>G (p.Ser458Argfs*120), in KRT10 on 17q21.2. This mutation was previously reported in patients with ichthyosis with confetti type I (IWC-I), a prominent skin disease characterized by the frequent occurrence of recombination-induced reversion of pathogenic mutations. Intriguingly, the number of revertant skin areas in this patient is considerably reduced compared with typical IWC-I cases. G-banded karyotyping revealed that the patient harbors a heterozygous nonpathogenic inversion, inv(17)(p13q12), whose long-arm breakpoint was subsequently refined to chromosomal positions (chr17: 36,544,407-36,639,830) via FISH. Collectively, the only chance of revertant mosaicism through somatic recombination appears to involve recombination between the KRT10 mutation and the inversion breakpoint. Indeed, in the examined revertant spot, the KRT10 mutation was diminished by somatic recombination starting from chromosomal positions (chr17: 36,915,505-37,060,285) on 17q12. This study provides the first evidence to our knowledge implicating chromosomal inversions as a potential modifier of clinical phenotypes. Furthermore, the reduced occurrence of revertant spots in the recombination-suppressed patient suggests that somatic recombination is the main mechanism of revertant mosaicism in IWC-I.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.97595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5926924PMC
March 2018

Establishment of integration-free induced pluripotent stem cells from human recessive dystrophic epidermolysis bullosa keratinocytes.

J Dermatol Sci 2018 Mar 1;89(3):263-271. Epub 2017 Dec 1.

Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Electronic address:

Background: Induced pluripotent stem cell (iPSC) technology enables patient-specific pluripotent stem cells to be derived from adult somatic cells without the use of an embryonic cell source. To date, recessive dystrophic epidermolysis bullosa (RDEB)-specific iPSCs have been generated from patients using integrating retroviral vectors. However, vector integration into the host genome can endanger the biosafety and differentiation propensities of iPSCs. Although various integration-free reprogramming systems have been reported, their utility in reprogramming somatic cells from patients remains largely undetermined.

Objective: Our study aims to establish safe iPSCs from keratinocytes of RDEB patients using non-integration vector.

Method: We optimized and infected non-integrating Sendai viral vectors to reprogram keratinocytes from healthy volunteers and RDEB patients.

Results: Sendai vector infection led to the reproducible generation of genomic modification-free iPSCs from these keratinocytes, which was proved by immunohistochemistry, reverse transcription polymerase chain reaction, methylation assay, teratoma assay and embryoid body formation assay. Furthermore, we confirmed that these iPSCs have the potential to differentiate into dermal fibroblasts and epidermal keratinocytes.

Conclusion: This is the first report to prove that the Sendai vector system facilitates the reliable reprogramming of patient keratinocytes into transgene-free iPSCs, providing another pluripotent platform for personalized diagnostic and therapeutic approaches to RDEB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jdermsci.2017.11.017DOI Listing
March 2018

Gentamicin-Induced Readthrough and Nonsense-Mediated mRNA Decay of SERPINB7 Nonsense Mutant Transcripts.

J Invest Dermatol 2018 04 26;138(4):836-843. Epub 2017 Oct 26.

Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Electronic address:

Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive skin disorder with a high, unmet medical need that is caused by mutations in SERPINB7. Almost all NPPK patients carry the founder nonsense mutation c.796C>T (p.Arg266Ter) in the last exon of SERPINB7. Here we sought to determine whether topical nonsense-suppression (readthrough) therapy using gentamicin is applicable to NPPK. First, we demonstrated that gentamicin enhanced readthrough activity in cells transfected with SERPINB7 cDNA carrying the mutation and promoted full-length SERPINB7 protein synthesis in NPPK keratinocytes. We next conducted an investigator-blinded, randomized, bilaterally controlled compassionate use study of topical gentamicin in which five NPPK patients with c.796C>T were enrolled. Patients' self-reported improvement of hyperkeratosis was significantly greater on the gentamicin side than the control side (P = 0.0349). In two patients, hyperkeratosis was improved on the gentamicin side, as determined by a blinded-investigator assessment. These results indicate the therapeutic potential of topical gentamicin for NPPK. Unexpectedly, we also found that mutant SERPINB7 mRNAs harboring r.796c>u were degraded by nonsense-mediated mRNA decay. Furthermore, the truncated SERPINB7 protein was degraded via a proteasome-mediated pathway. These findings provide important insights into the mRNA/protein quality-control system in humans, which could be a potential therapeutic target for genetic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2017.10.014DOI Listing
April 2018

Type XVII collagen coordinates proliferation in the interfollicular epidermis.

Elife 2017 07 11;6. Epub 2017 Jul 11.

Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Type XVII collagen (COL17) is a transmembrane protein located at the epidermal basement membrane zone. COL17 deficiency results in premature hair aging phenotypes and in junctional epidermolysis bullosa. Here, we show that COL17 plays a central role in regulating interfollicular epidermis (IFE) proliferation. Loss of COL17 leads to transient IFE hypertrophy in neonatal mice owing to aberrant Wnt signaling. The replenishment of COL17 in the neonatal epidermis of COL17-null mice reverses the proliferative IFE phenotype and the altered Wnt signaling. Physical aging abolishes membranous COL17 in IFE basal cells because of inactive atypical protein kinase C signaling and also induces epidermal hyperproliferation. The overexpression of human COL17 in aged mouse epidermis suppresses IFE hypertrophy. These findings demonstrate that COL17 governs IFE proliferation of neonatal and aged skin in distinct ways. Our study indicates that COL17 could be an important target of anti-aging strategies in the skin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.26635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505703PMC
July 2017

Filaggrin Mutation in Korean Patients with Atopic Dermatitis.

Yonsei Med J 2017 Mar;58(2):395-400

Department of Dermatology, Cutaneous Biology Research Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

Purpose: Atopic dermatitis (AD) is a chronic, relapsing eczematous inflammatory skin disease. Mutations in the filaggrin gene (FLG) are major predisposing factors for AD. Ethnic differences exist between Asian and European populations in the frequency and spectrum of FLG mutations. Moreover, a distinct set of FLG mutations has been reported in Asian populations. The aim of this study was to examine the spectrum of FLG mutations in Koreans with AD. We also investigated the association of FLG mutations and clinical features of AD and compared the Korean FLG landscape with that of other East Asian countries.

Materials And Methods: Seventy Korean patients with AD were enrolled in this study. Fourteen FLG mutations previously detected in Korean, Japanese, and Chinese patients were screened by genotyping.

Results: Four FLG null mutations (3321delA, K4022X, S3296X, and S2889X) were identified in eleven patients (15.7%). The most commonly detected mutations in Korean patients with AD were 3321delA (n=6, 9.1%) and K4022X (n=3, 4.5%). FLG mutations were significantly associated with elevated IgE (≥200 KIU/L and/or MAST-CLA >3+, p=0.005), palmar hyperlinearity (p<0.001), and a family history of allergic disease (p=0.021).

Conclusion: This study expanded our understanding of the landscape of FLG mutations in Koreans and revealed an association between FLG mutations and AD phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3349/ymj.2017.58.2.395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290020PMC
March 2017

Altered balance of epidermis-related chemokines in epidermolysis bullosa.

J Dermatol Sci 2017 Apr 5;86(1):37-45. Epub 2017 Jan 5.

Department of Dermatology, Hokkaido University Graduate School of Medicine, N15 W7, Kita-ku, Sapporo 060-8638, Japan. Electronic address:

Background: Epidermolysis bullosa (EB) is a congenital, refractory skin disease and there are no fundamental treatments. Recently, allogenic cell therapies are beginning to be applied as potential treatments, that are based on the concept that the allogenic cells can migrate into the skin and reconstitute the skin components. Although the mechanisms of cell migration into skin are not fully understood, chemokines are regarded as key factors in recruiting bone marrow-derived cells.

Objectives: Our study aims to elucidate the expression of chemokines in the EB patients.

Methods: We determined the expression of wound-healing related chemokines in the sera, keratinocytes, and skin tissues of EB patients and compared them to those of healthy volunteers by enzyme-linked immunosorbent assays, quantitative reverse transcription PCR, and immunofluorescence staining.

Results: The serum levels of CXCL12 and HMGB1 were found to be significantly elevated in the EB patients. Conversely, the serum levels of CCL21 were found to be lower in the EB patients than in healthy controls. In addition, the serum levels of CXCL12 tended to increase and the serum levels of CCL27 tended to decrease with an increase in the affected body surface areas. To detect the origin of the circulating chemokines, we performed immunofluorescence staining. CCL21, CCL27, HMGB1 and CXCL12 were stained more broadly in the EB patient tissues than those in the control tissues.

Conclusions: These results suggest that fluctuations in chemokine levels may contribute in a coordinated way to the wound-healing process and lend clues toward efficient cell therapies for EB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jdermsci.2016.12.021DOI Listing
April 2017

Identification of SERPINB7 mutations in Korean patients with Nagashima-type palmoplantar keratosis.

J Dermatol 2017 Jul 20;44(7):840-841. Epub 2016 Aug 20.

Department of Dermatology and Cutaneous Biology Research Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.13545DOI Listing
July 2017

Possible association of diazotrophs with marine zooplankton in the Pacific Ocean.

Microbiologyopen 2016 12 28;5(6):1016-1026. Epub 2016 Jun 28.

Atmosphere and Ocean Research Institute, The University of Tokyo, Kashiwa, Chiba, Japan.

Dinitrogen fixation, the biological reduction in N gas to ammonia contributes to the supply of new nitrogen in the surface ocean. To understand the diversity and abundance of potentially diazotrophic (N fixing) microorganisms associated with marine zooplankton, especially copepods, the nifH gene was studied using zooplankton samples collected in the Pacific Ocean. In total, 257 nifH sequences were recovered from 23 nifH-positive DNA extracts out of 90 copepod samples. The nifH genes derived from cyanobacteria related to Trichodesmium, α- and γ-subdivisions of proteobacteria, and anaerobic euryarchaeota related to Methanosaeta concilii were detected. Our results indicated that Pleuromamma, Pontella, and Euchaeta were the major copepod genera hosting dinitrogen fixers, though we found no species-specific association between copepods and dinitrogen fixers. Also, the digital PCR provided novel data on the number of copies of the nifH gene in individual copepods, which we report the range from 30 to 1666 copies per copepod. This study is the first systematic study of zooplankton-associated diazotrophs, covering a large area of the open ocean, which provide a clue to further study of a possible new hotspot of N fixation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mbo3.385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5221459PMC
December 2016

Revertant Mosaicism in Ichthyosis with Confetti Caused by a Frameshift Mutation in KRT1.

J Invest Dermatol 2016 10 7;136(10):2093-2095. Epub 2016 Jun 7.

Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2016.05.109DOI Listing
October 2016
-->