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Competing Interests: Conflicts of interest None disclosed.

Background: Atopic dermatitis (AD) is a common chronic eczematous skin disease with severe pruritus. Several new therapeutic agents for AD such as dupilumab, an anti-IL-4Rα antibody, have been developed in recent years. We need to predict which agent is the best choice for each patient, but this remains difficult., Objective: Our aim was to examine clinical background factors and baseline biomarkers that could predict the achievement of improved clinical outcomes in patients with AD treated with dupilumab., Methods: A multicenter, prospective observational study was conducted on 110 patients with AD. The Eczema Area and Severity Index was used as an objective assessment, and the Patient-Oriented Eczema Measure and Numerical Rating Scale for Pruritus were used as patient-reported outcomes. In addition, some clinical background factors were evaluated., Results: The achievement of an absolute Eczema Area and Severity Index of 7 or less was negatively associated with current comorbidity of food allergy and baseline serum lactate dehydrogenase (LDH) levels. There were negative associations between achievement of a Patient-Oriented Eczema Measure score of 7 or less and duration of severe AD and between achievement of an itching Numerical Rating Scale for Pruritus score of 1 or less and current comorbidity of allergic conjunctivitis or baseline serum periostin level. Furthermore, signal detection analysis showed that a baseline serum LDH level less than 328 U/L could potentially be used as a cutoff value for predicting the efficacy of dupilumab., Conclusion: Baseline biomarkers such as LDH and periostin and clinical background factors such as current comorbidity of food allergy and a long period of severe disease may be useful indicators when choosing dupilumab for systemic treatment for AD, as they can predict the efficacy of dupilumab., Competing Interests: Supported by 10.13039/100004339Sanofi and 10.13039/100009857Regeneron (grant SGZ-2018-11996). These companies had no influence on the design of the study, collection and analysis of the data, or decision to publish the article. Disclosure of potential conflict of interest: K. Izuhara has received grants and personal fees from Shino-test Co, Ltd. H. Saeki has received lecture fees, research costs, or scholarship donations from Mitsubishi Tanabe Pharma, Taiho Pharmaceutical, 10.13039/100016730Torii Pharmaceutical, Maruho, Kyowa Kirin, Sanofi, AbbVie, Novartis Pharma, Eli Lilly Japan, Kyorin Pharmaceutical, Eisai, Tokiwa Pharmaceutical, Japan Tobacco, and LEO Pharma. Y. Kataoka has received lecturer honoraria from Sanofi and AbbVie and research funding from Sanofi, Leo Pharma, Pfizer, Maruho, Lilly, AbbVie, and Otsuka. S. Kaneko has received grants as an investigator from Eli Lilly Japan and honoraria as a speaker from Eli Lilly Japan. A. Tanaka has received honoraria from Eli Lilly, Kaken Seiyaku, Sanofi, Taiho Pharma, AbbVie, Kyorin Pharmaceutical, Mitsubishi-Tanabe, Torii Pharmaceutical, and Maruho as a speaker and research grants from Eli Lilly, Sanofi, Teijin Pharma, Taiho Pharma, Mitsubishi-Tanabe, Torii Pharmaceutical, and Maruho. M. Hide has received lecture and/or consultation fees from AbbVie, Eli Lilly, Kaken Pharmaceutical, Kyowa Kirin, Kyorin Pharmaceutical, Maruho, Mitsubishi-Tanabe Pharma, MSD, Novartis, Sanofi, Taiho Pharma, Teikoku Seiyaku, Torii, and Uriach. R. Tamagawa-Mineoka has received research grants from Maruho and 10.13039/501100012351Mitsubishi Tanabe Pharma. K. Masuda has received honoraria as a speaker for Sanofi and grants as an investigator for Eli Lilly Japan. T. Takeichi has received grants paid to his institution (10.13039/501100004823Nagoya University) from Boehringer Ingelheim. M. Akiyama has received research support from Novartis and Boehringer Ingelheim; personal fees from Maruho and Sanofi; and grants paid to his institution (Nagoya University) from Mitsubishi-Tanabe, Taiho, AbbVie, Maruho, Ono, and Sun Pharma. Y. Ishiuji has received honoraria as a speaker for Eli Lilly Japan. Y. Hatano has received honoraria and consultancies to sponsoring organizations from 10.13039/100004339Sanofi, Taiho Pharma, Janssen Pharma, Maruho, Pfizer Japan, Sun Pharma Japan, Torii Pharmaceutical, AbbVie, KAKEN, and UCB Japan. N. Katoh has received honoraria as a speaker/consultant for Sanofi, Maruho, AbbVie, Eli Lilly Japan, and Leo Pharma and grants as an investigator from Maruho, Eli Lilly Japan, Sun Pharma, Taiho Pharmaceutical, Torii Pharmaceutical, Boehringer Ingelheim Japan, and Leo Pharma. Takeshi Nakahara has received lecture fees and research costs from Mitsubishi Tanabe Pharma, Taiho Pharmaceutical, Torii Pharmaceutical, Maruho, Sanofi, AbbVie, Eli Lilly Japan, and Sun Pharma. The rest of the authors declare that they have no relevant conflicts of interest., (© 2024 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.)

Background: To develop precision medicine for atopic dermatitis (AD), it is critical to establish relevant biomarkers. However, the characteristics of various biomarkers have not been fully understood. We previously carried out the Biomarkers to Predict Clinical Improvement of AD in Patients Treated with Dupilumab (B-PAD) study, a comprehensive nationwide study in Japan, to explore biomarkers for AD., Objective: The aim of this study is to find biomarkers associated with objective and subjective clinical findings in patients with moderate-to-severe AD based on the B-PAD study and to identify biomarkers sensitive enough to assess the severity of AD., Methods: We performed the B-PAD study as a consortium composed of 19 medical facilities in Japan, enrolling 110 patients with moderate-to-severe AD. We evaluated the Eczema Area and Severity Index (EASI) for objective assessment as well as the Patient-Oriented Eczema Measure (POEM) and a numeric rating scale for pruritus (pruritis-NRS) for subjective assessment, measuring 19 biomarkers at baseline., Results: We found that 12, 6, and 7 biomarkers showed significant and positive associations with the EASI, POEM, and pruritis-NRS, respectively. Most of the biomarkers associated with either the POEM or the pruritis-NRS were included among the biomarkers associated with EASI. Of the biomarkers examined, CCL26/eotaxin-3 and SCCA2 were the most capable of assessing severity for EASI, as shown by the 2 kinds of receiver operating characteristic analyses, respectively, whereas lactate dehydrogenase was the best for both the POEM and pruritis-NRS, again using the 2 analyses., Conclusion: We found biomarkers associated with the EASI, POEM, and pruritis-NRS, respectively, based on the B-PAD study. Moreover, we identified CCL26/eotaxin-3 and/or SCCA2 as the biomarkers having the greatest ability to assess severity in the EASI; lactate dehydrogenase did the same for the POEM and pruritis-NRS. These findings will be useful in treating patients with moderate-to-severe AD., (© 2023 The Author(s).)

We accumulated the demographic information and analyzed the prevalence of myositis-specific antibodies (MSAs) in a large cohort across Japan as standard testing for MSAs becomes more widely available. This retrospective, observational, cohort study analyzed the records of individuals aged 0-99 years who are tested for serum MSAs at SRL Incorporation from January 2014 to April 2020 across Japan. An enzyme-linked immunosorbent assay testing was applied to determine the presence of anti-aminoacyl tRNA synthetase (anti-ARS), anti-Mi-2, anti-melanoma differentiation-associated gene 5 (anti-MDA5), or anti-transcriptional intermediary factor 1-γ (anti-TIF1γ) (Medical and Biological Laboratories). Anti-TIF1γ antibody was detected more in male patients than female patients. In contrast, women were predominant in patients with other MSAs. More than half of the anti-ARS or anti-TIF1γ antibody-positive patients were over 60 years old, although anti-MDA5 or anti-Mi-2-positive patients were mostly under <60 years old. Anti-MDA5 antibody-positive patients were mostly aged 40-59 years, while other MSA groups were mostly 60-79 years. Anti-MDA5 antibody was detected most frequently in the age range of 0-29 years. Anti-TIF1γ antibody was the second most commonly detected autoantibody in the age range of 0-19 years. Anti-ARS antibody was the most frequently detected autoantibody after the age of 30 years, and the frequency of anti-ARS gradually increased at more advanced ages. The second and third most detected autoantibodies were anti-MDA5 and anti-TIF1γ, respectively, in ages 30-79 years. We performed a nationwide >3-year evaluation of MSA detection in a routine diagnostic setting. This paper provides clinical images concerning the relationship between four MSA types and the distribution of sex and age in a large population., (© 2023 Japanese Dermatological Association.)

Objectives: Endoscopic submucosal dissection (ESD) is effective for the resection of colorectal intramucosal lesions. This study was performed to examine the safety and effectiveness of using dexmedetomidine (DEX) in the anesthesia regimen of patients with colorectal lesions undergoing ESD., Methods: We retrospectively examined 287 consecutive patients who underwent ESD for colorectal lesions in our institution from January 2015 to December 2021. Outcomes including the frequency of intraprocedural pain and adverse events were compared between the DEX and no DEX groups. Moreover, univariate and multivariate analyses were conducted for each clinical factor of intraprocedural pain. Intraprocedural pain was defined as patient-reported abdominal pain or body movement during the procedure., Results: The incidence of intraprocedural pain was significantly lower in the DEX than in the no DEX group (7% vs. 17%, p = 0.02). The incidence of hypotension was also significantly higher in the DEX group (7% vs. 0%, p = 0.01), but no cerebrovascular or cardiac ischemic events occurred. In the univariate analyses, the diameter of the resected specimen, procedure time, no use of DEX, and total midazolam dose was associated with intraprocedural pain. The midazolam dose and DEX administration were significantly negatively correlated and the diameter of resected specimen and procedure time were significantly positively correlated. Multivariate logistic regression showed that no use of DEX was independently associated with intraprocedural pain ( p = 0.02)., Conclusions: Adding DEX to the anesthesia regimen in patients undergoing colorectal ESD appears to be safe and effective for reducing intraprocedural pain., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

An 82-year-old man with fever and back pain was referred to our hospital and was thus found to be thrombocytopenic. A bone marrow biopsy revealed the diffuse infiltration of poorly differentiated neuroendocrine carcinoma (NEC). Computed tomography revealed a large hepatic mass. Considering the risk of bleeding due to thrombocytopenia, a needle biopsy was not performed. The patient rapidly deteriorated and died 10 days after presentation. An autopsy confirmed the diagnosis of primary hepatic NEC, with diffuse metastasis to the spleen, bone marrow, and systemic lymph nodes. This is an extremely rare case of NEC presenting with thrombocytopenia due to extensive bone marrow and splenic infiltration.

Intracellular proteins are often targeted by autoantibodies in autoimmune diseases; however, the mechanism through which intracellular molecules are targeted remains unknown. We previously found that several intracellular misfolded proteins are transported to the cell surface by HLA class II molecules and are recognized by autoantibodies in some autoimmune diseases, such as rheumatoid arthritis, antiphospholipid syndrome, and microscopic polyangiitis. Ro52 is an intracellular Fc receptor that is a target antigen for myositis-associated autoantibodies. We analyzed the role of HLA class II molecules in the autoantibody recognition of Ro52. Ro52 alone was not transported to the cell surface by HLA class II molecules; however, it was transported to the cell surface in the presence of both IgG heavy chain and HLA class II molecules to form a Ro52/IgG/HLA-DR complex. The Ro52/IgG/HLA-DR complex was specifically recognized by autoantibodies from some patients with inflammatory myopathies. We then evaluated 120 patients with inflammatory myopathies with four types of myositis-specific antibodies and analyzed the autoantibodies against the Ro52/IgG/HLA-DR complex. The specific antibodies against the Ro52/IgG/HLA-DR complex were detected in 90% and 93% of patients who were positive for anti-MDA5 and anti-ARS antibodies, respectively. In individual patients with these two inflammatory myopathies, changes in serum titers of anti-Ro52/IgG/HLA-DR-specific antibodies were correlated with the levels of KL-6 (R = 0.51 in anti-MDA5 antibody-positive DM patients, R = 0.67 in anti-ARS antibody-positive PM/DM patients with respiratory symptoms) and CK (R = 0.63 in anti-ARS antibody-positive PM/DM patients with muscle symptoms) over time. These results suggest that antibodies against Ro52/IgG/HLA-DR expressed on the cell surface could be involved in the pathogenesis of inflammatory myopathy subgroups., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Recently, great advancements have been made towards understanding the mechanisms underlying dermatomyositis (DM). Many novel autoantibodies, such as anti-MDA5, anti-TIF1γ, anti-NXP2, and anti-SAE, have been reported to be involved in DM. DM is now classified based on these myositis-specific autoantibodies. Anti-TIF1γ antibodies are closely associated with juvenile DM and adult cancer-associated DM. Anti-TIF1γ antibody-positive DM tends to present severe cutaneous manifestations, mild myositis, and dysphagia. TIF1γ (also known as TRIM33) plays a role in transcriptional elongation, DNA repair, differentiation of cells, embryonic development, and mitosis. Moreover, TIF1γ has been shown to suppress various tumors via the TGF-β/Smad and the Wnt/β-Catenin signaling pathways. In this review, we explore the relationship between TIF1γ, cancer, and DM. We also discuss the pathogenesis of anti-TIF1γ antibody-positive DM.

Objectives: To collect clinical information and NOD2 mutation data on patients with Blau syndrome and to evaluate their prognosis., Methods: Fifty patients with NOD2 mutations were analysed. The activity of each NOD2 mutant was evaluated in HEK293 cells by reporter assay. Clinical information was collected from medical records through the attending physicians., Results: The study population comprised 26 males and 24 females aged 0-61 years. Thirty-two cases were sporadic, and 18 were familial from 9 unrelated families. Fifteen different mutations in NOD2 were identified, including 2 novel mutations (p.W490S and D512V); all showed spontaneous nuclear factor kappa B activation, and the most common mutation was p.R334W. Twenty-six patients had fever at relatively early timepoints in the disease course. Forty-three of 47 patients had a skin rash. The onset of disease in 9 patients was recognised after BCG vaccination. Forty-five of 49 patients had joint lesions. Thirty-eight of 50 patients had ocular symptoms, 7 of which resulted in blindness. After the diagnosis of Blau syndrome, 26 patients were treated with biologics; all were antitumour necrosis factor agents. Only 3 patients were treated with biologics alone; the others received a biologic in combination with methotrexate and/or prednisolone. None of the patients who became blind received biologic treatment., Conclusions: In patients with Blau syndrome, severe joint contractures and blindness may occur if diagnosis and appropriate treatment are delayed. Early treatment with a biologic agent may improve the prognosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Atopic dermatitis (AD) is a common eczematous skin disorder that profoundly reduces the quality of life due to intractable pruritus. Excellent therapeutic success of the anti-interleukin 4 receptor-α antibody dupilumab in clinical trials and a real-world clinical context indicates the crucial roles of interleukin (IL)-4 and IL-13 in the pathogenesis of AD. Along with the clinical improvement in skin scores and pruritus, dupilumab significantly and progressively reduces and normalizes the upregulated expression of T helper type 2 signatures such as Chemokine (C-C motif) ligand (CCL)17, CCL18, CCL22, and CCL26 in the lesional skin of AD. However, no blood/serum biomarkers are known to predict good or poor outcome in patients with AD treated with dupilumab., Methods: Patients are at least 18 years of age and have moderate-to-severe AD with Eczema Area and Severity Index (EASI) ≥16, Investigator's Global Assessment ≥3, and body surface area ≥10%. We are going to enroll more than 130 subjects from 18 medical facilities. Clinical objective findings will be evaluated by EASI. Subjective symptoms will be assessed by Patient-Oriented Eczema Measure, Numerical Rating Scale for Pruritus (Pruritus-NRS), Skin Comfort-NRS, and Treatment Satisfaction-NRS. We will measure 18 blood/serum biomarkers including % eosinophils in blood cell count, lactate dehydrogenase, total IgE, soluble interleukin 2 receptor, CCL17, CCL18, CCL22, CCL26, CCL27, IL-13, IL-22, IL-24, IL-25, IL-31, IL-33, thymic stromal lymphopoietin, periostin, and squamous cell carcinoma antigen-2. The clinical evaluation and biomarker sampling will be performed at 0, 2, 4, 8, and 16 weeks of dupilumab treatment. We will also perform proteomic analysis (of roughly 300 proteins) of the patients' sera obtained at 0 and 2 weeks of treatment. The primary endpoint is the association between "baseline levels of 18 biomarkers" and "% change from baseline of EASI at 16 weeks of dupilumab treatment.", Discussion: This is the first clinical trial to explore the biomarkers, including potential proteomic markers, most strongly associated with improvement in EASI in patients with moderate-to-severe AD treated with dupilumab for 16 weeks (B-PAD study). A limitation is that we will only enroll Japanese patients.

A 16-year-old male high-school student experienced generalized itchy wheal and dyspnea during physical exercise after lunch. Each food material of his lunch was examined using a prick-prick test, allergen-specific IgE test (ImmunoCAP ® ), and provocation test. The prick-prick test was positive for black tiger shrimp (raw and heated) and white leg shrimp (heated). Allergen-specific IgE test (ImmunoCAP ® ) showed absolutely negativity for all suspected foods. The food-exercise provocation test using heated black tiger shrimp with additional aspirin intake finally induced anaphylaxis.We studied the IgE-binding molecules from shrimp using a purification procedure and Western blotting, with sera from the patient and several controls. A 40-kDa protein, corresponding to FBA, was found to be the major IgE-binding allergen component in this patient. Currently, the precise history and the prick-prick test using both raw and heated shrimps are useful to diagnose shrimp-induced FDEIA. Because the allergen-specific IgE test is insufficient to diagnose the cause of the symptoms, a component allergen-specific IgE test after the identification of the causative allergenic protein, such as FBA, is required.

G-protein coupled receptors (GPCRs) represent one of the most important families of drug targets in pharmaceutical development. GLIDA is a public GPCR-related Chemical Genomics database that is primarily focused on the integration of information between GPCRs and their ligands. It provides interaction data between GPCRs and their ligands, along with chemical information on the ligands, as well as biological information regarding GPCRs. These data are connected with each other in a relational database, allowing users in the field of Chemical Genomics research to easily retrieve such information from either biological or chemical starting points. GLIDA includes a variety of similarity search functions for the GPCRs and for their ligands. Thus, GLIDA can provide correlation maps linking the searched homologous GPCRs (or ligands) with their ligands (or GPCRs). By analyzing the correlation patterns between GPCRs and ligands, we can gain more detailed knowledge about their conserved molecular recognition patterns and improve drug design efforts by focusing on inferred candidates for GPCR-specific drugs. This article provides a summary of the GLIDA database and user facilities, and describes recent improvements to database design, data contents, ligand classification programs, similarity search options and graphical interfaces. GLIDA is publicly available at http://pharminfo.pharm.kyoto-u.ac.jp/services/glida/. We hope that it will prove very useful for Chemical Genomics research and GPCR-related drug discovery.

We present a SAR method that can predict estrogen-like endocrine disrupting chemical (EDC) activity as well as key biodegradation steps for detoxification. This method is based on a recent graph-mining algorithm developed by Kudo et al., which generates a set of descriptors from all potent chemical fragments (including rings). This method is novel in that it achieves chemical diversity in the training data set by sampling another data set of larger diversity. The model achieved an 83% accuracy prediction rate, and identified 1291 EDC candidates from the KEGG database. From this set of candidate compounds, bisphenol A was chosen for assay validation and biodegradation pathway analysis. Results showed that bisphenol A exhibited estrogen-like activity and was degraded in three distinct reactions. The prediction model provided information on the mechanism of the ligand-target binding, such as key functional groups involved. We focused on the enzyme commission number, which is useful for analyses of biodegradation pathways. Results identified oxygenases, ether hydrolases, and carbon-halide lyases as being important in the biodegradation pathway. This combined approach provided new information regarding the biodegradation of EDCs, and can potentially be extended to applications with transcriptomic, proteomic, and metabolomic data to provide a quick screen of biological activity and biodegradation pathway(s).