Publications by authors named "Takashi Hashimoto"

869 Publications

Natural and induced variations in transcriptional regulator genes result in low-nicotine phenotypes in tobacco.

Plant J 2022 Jul 26. Epub 2022 Jul 26.

RIKEN Center for Sustainable Resource Science, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.

In tobacco, the homologous ETHYLENE RESPONSE FACTOR (ERF) transcription factors ERF199 and ERF189 coordinate the transcription of multiple metabolic genes involved in nicotine biosynthesis. Natural alleles at the NIC1 and NIC2 loci greatly affect alkaloid accumulation and overlap with ERF199 and ERF189 in the tobacco genome, respectively. In this study, we identified several low-nicotine tobacco varieties lacking ERF199 or ERF189 from a tobacco germplasm collection. We characterized the sequence of these new nic1 and nic2 alleles, as well as the previously defined alleles nic1-1 and nic2-1. Moreover, we examined the influence of different nic alleles on alkaloid contents and expression levels of genes related to nicotine biosynthesis. We also demonstrated that the deletion of a distal genomic region attenuates ERF199 expression, resulting in a moderately negative effect on the alkaloid phenotype. Our study provides new insights into the regulation of nicotine biosynthesis and novel genetic resources to breed low-nicotine tobacco.
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http://dx.doi.org/10.1111/tpj.15923DOI Listing
July 2022

Role of ADAM10 and ADAM17 in the Regulation of Keratinocyte Adhesion in Pemphigus Vulgaris.

Front Immunol 2022 30;13:884248. Epub 2022 Jun 30.

Chair of Vegetative Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany.

The severe autoimmune blistering disease Pemphigus vulgaris (PV) is mainly caused by autoantibodies (IgG) against desmoglein (Dsg) 3 and Dsg1. The mechanisms leading to the development of blisters are not fully understood, but intracellular signaling seems to play an important role. Sheddases ADAM10 and ADAM17 are involved in the turnover of the desmosomal cadherin Dsg2 and ADAM10 has been shown to contribute to acantholysis in a murine pemphigus model. In the present study, we further examined the role of ADAM10 and ADAM17 both in keratinocyte adhesion and in the pathogenesis of PV. First, we found that inhibition of ADAM10 enhanced adhesion of primary human keratinocytes but not of immortalized keratinocytes. In dissociation assays, inhibition of ADAM10 shifted keratinocyte adhesion towards a hyperadhesive state. However, ADAM inhibition did neither modulate protein levels of Dsg1 and Dsg3 nor activation of EGFR at Y1068 and Y845. In primary human keratinocytes, inhibition of ADAM10, but not ADAM17, reduced loss of cell adhesion and fragmentation of Dsg1 and Dsg3 immunostaining in response to a PV1-IgG from a mucocutaneous PV patient. Similarly, inhibition of ADAM10 in dissociation assay decreased fragmentation of primary keratinocytes induced by a monoclonal antibody against Dsg3 and by PV-IgG from two other patients both suffering from mucosal PV. However, such protective effect was not observed in both cultured cells and disease models, when another mucocutaneous PV4-IgG containing more Dsg1 autoantibodies was used. Taken together, ADAM10 modulates both hyperadhesion and PV-IgG-induced loss of cell adhesion dependent on the autoantibody profile.
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http://dx.doi.org/10.3389/fimmu.2022.884248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279611PMC
July 2022

Case Report: Mucous Membrane Pemphigoid With IgG and IgA Anti-Laminin γ1 Antibodies and IgA Anti-Laminin α5 Antibodies.

Front Immunol 2022 1;13:903174. Epub 2022 Jun 1.

Dermatology Hospital of Jiangxi Province, Jiangxi Provincial Clinical Research Center for Skin Diseases, Candidate Branch of National Clinical Research Center for Skin Diseases, Dermatology Institute of Jiangxi Province, The Affiliated Dermatology Hospital of Nanchang University, Nanchang, China.

Mucous membrane pemphigoid (MMP) and anti-laminin (LM) γ1 pemphigoid, two subtypes of subepidermal autoimmune bullous diseases characterized by autoantibodies against epidermal basement membrane zone proteins, mainly show mucosal and skin lesions, respectively. The known autoantigens of MMP includes BP180, BP230, LM332, integrin α6β4 and type VII collagen, and anti-LMγ1 pemphigoid targets LMγ1. In this study, we present an unique MMP case with oral mucosal lesions, which showed positive IgA signals on basement membrane zone in indirect immunofluorescence using normal human skin and on dermal side in indirect immunofluorescence using salt-split skin, positive IgA autoantibodies against LMγ1 by immunoblotting of epidermal extracts, positive IgA autoantibodies against LMα5 by immunoblotting of LM521 recombinant protein (rLM521) and positive IgG autoantibodies against LMγ1 by immunoblotting of rLM111 and rLM521 at first visit (Day 0). After therapy, further serological analyses of serum samples collected at Day 30 and Day 50 indicated that IgA autoantibodies against LMγ1 were likely to be pathogenic. These results suggest that LMγ1 is another autoantigen of MMP, and our patient might be the first reported case of anti-LMγ1 MMP.
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http://dx.doi.org/10.3389/fimmu.2022.903174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9198329PMC
June 2022

Clinicopathological and mutational analysis of esophageal basaloid squamous cell carcinoma.

Virchows Arch 2022 May 31. Epub 2022 May 31.

Department of Human Pathology, Juntendo University, Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Esophageal basaloid squamous cell carcinoma (EBSCC) is a poorly differentiated variant of esophageal squamous cell carcinoma (ESCC). We aimed to investigate the clinicopathological and molecular biological characteristics of EBSCC and enrolled 58 patients with EBSCCs. Clinicopathological factors including age, sex, tumor size and location, gross tumor type (superficial, protrusive, ulcerative, and unclassifiable), lymphovascular invasion, infiltrative growth, intramural invasion, TNM stage, and dominant histological type were examined. EBSCCs were classified into four types (solid, cribri, microcystic, and tubular) according to the dominant histology. Next-generation sequencing (NGS) of a cancer hotspot panel was performed in 19 cases. NGS identified TP53 as the most frequently mutated gene, and copy number variation analysis revealed the most frequent loss of heterozygosity (LOH) at the ataxia telangiectasia mutated (ATM) and retinoblastoma 1 (RB1) loci. Target sequencing for TP53 was performed for the remaining 39 cases. We also performed LOH analysis for TP53, ATM, and RB1 and immunohistochemical staining for p53, ATM, and Rb in all cases. The rates of TP53 mutations and LOH and p53 aberrant expression were high (79.3%, 63.2%, and 72.4%, respectively); however, the frequencies were similar to those reported for ESCC. LOH rates of the RB1 and ATM loci were also high (55.3% and 67.2%, respectively). Overall survival rate was 66.5%, and recurrence-free survival rate was 55.0%. Only conventional clinicopathological factors had a prognostic impact in EBSCC; the microcystic type had the poorest prognosis. Our findings could be useful in developing novel treatment strategies for EBSCC.
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http://dx.doi.org/10.1007/s00428-022-03350-3DOI Listing
May 2022

Bullous pemphigoid and milia: prevalence and clinical laboratory findings in a Brazilian sample.

An Bras Dermatol 2022 Jul-Aug;97(4):435-442. Epub 2022 May 27.

Laboratory of Dermatology, University Hospital, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil; University Hospital, Dermatology Division, Department of Clinical Medicine, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil. Electronic address:

Background: Bullous pemphigoid (BP) associated with milia lesions has been increasingly reported, but its prevalence has not been reported in a Brazilian BP population yet.

Objectives: To describe the occurrence and clinical-laboratorial findings of BP-milia association in a southeastern Brazilian sample.

Methods: A descriptive study based on the medical charts of 102 BP patients was accomplished. Clinical and laboratory data of BP-milia patients were compiled. Total serum IgE measurements, immunoblot assays based on basement membrane zone antigens, and HLA-DQ alleles typing were performed.

Results: Milia was evident in 8 (7.8%) BP patients, five males, aged between 46 and 88 years. Increased total IgE levels were determined in 7 (87.5%) of the eight patients. In five of eight patients, immunoblotting showed IgG reactivity against the BP180-NC16a domain but not against collagen VII or laminin-332; it also revealed reactivity against the BP180 C-terminal domain or LAD-1, or both in four of them. The HLA-DQB1*03:01 and HLA-DQA1*05:05 alleles were identified in three of five BP-milia patients. Moreover, three of five cases presented the HLA-DQB1*06 allelic group.

Study Limitations: HLA determination was performed in five patients.

Conclusions: Milia formation in BP patients seems to be less uncommon than previously admitted. Laboratory data revealed increased IgE; autoantibodies against the BP180 C-terminal domain or LAD-1, or both; and the HLA-DQB1*06 allelic group, described for the BP-milia association. Careful determination of antibodies against basement membrane zone molecules and HLA characterization in different populations may provide further insights into this association.
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http://dx.doi.org/10.1016/j.abd.2021.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9263636PMC
July 2022

Linear morphea following Blaschko's line with epidermal downmodulation of friend leukemia integration 1 transcription factor.

Int J Dermatol 2022 May 11. Epub 2022 May 11.

Department of Dermatology, National Defense Medical College, Tokorozawa, Japan.

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http://dx.doi.org/10.1111/ijd.16260DOI Listing
May 2022

Radiographic Factors for Adjacent Vertebral Fractures and Cement Loosening Following Balloon Kyphoplasty in Patients with Osteoporotic Vertebral Fractures.

Spine Surg Relat Res 2022 11;6(2):159-166. Epub 2021 Oct 11.

Department of Orthopaedic Surgery, JA Hiroshima General Hospital, Hatsukaichi, Japan.

Introduction: Balloon kyphoplasty (BKP) is a minimally invasive surgical approach for the treatment of osteoporotic vertebral fractures (OVF). Some risks have been reported after treatment with BKP; therefore, it is necessary to determine when BKP does not work. Thus, in this study, we aim to clarify the radiographic predictors of secondary vertebral fractures and cement loosening after BKP for OVF.

Methods: This study enrolled patients with single-level OVF at the thoracolumbar junction (T11-L2) who underwent BKP for the first time between January 2011 and March 2014. The clinical outcomes were evaluated using the visual analog scale (VAS) and a modified Oswestry Disability Index (ODI) at 1 week and 1, 3, 6, and 12 months after surgery. Radiographic assessments were performed preoperatively and within 1 year after BKP using plain radiography and computed tomography.

Results: The 85 patients who met the inclusion criteria underwent BKP. The average age of participants (21 men, 64 women) was 77.8 years (range, 57-92 years). Postoperative VAS and ODI scores were all significantly better than preoperative scores. Polymethyl methacrylate (PMMA)-cement leakage was observed in 18 patients (21.2%) but was asymptomatic in all cases. Secondary vertebral fractures were detected in 20 patients (23.5%), including adjacent levels in 15 patients (17.6%) and non-adjacent levels in 5 patients (5.9%). Rostral bridging osteophyte formation was found to be significantly associated with the occurrence of adjacent vertebral fractures (odds ratio 12.746; =0.010). PMMA-cement loosening was observed in three patients (3.5%). A high prevalence (100%) of bridging osteophytes, vacuum clefts, and spinous process fractures was observed in patients with PMMA-cement loosening. PMMA-cement loosening was found in 3 out of 10 patients with all three of these factors.

Conclusions: Rostral bridging osteophyte formation was determined to be a risk factor for both adjacent vertebral fractures and PMMA-cement loosening.

Level of Evidence: 3.
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http://dx.doi.org/10.22603/ssrr.2021-0112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8995113PMC
October 2021

Prurigo Nodularis in a Patient with Anaplastic Large Cell Lymphoma: A Potential Role for M2-Macrophages in Its Pathogenesis.

Ann Dermatol 2022 Apr 24;34(2):149-151. Epub 2022 Mar 24.

Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

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http://dx.doi.org/10.5021/ad.2022.34.2.149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8989897PMC
April 2022

Suppression of Cortical Microtubule Reorientation and Stimulation of Cell Elongation in Arabidopsis Hypocotyls under Microgravity Conditions in Space.

Plants (Basel) 2022 Feb 8;11(3). Epub 2022 Feb 8.

Department of Biology, Graduate School of Science, Osaka City University, Osaka 558-8585, Japan.

How microgravity in space influences plant cell growth is an important issue for plant cell biology as well as space biology. We investigated the role of cortical microtubules in the stimulation of elongation growth in Arabidopsis () hypocotyls under microgravity conditions with the Resist Tubule space experiment. The epidermal cells in the lower half of the hypocotyls of wild-type Columbia were longer in microgravity than at on-orbit 1 , which precipitated an increase in the entire hypocotyl length. In the apical region, cortical microtubules adjacent to the outer tangential wall were predominantly transverse to the long axis of the cell, whereas longitudinal microtubules were predominant in the basal region. In the 9th to 12th epidermal cells (1 to 3 mm) from the tip, where the modification of microtubule orientation from transverse to longitudinal directions (reorientation) occurred, cells with transverse microtubules increased, whereas those with longitudinal microtubules decreased in microgravity, and the average angle with respect to the transverse cell axis decreased, indicating that the reorientation was suppressed in microgravity. The expression of tubulin genes was suppressed in microgravity. These results suggest that under microgravity conditions, the expression of genes related to microtubule formation was downregulated, which may cause the suppression of microtubule reorientation from transverse to longitudinal directions, thereby stimulating cell elongation in Arabidopsis hypocotyls.
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http://dx.doi.org/10.3390/plants11030465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8837939PMC
February 2022

Case Report: Variety of Target Antigens During 1 Year Follow-Up of a Patient Initially Diagnosed With Bullous Pemphigoid.

Front Immunol 2021 13;12:825226. Epub 2022 Jan 13.

Dermatology Hospital of Jiangxi Province, Jiangxi Provincial Clinical Research Center for Skin Diseases, Candidate Branch of National Clinical Research Center for Skin Diseases, Dermatology Institute of Jiangxi Province, The Affiliated Dermatology Hospital of Nanchang University, Nanchang, China.

Autoimmune bullous diseases (AIBDs), presenting cutaneous and/or mucosal bullous lesions, are classified into pemphigus and pemphigoid diseases. A longtime observation for complicated AIBD cases is rarely reported. In this study, serum samples of one AIBD patient were collected at seven different time points during the disease course including a relapse, which were examined by our conventional and newly developed methods for the detection of autoantibodies. Interestingly, we found changes of both the presence and the titers of various autoantibodies in accordance with the changes of clinical features during the whole disease course, which indicated that the patient started as bullous pemphigoid and relapsed as concurrence of bullous pemphigoid and mucosal-dominant-type pemphigus vulgaris.
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http://dx.doi.org/10.3389/fimmu.2021.825226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8791857PMC
March 2022

Erosive pustular dermatosis of the scalp-like eruption from panitumumab.

Australas J Dermatol 2022 05 24;63(2):271-272. Epub 2022 Jan 24.

Department of Dermatology, National Defense Medical College, Tokorozawa, Japan.

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http://dx.doi.org/10.1111/ajd.13791DOI Listing
May 2022

Hyperosmotic stress-induced microtubule disassembly in Chlamydomonas reinhardtii.

BMC Plant Biol 2022 Jan 22;22(1):46. Epub 2022 Jan 22.

Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma, Nara, 630-0192, Japan.

Background: Land plants respond to drought and salinity by employing multitude of sophisticated mechanisms with physiological and developmental consequences. Abscisic acid-mediated signaling pathways have evolved as land plant ancestors explored their habitats toward terrestrial dry area, and now play major roles in hyperosmotic stress responses in flowering plants. Green algae living in fresh water habitat do not possess abscisic acid signaling pathways but need to cope with increasing salt concentrations or high osmolarity when challenged with adverse aquatic environment. Hyperosmotic stress responses in green algae are largely unexplored.

Results: In this study, we characterized hyperosmotic stress-induced cytoskeletal responses in Chlamydomonas reinhardtii, a fresh water green algae. The Chlamydomonas PROPYZAMIDE-HYPERSENSITEVE 1 (PHS1) tubulin kinase quickly and transiently phosphorylated a large proportion of cellular α-tubulin at Thr349 in G1 phase and during mitosis, which resulted in transient disassembly of microtubules, when challenged with > 0.2 M sorbitol or > 0.1 M NaCl. By using phs1 loss-of-function algal mutant cells, we demonstrated that transient microtubule destabilization by sorbitol did not affect cell growth in G1 phase but delayed mitotic cell cycle progression. Genome sequence analyses indicate that PHS1 genes evolved in ancestors of the Chlorophyta. Interestingly, PHS1 genes are present in all sequenced genomes of freshwater Chlorophyta green algae (including Chlamydomonas) but are absent in some marine algae of this phylum.

Conclusion: PHS1-mediated tubulin phosphorylation was found to be partly responsible for the efficient stress-responsive mitotic delay in Chlamydomonas cells. Ancient hyperosmotic stress-triggered cytoskeletal remodeling responses thus emerged when the PHS1 tubulin kinase gene evolved in freshwater green algae.
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http://dx.doi.org/10.1186/s12870-022-03439-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8783414PMC
January 2022

Overall Impairment of Quality of Life in Japanese Patients with Hidradenitis Suppurativa: Comparison with National Standard.

Acta Derm Venereol 2022 Jan 18;102:adv00632. Epub 2022 Jan 18.

Division of Cutaneous Science, Department of Dermatology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan.

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http://dx.doi.org/10.2340/actadv.v101.1013DOI Listing
January 2022

Effect of enterally administered sleep-promoting medication on the intravenous sedative dose and its safety and cost profile in mechanically ventilated patients: A retrospective cohort study.

PLoS One 2021 20;16(12):e0261305. Epub 2021 Dec 20.

Department of Emergency and Critical Care Medicine, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan.

Background: The clinical effect of enteral administration of sleep-promoting medication (SPM) in mechanically ventilated patients remains unclear. This study aimed to investigate the relationship between enteral SPM administration and the intravenous sedative dose and examine the safety and cost of enteral SPM administration.

Methods: This single-center retrospective cohort study was conducted in a Japanese tertiary hospital intensive care unit (ICU). The exposure was enteral SPM administration during mechanical ventilation. The outcome was the average daily propofol dose per body weight administered as a continuous sedative during mechanical ventilation. Patients were divided into three groups based on the timing of SPM administration at ICU admission: "administration within 48 hours (early administration [EA])," "administration after 48 hours (late administration [LA])," and "no administration (NA)." We used multiple linear regression models.

Results: Of 123 included patients, 37, 50, and 36 patients were assigned to the EA, LA, and NA groups, respectively. The average daily propofol dose per body weight was significantly lower in the EA group than in the LA and NA groups (β -5.13 [95% confidence interval (CI) -8.93 to -1.33] and β -4.51 [95% CI -8.59 to -0.43], respectively). Regarding safety, enteral SPM administration did not increase adverse events, including self-extubation. The total cost of neuroactive drugs tended to be lower in the EA group than in the LA and NA groups.

Conclusions: Early enteral SPM administration reduced the average daily propofol dose per body weight without increasing adverse events.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0261305PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8687529PMC
January 2022

A gene-centric approach to biomarker discovery identifies transglutaminase 1 as an epidermal autoantigen.

Proc Natl Acad Sci U S A 2021 12;118(51)

Center for Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm 171 76, Sweden.

Autoantigen discovery is a critical challenge for the understanding and diagnosis of autoimmune diseases. While autoantibody markers in current clinical use have been identified through studies focused on individual disorders, we postulated that a reverse approach starting with a putative autoantigen to explore multiple disorders might hold promise. We here targeted the epidermal protein transglutaminase 1 (TGM1) as a member of a protein family prone to autoimmune attack. By screening sera from patients with various acquired skin disorders, we identified seropositive subjects with the blistering mucocutaneous disease paraneoplastic pemphigus. Validation in further subjects confirmed TGM1 autoantibodies as a 55% sensitive and 100% specific marker for paraneoplastic pemphigus. This gene-centric approach leverages the wealth of data available for human genes and may prove generally applicable for biomarker discovery in autoimmune diseases.
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http://dx.doi.org/10.1073/pnas.2100687118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8713791PMC
December 2021

Subunit-Specific Reactivity of Autoantibodies Against Laminin-332 Reveals Direct Inflammatory Mechanisms on Keratinocytes.

Front Immunol 2021 25;12:775412. Epub 2021 Nov 25.

Division of Dermatology, Rush University Medical Center, Chicago, IL, United States.

Laminin-332 pemphigoid is a rare and severe autoimmune blistering disease, caused by IgG autoantibodies targeting laminin-332 in the dermal-epidermal basement zone. Laminin-332 pemphigoid is characterized by variable inflammatory infiltrate and the predominance of non-complement-fixing antibodies. Given these findings, we hypothesized that IgG autoantibodies to laminin-332 directly resulted in keratinocyte expression of inflammatory factors. We performed RNA-seq on primary human keratinocytes treated with IgG from patients with laminin-332 pemphigoid. Genes for numerous cytokines and chemokines were upregulated, including CSF2, CSF3, CXCL1, CXCL5, CXCL3, CXCL8, CXCL10, CXCL1, IL6, IL7, IL15, IL23, IL32, IL37, TGFB2 as well as metalloproteases. Considering the pro-inflammatory and proteolytic effect of autoantibodies from patients with laminin-332 pemphigoid identified in our initial experiment, we next questioned whether the reactivity against specific laminin subunits dictates the inflammatory and proteolytic keratinocyte response. Then, we treated keratinocytes with IgG from a separate cohort of patients with reactivity against individual subunits of laminin-332. We identified upregulation of IL-1α, IL-6, IL-8, CXCL1, MMP9, TSLP, and GM-CSF at the protein level, most notably in keratinocytes treated with IgG from laminin β3-reactive patients. We for the first time demonstrated a pro-inflammatory response, similar to that described in keratinocytes treated with IgG autoantibodies from patients with bullous pemphigoid, providing novel insight into the pathogenesis of laminin-332 pemphigoid and laminin-332 biology.
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http://dx.doi.org/10.3389/fimmu.2021.775412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8655097PMC
February 2022

Comparison of Two Diagnostic Assays for Anti-Laminin 332 Mucous Membrane Pemphigoid.

Front Immunol 2021 25;12:773720. Epub 2021 Nov 25.

Center for Blistering Diseases, University of Groningen, Groningen, Netherlands.

Anti-laminin 332 mucous membrane pemphigoid (MMP) is an autoimmune blistering disease characterized by predominant mucosal lesions and autoantibodies against laminin 332. The exact diagnosis of anti-laminin 332 MMP is important since nearly 30% of patients develop solid cancers. This study compared two independently developed diagnostic indirect immunofluorescence (IF) tests based on recombinant laminin 332 expressed in HEK239 cells (biochip mosaic assay) and the migration trails of cultured keratinocytes rich in laminin 332 (footprint assay). The sera of 54 anti-laminin 332 MMP, 35 non-anti-laminin 332 MMP, and 30 pemphigus vulgaris patients as well as 20 healthy blood donors were analyzed blindly and independently. Fifty-two of 54 and 54/54 anti-laminin 332 MMP sera were positive in the biochip mosaic and the footprint assay, respectively. In the 35 non-anti-laminin 332 MMP sera, 3 were positive in both tests and 4 others showed weak reactivity in the footprint assay. In conclusion, both assays are easy to perform, highly sensitive, and specific, which will further facilitate the diagnosis of anti-laminin 332 MMP.
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http://dx.doi.org/10.3389/fimmu.2021.773720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657402PMC
February 2022

The Second Study of Clinical and Immunological Findings in Anti-laminin 332-Type Mucous Membrane Pemphigoid Examined at Kurume University-Diagnosis Criteria Suggested by Summary of 133 Cases.

Front Immunol 2021 26;12:771766. Epub 2021 Nov 26.

Department of Dermatology, Kurume University School of Medicine, and Kurume University Institute of Cutaneous Cell Biology, Kurume, Japan.

Background: Recently, we published an article retrospectively summarizing the results in 55 anti-laminin 332 (LM332)-type mucous membrane pemphigoid (MMP) cases examined at Kurume University, which were diagnosed by strict inclusion criteria, including positive reactivity in direct immunofluorescence and absence of antibodies to non-LM332 autoantigens. However, indirect immunofluorescence using 1M-NaCl-split normal human skin (ssIIF) is also valuable for diagnosis of anti-LM332-type MMP.

Methods: In this second study, we selected 133 anti-LM332-type MMP cases, which were diagnosed by our different inclusion criteria: (i) immunoglobulin G (IgG) deposition to basement membrane zone (BMZ) by direct immunofluorescence or IgG reactivity with dermal side of split skin by ssIIF, (ii) positivity for at least one of the three subunits of LM332 by immunoblotting of purified human LM332, and (iii) the presence of mucosal lesions. Clinical, histopathological, and immunological findings were summarized and analyzed statistically. Although these cases included the 55 previous cases, the more detailed study for larger scale of patients was conducted for further characterization.

Results: Clinically, among the 133 patients, 89% and 43% patients had oral and ocular mucosal lesions, respectively, 71% had cutaneous lesions, and 17% had associated malignancies. Histopathologically, 93% patients showed subepidermal blisters. The sensitivities of ssIIF and direct immunofluorescence are similar but are significantly higher than indirect immunofluorescence using non-split human skin (both p < 0.001). In immunoblotting of purified LM332, patient IgG antibodies most frequently reacted with LMγ2 subunit (58%), followed by LMα3 (49%) and LMβ3 (36%). Thirty-four percent patients recognized additional non-LM332 autoantigens. Statistical analysis revealed that autoantibodies against non-LM332 autoantigens might stimulate the production of anti-LMγ2 antibodies.

Conclusions: This retrospective study further characterized in more detail the clinical and immunological features of 133 cases of anti-LM332-type MMP, in which the new diagnostic criteria without positive direct immunofluorescence reactivity were useful for the diagnosis. Higher frequency with anti-LMγ2 antibodies suggested more significant pathogenic role of this subunit. Additional autoantibodies to non-LM332 autoantigens detected in one-third of the patients may contribute to complexity in anti-LM332-type MMP, including the induction of anti-LMγ2 antibodies.
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http://dx.doi.org/10.3389/fimmu.2021.771766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8660687PMC
February 2022

Sudden endograft collapse due to type B aortic dissection after open conversion of endovascular aortic repair.

Interact Cardiovasc Thorac Surg 2022 02;34(3):507-509

Department of Cardiovascular Surgery, Keio University, Shinjuku, Tokyo, Japan.

A 58-year-old man was admitted for sudden numbness of the right leg and abdominal pain 6 months following late open conversion for endotension after endovascular aortic repair. Computed tomography demonstrated residual endograft collapse due to Stanford type B dissection. Emergent right axillobifemoral bypass was performed to perfuse the lower extremities. We performed subsequent total arch replacement with secondary thoracic endovascular aortic repair.
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http://dx.doi.org/10.1093/icvts/ivab333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8860422PMC
February 2022

Prediction of Membrane Failure in a Water Purification Plant Using Nonhomogeneous Poisson Process Models.

Membranes (Basel) 2021 Oct 20;11(11). Epub 2021 Oct 20.

Department of Urban Engineering, the University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-8656, Japan.

The prediction of membrane failure in full-scale water purification plants is an important but difficult task. Although previous studies employed accelerated laboratory-scale tests of membrane failure, it is not possible to reproduce the complex operational conditions of full-scale plants. Therefore, we aimed to develop prediction models of membrane failure using actual membrane failure data. Because membrane filtration systems are repairable systems, nonhomogeneous Poisson process (NHPP) models, i.e., power law and log-linear models, were employed; the model parameters were estimated using the membrane failure data from a full-scale plant operated for 13 years. Both models were able to predict cumulative failures for forthcoming years; nonetheless, the power law model showed higher stability and narrower confidence intervals than the log-linear model. By integrating two membrane replacement criteria, namely deterioration of filtrate water quality and reduction of membrane permeability, it was possible to predict the time to replace all the membranes on a water purification plant. Finally, the NHPP models coupled with a nonparametric bootstrap method provided a method to select membrane modules for earlier replacement than others. Although the criteria for membrane replacement may vary among membrane filtration plants, the NHPP models presented in this study could be applied to any other plant with membrane failure data.
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http://dx.doi.org/10.3390/membranes11110800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624650PMC
October 2021

A Case of Systemic Lupus Erythematosus with Cutaneous Leukocytoclastic Vasculitis Mimicking Bullous SLE.

Case Rep Dermatol 2021 Sep-Dec;13(3):464-469. Epub 2021 Sep 20.

Department of Dermatology, Nara Medical University School of Medicine, Kashihara, Japan.

Rarely, patients with systemic lupus erythematosus (SLE) develop bullous eruptions, a disease called bullous SLE in a narrow sense that has autoantibodies against type VII collagen. We describe an unusual case in which a patient with SLE developed extensive bullae on her lower extremities. Histologically, the bullous lesions were suggestive of leukocytoclastic vasculitis with deposition of C3 within blood vessel walls. Immunoblot analyses and enzyme-linked immunosorbent assays were negative for anti-type VII collagen antibodies. We initially considered bullous SLE, but eventually made a diagnosis of secondary vasculitis in SLE. The oral prednisolone dose was increased, and the vesiculobullous lesions resolved. The clinical presentations of cutaneous vasculitis in SLE include palpable purpura, petechiae, papulonodular lesions, and livedo reticularis. Bullous lesions seem to be uncommon. Physicians need to be aware that extensive bullae can occur as a result of secondary vasculitis in SLE, even if the patient does not exhibit high disease activity.
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http://dx.doi.org/10.1159/000519022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525288PMC
September 2021

Outcomes of esophagectomy for patients with esophageal squamous cell carcinoma accompanied by recurrent laryngeal nerve palsy at diagnosis.

Esophagus 2022 04 27;19(2):233-239. Epub 2021 Oct 27.

Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan.

Background: Hoarseness is one of the classical symptoms in patients with locally advanced thoracic esophageal squamous cell carcinoma (ESCC), and it results from recurrent laryngeal nerve palsy, which is caused by nodal metastasis along the recurrent laryngeal nerve or by main tumors. We reviewed the short-term and long-term results of esophagectomy for patients with locally advanced ESCC and hoarseness at diagnosis.

Patients: Patients who initially presented with hoarseness from recurrent laryngeal nerve palsy between 2009 and 2018 and underwent esophagectomy for thoracic ESCC were eligible for this study. Pharyngolaryngectomy or cervical ESCC were exclusionary.

Results: A total of 15 patients were eligible, and 14 underwent resection of the recurrent laryngeal nerves. The remaining patient had nerve-sparing surgery. Nine patients (60%) had post-operative complications ≥ Clavien-Dindo class II and, pulmonary complications were most common. Two patients (13%) died in the hospital. The 5-year overall survival rate for all patients was 16%. Age (≤ 65 years), cT1/T2 tumor, and remarkably good response to neoadjuvant treatment were likely related to longer survival; however, these relationships were not statistically significant.

Conclusions: Esophagectomy for ESCC patients who are diagnosed with recurrent laryngeal nerve paralysis at initial presentation could be a treatment option if the patient is relatively young, has a cT1/T2 tumor, or shows a remarkably good response to neoadjuvant treatment. However, clinicians should be aware of the possibility of postoperative pulmonary complications, which were frequently observed with the procedure.
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http://dx.doi.org/10.1007/s10388-021-00890-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8921150PMC
April 2022

Clinical outcome and B-cell kinetics in intercellular immunoglobulin A dermatosis treated with rituximab.

J Dermatol 2022 Jan 21;49(1):e22-e23. Epub 2021 Oct 21.

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

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http://dx.doi.org/10.1111/1346-8138.16194DOI Listing
January 2022

CRISPR/Cas9-mediated disruption of the PYRROLIDINE KETIDE SYNTHASE gene reduces the accumulation of tropane alkaloids in Atropa belladonna hairy roots.

Biosci Biotechnol Biochem 2021 Nov;85(12):2404-2409

RIKEN Center for Sustainable Resource Science, Tsurumi-ku, Yokohama, Kanagawa, Japan.

Tropane alkaloids, including clinically important hyoscyamine and scopolamine, are produced in the roots of medicinal plant species, such as Atropa belladonna, from the Solanaceae family. Recent molecular and genomic approaches have advanced our understanding of the metabolic enzymes involved in tropane alkaloid biosynthesis. A noncanonical type III polyketide synthase, pyrrolidine ketide synthase (PYKS) catalyzes a two-step decarboxylative reaction, which involves imine-ketide condensation indispensable to tropane skeleton construction. In this study, we generated pyks mutant A. belladonna hairy roots via CRISPR/Cas9-mediated genome editing and analyzed the metabolic consequences of the loss of PYKS activity on tropane alkaloids, providing insights into a crucial role of the scaffold-forming reaction in the biosynthetic pathway.
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http://dx.doi.org/10.1093/bbb/zbab165DOI Listing
November 2021

Dipeptidyl peptidase-4 inhibitor-related bullous pemphigoid showing positive autoantibody responses to multiple epitopes.

J Dermatol Sci 2021 Sep 20;103(3):190-192. Epub 2021 Aug 20.

Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.

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http://dx.doi.org/10.1016/j.jdermsci.2021.08.004DOI Listing
September 2021

A Case of Possible Concurrence of Dermatitis Herpetiformis and Linear Immunoglobulin A / Immunoglobulin G Bullous Dermatosis.

Acta Dermatovenerol Croat 2021 Jul;29(2):116-117

Satoko Minakawa, MD, PhD, Department of Dermatology Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan;

Dear Editor, Linear immunoglobulin (Ig) A bullous dermatosis (LABD), one subtype of subepidermal autoimmune bullous skin diseases (AIBDs), is characterized by linear deposit of only IgA along the basement membrane zone (BMZ) on direct immunofluorescence (DIF) (1,2). Patients showing linear deposits of both IgA and IgG are diagnosed with linear IgA/IgG bullous dermatosis (LAGBD) (3,4). Dermatitis herpetiformis (DH) is another type of subepidermal AIBD characterized by clinically pruritic erythematous skin lesions with vesicles on the elbows, knees, and buttocks with granular IgA deposits of IgA by DIF (5). In this study, we report a Japanese case of a patient who showed possible concurrence of DH and LAGBD based on clinical, histological, and immunological findings. A 72-year-old Japanese man who had a past history of dyslipidemia and resected lung cancer but was not taking any medicines, presented with a one-year history of blistering skin lesions. Physical examination revealed erythemas and peripherally arranged vesicles and erosions on the bilateral elbows, knees, and the buttock (Figure 1, a-c). Mucous membranes were not involved. The results of all laboratory tests were within normal ranges, except for increased serum IgA level 351 mg/dL (normal ranges; 46-260 mg/dL). Skin biopsy histopathologically showed subepidermal blisters infiltrated with neutrophils and eosinophils (Figure 1, d). DIF showed deposits of IgG, IgA, and complement component 3 along the BMZ mainly in granular but partially in a linear pattern (Figure 1, e-g). Circulating IgG (Figure 1, h) and IgA (Figure 1, i) autoantibodies were not detected by indirect immunofluorescence (IIF) of normal skin, however, circulating IgA (Figure 1, j) but not IgG (Figure 1, k) antibodies were bound to both the epidermal and dermal sides by IIF of 1M NaCl-split normal skin. Commercially available enzyme-linked immunosorbent assays (ELISAs) for BP180 NC16a domain, BP230, and type Vll collagen (MBL, Nagoya, Japan), showed negative results for both IgG and IgA antibodies. IgG in-house ELISA for full length BP180 was also negative. IgG and IgA immunoblotting analyses of different antigen sources, including normal human epidermal and dermal extracts, recombinant proteins of NC16a, and C-terminal domains of BP180 region, BP230, purified laminin 332, and concentrated culture supernatant of HaCaT cells for LAD-1, were all negative. IgA ELISAs of tissue- and epidermal-transglutaminases were negative (1.92 AU/mL and 20.98 AU/mL, respectively; normal range <22.0 AU/mL). The patient was successfully treated with only topical corticosteroids with occasional mild local relapses. Japanese DH is different from European DH in some respects, i.e., DH is very rare in Japan due to genetic/HLA difference, absence of celiac disease, and frequent fibrillar IgA deposition in DIF. Therefore, we believe that this case is interesting as a rare Japanese DH case with complicated conditions. The clinical and immunochemical characteristics in the present case were compatible for both DH and LAGBD. Clinical features of vesicles on erythemas on the knees and buttock suggested DH, while histopathological features were compatible with LAGBD but also with DH, DIF results suggested both LAGBD and DH, and the results of IIF of 1M NaCl-split skin suggested LAGBD. All biochemical studies for autoantigens were negative, which suggested DH. However, autoantigens are not clearly detected in many LAGBD cases, either. IgA anti-epidermal transglutaminase antibody, a DH marker, was negative, but the titer was relatively high but within normal range. Therefore, we considered that this case might have developed DH and LAGBD concurrently. However, there may be two other possibilities: [1] this case was DH and non-pathogenic circulating autoantibodies were secondary production, and [2] LAGBD cases may sometimes show granular-linear BMZ deposition of IgG and IgA. Future studies on similar cases are needed to clarify our speculations.
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July 2021

Symmetrical Skin Lesions on the Gluteal Region in a Patient with Anti-Laminin-332 Mucous Membrane Pemphigoid.

Acta Dermatovenerol Croat 2021 Jul;29(2):105-107

Nobuki Maki; MD, Department of Dermatology Akita National Hospital, 84-40 Idonosawa, Iwakiuchimichikawa, Yurihonjo, Akita 018-1393 Japan;

Mucous membrane pemphigoid (MMP), previously called cicatricial pemphigoid, is a rare subepidermal immunobullous disorder that primarily affects the mucous membranes (1,2). MMP is divided into two major subtypes, anti-BP180-type MMP and anti-laminin-332 (previously called laminin 5 or epiligrin) MMP. Anti-laminin-332 MMP is known to be associated with malignant tumors (3), which may cause overexpression of autoantibodies and induce autoimmunity to laminin-332 (4). MMP primarily affects the mucous membranes, and widespread skin lesions are rare. In MMP, circumscribed skin lesions have been previously reported as occurring on the head, neck, and upper trunk (5). We report a case of anti-laminin-332 MMP presenting with symmetrical skin lesions characteristic of MMP on the weight-bearing areas of the gluteal region. A 66-year-old Japanese man presented with a month-long history of multiple erosions and blisters on the mucous membranes and skin, with conjunctival hyperemia, nasal obstruction, oral pain, and hoarseness of voice. Three days before the first visit, he was diagnosed with gastric cancer with liver metastasis by gastrointestinal endoscopy and abdominal ultrasound examination for tarry stool. Physical examination demonstrated erosions and tense bullae on the conjunctivae, tongue, and lips (Figure 1, a,b), as well as erosive erythematous skin lesions on the nape, right index finger, both legs, and symmetric lesions on the gluteal region (Figure 1, c). His body weight was 86 kg. Laboratory examinations showed slight liver dysfunction and elevation of C-reactive protein levels. Histopathologic examination of the skin lesions demonstrated subepidermal blisters with lymphocytic and eosinophilic infiltrates (Figure 1, d,e). Direct immunofluorescence (IF) revealed linear deposits of IgG and C3, but not IgA, along the basement membrane zone (BMZ) (Figure 1, f,g). An IgG subclass study showed IgG1 and IgG4 deposits. Indirect IF on normal human skin revealed weak positivity for IgA anti-keratinocyte cell surface antibodies and IgG anti-BMZ antibodies, which were bound to the dermal side of 1 mol/L NaCl-split skin (Figure 1, h). IgG immunoblot analyses of both normal human epidermal and dermal extracts showed negative results (including BP230, BP180, 290 kDa type VII collagen, and 200 kDa laminin-γ1). Immunoprecipitation using radio-labeled cultured keratinocyte lysate demonstrated positive reactivity with laminin-332 (Figure 1, i). We established the diagnosis of anti-laminin-332 MMP. We started treatment with oral minocycline (200 mg/day) and niacinamide (900 mg/day) with topical corticosteroids without any effect after 2 weeks of therapy. Administration of oral prednisolone (40 mg/day) with topical corticosteroids and alprostadil ointment on the skin lesions, as well as beclometasone dipropionate powder on the oral lesions resulted in significant improvement of mucocutaneous lesions within 10 days. Although the gastric cancer and liver metastasis initially responded to chemotherapy with fluorouracil and cisplatin, the patient succumbed to multiple organ failure 9 months after the initial visit. Anti-laminin-332 antibodies were originally detected by immunoprecipitation, as in our case. Immunoblotting of purified human laminin-332 have been subsequently developed, which detects the 165/145 kDa α3, 140 kDa β3, and 105 kDa γ2 subunits of laminin-332 in various patterns (6). Today, the ELISA system uses laminin-332 preparations as adjunct diagnostic tools in MMP (7). Occasionally, a wide spectrum of autoantibodies is detected in MMP, for example, MMP with IgG antibodies to both BP180 and laminin-332, which were considered to be developed via epitope spreading. Detection of circulating IgA autoantibodies against the skin have also been reported in MMP (8). However, the pathogenic significance and mechanisms of coexistence of IgG anti-laminin-332 antibodies and IgA anti-keratinocyte cell surface antibodies found in our case are currently unknown. It is generally considered that IgG1 antibodies activate complements and are pathogenic in MMP, while IgG4 antibodies behave as blocking antibodies and are protective. In our case, direct IF revealed IgG1 and IgG4 deposits; the same was reported in a previous case report (9). The pathogenic roles of autoantibodies with different IgG subclasses need to be analyzed in further studies. Conjunctival mucosal lesions in MMP may occur by rubbing of the eyes due to irritation. Blinking subjects the conjunctivae to repeated friction. Vocal cords vibrate during breathing and speaking. The tongue moves while eating and drinking; in particular, the tip of the tongue gets into frequent contact with the inner sides of the incisor teeth. In the present case, characteristic symmetrical skin lesions were seen on the weight-bearing areas of the gluteal region on bony prominences which receive mechanical stresses in the sitting position. These skin lesions were subjected to repeated stretch and pressure stresses, but no ischemic changes were observed, such as decubitus ulcers. Therefore, the symmetrical skin lesions in the gluteal region as well as the ocular and oral mucosal lesions seen in our patient might have resulted from the same mechanism of pathogenesis. We reported a case of anti-laminin-332 MMP presenting with symmetrical gluteal skin lesions, probably induced by mechanical stress. MMP primarily affects the mucous membranes, and widespread skin lesions are rare. Our case emphasizes that clinicians need to specifically check for the presence of skin lesions on weight-bearing parts of the body during examination of patients with suspected MMP.
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July 2021
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