研究者詳細 - 涌井　昌俊

論文 - 涌井　昌俊

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Clot waveform analysis potentially provides predictive information on the sensitivity of activated partial thromboplastin time reagents to lupus anticoagulants

Oka S, Wakui M, Fujimori Y, Nakagawa T, Ziparo M, Haniu H, Matsushita H

Clin Chim Acta 579 120628 2026年01月

研究論文（学術雑誌）, 共著, 筆頭著者, 責任著者, 査読有り, ISSN 00098981

Background: While previous studies have assessed the clinical values of clot waveform analysis (CWA) for detecting lupus anticoagulants (LA), there are no reports focusing on whether CWA predicts the LA sensitivity of activated partial thromboplastin time (APTT) reagents. The present study aimed to assess the usefulness of CWA in evaluating the LA sensitivity of APTT reagents. Methods: Commercially available pooled normal plasma (PNP) and LA-positive plasma control (LPC) were used. CWA findings were compared among nine APTT reagents. Results: Waveform abnormality appeared in assays with six APTT reagents for LPC but not for PNP. No waveform abnormality was evident in assays with three reagents for LPC or for PNP. In assays using reagents exhibiting waveform abnormality, APTT for LPC was longer and ratios of APTT for LPC/APTT for PNP were higher. Waveform abnormality was associated with indexes for evaluating mixing tests. Quantitative evaluation regarding the reduction of CWA parameters adjusted to compensate the influence of fibrinogen was likely applicable for predicting the LA sensitivity of APTT reagents. Conclusion: The present study suggested the usefulness of CWA for evaluating the LA sensitivity of APTT reagents. The results provide insights into use of APTT reagents for LA screening.

第26回日本検査血液学会学術集会ワークショップ2：臨床検査におけるAI活用の最前線：司会のことば

涌井昌俊、中西加代子

日本検査血液学会雑誌 26 （ 3 ） 450 - 450 2025年11月

研究論文（学術雑誌）, 共著, 筆頭著者, 責任著者

全領域をコンプリート！超進化！AI時代の臨床検査：凝固関連検査

涌井昌俊

検査と技術 53 （ 8 ） 838 - 843 2025年08月

研究論文（学術雑誌）, 単著, 筆頭著者, 最終著者, 責任著者

Anti-nucleocapsid IgG antibody as a marker of SARS-CoV-2 infection for hemodialysis patients

Hara A, Watanabe S, Sawano T, Sonoda Y, Saito H, Ozaki A, Wakui M, Zhao T, Yamamoto C, Kobashi Y, Abe T, Kawamura T, Sugiyama A, Nakayama A, Kaneko Y, Shimmura H, Tsubokura M

Vaccines 13 （ 7 ） 750 2025年

研究論文（学術雑誌）, 共著, 査読有り

Background: Hemodialysis patients, due to impaired kidney function and compromised immune responses, face increased risks from SARS-CoV-2. Anti-nucleocapsid IgG (anti-IgG N) antibodies are a commonly used marker to assess prior infection in the general population; however, their efficacy for hemodialysis patients remains unclear. Methods: A retrospective study of 361 hemodialysis patients evaluated anti-IgG N antibodies for detecting prior SARS-CoV-2 infection. Antibody levels were measured using a chemiluminescence immunoassay (CLIA) over the four time points. Boxplots illustrated antibody distribution across sampling stages and infection status. Logistic regression and receiver operating characteristic (ROC) curve analysis determined diagnostic accuracy, sensitivity, specificity, and optimal cutoff values. Results: Among the 361 hemodialysis patients, 36 (10.0%) had SARS-CoV-2 infection. Sex distribution showed a trend toward significance (p = 0.05). Boxplot analysis showed that anti-IgG N levels remained low in non-infected patients but increased in infected patients, peaking at the third sampling. Anti-IgG N demonstrated high diagnostic accuracy (AUC: 0.973–0.865) but declined over time (p = 0.00525). The optimal cutoff at C1 was 0.01 AU/mL (sensitivity 1.00, specificity 0.94). Adjusted models had lower predictive value. Conclusions: Anti-IgG N antibodies showed high diagnostic accuracy for detecting prior SARS-CoV-2 infection in hemodialysis patients, though performance declined over time. These findings highlight the need for tailored diagnostic strategies in this vulnerable population.

Germline variants and mosaic chromosomal alterations affect COVID-19 vaccine immunogenicity

Sonehara K, Uwamino Y, Saiki R, Takeshita M, Namba S, Uno S, Nakanishi T, Nishimura T, Naito T, Sato G, Kanai M, Liu A, Uchida S, Kurafuji T, Tanabe A, Arai T, Ohno A, Shibata A, Tanaka S, Wakui M, Kashimura S, Tomi C, Hara A, Yoshikawa S, Gotanda K, Misawa K, Tanaka H, Azekawa S, Wang QS, Edahiro R, Shirai Y, Yamamoto K, Nagao G, Suzuki T, Kiyoshi M, Ishii-Watabe A, Higashiue S, Kobayashi S, Yamaguchi H, Okazaki Y, Matsumoto N, Masumoto A, Koga H, Kanai A; Japan COVID-19 Task Force; Biobank Japan Project; Oda Y, Suzuki Y, Matsuda K, Kitagawa Y, Koike R, Kimura A, Kumanogoh A, Yoshimura A, Imoto S, Miyano S, Kanai T, Fukunaga K, Hasegawa N, Murata M, Matsushita H, Ogawa S, Okada Y, Namkoong H

Cell Genomics 5 （ 3 ） 100783 2025年

研究論文（学術雑誌）, 共著, 査読有り

Vaccine immunogenicity is influenced by the vaccinee's genetic background. Here, we perform a genome-wide association study of vaccine-induced SARS-CoV-2-specific immunoglobulin G (IgG) antibody titers and T cell immune responses in 1,559 mRNA-1273 and 537 BNT162b2 vaccinees of Japanese ancestry. SARS-CoV-2-specific antibody titers are associated with the immunoglobulin heavy chain (IGH) and major histocompatibility complex (MHC) locus, and T cell responses are associated with MHC. The lead variants at IGH contain a population-specific missense variant (rs1043109-C; p.Leu192Val) in the immunoglobulin heavy constant gamma 1 gene (IGHG1), with a strong decreasing effect (β = −0.54). Antibody-titer-associated variants modulate circulating immune regulatory proteins (e.g., LILRB4 and FCRL6). Age-related hematopoietic expanded mosaic chromosomal alterations (mCAs) affecting MHC and IGH also impair antibody production. MHC-/IGH-affecting mCAs confer infectious and immune disease risk, including sepsis and Graves’ disease. Impacts of expanded mosaic loss of chromosomes X/Y on these phenotypes were examined. Altogether, both germline and somatic mutations contribute to adaptive immunity functions.

Breakthrough infection after primary series of COVID-19 vaccination induces stronger humoral immunity and equivalent cellular immunity to the spike protein compared with booster shots

Uwamino Y*, Yokoyama T, Sato Y, S Tanaka S, Kamoshita Y, Shibata A, Kurafuji T, Tanabe A, Arai T, Ohno A, Namkoong H, Nishimura T, Wakui M, Murata M, Hasegawa N, Matsushita H

Vaccines 13 （ 7 ） 751 2025年

研究論文（学術雑誌）, 共著, 査読有り

Background: The long-term immune implications of administering more than four doses of COVID-19 vaccine and the impact of breakthrough infections are not fully understood. Research Design and Methods: We conducted a follow-up cohort study on Japanese healthcare workers who received more than three doses of the BNT162b2 vaccine. We assessed both the anti-SARS-CoV-2 antibody titer and cellular immunity in 429 participants and investigated the numbers, types, and brands of COVID-19 vaccines administered, as well as the episodes of COVID-19 infections after the third dose. Results: Individuals who received three total doses of vaccines with BTI episodes demonstrated higher antibody titers than those who received four total doses of vaccines with no BTIs. The cellular immune responses between these two groups were comparable. Conclusions: These findings suggest that BTIs occurring after the primary series of COVID-19 vaccinations (first to third dose) induced humoral immunity to the spike protein that is greater than that induced by booster doses (fourth or fifth dose) and elicit cellular immunity to the spike protein comparable to that of booster doses.

凝固波形解析の自動診断化

涌井昌俊

SRL宝函 46 （ 1 ） 2025年

研究論文（学術雑誌）, 単著, 筆頭著者, 最終著者, 責任著者, 査読有り

Validation of a candidate International Harmonisation Protocol-compliant measurement procedure for reticulocyte counting using an erythrocyte gating strategy excluding the platelet component

Nagai Y, Takeda T#*, Matsushita H#*, Arai T, Yatabe Y, Yokota H, Mitsuhashi T, Wakui M, Kawai Y, Kondo H

Cytometry B Clin Cytom in press 2025年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 15524949

The International Harmonisation Protocol (IHP) for Reticulocyte Percentage (%Retic) in CLSI-H44-A2 is a microscopic procedure performed on a new-methylene-blue-stained blood film (NMB-IHP). However, IHP-compliant Measurement Procedures (MPs) based on flow cytometry (FCM) are recommended for practical and accurately assigned reference values. Thiazole orange (TO) for nucleic acid staining and CD235a immunostaining for erythrocyte gating are currently widespread for MP using FCM (TO/CD235a-MP); however they have not been validated using NMB-IHP. We recently developed MP using FCM with anti-CD45/CD41a/CD61 antibodies, that are utilized for excluding platelets from the un-nucleated blood cell fraction to select erythrocytes (TO/CD41a/CD61-MP). The aim of this study is to validate TO/CD41a/CD61-MP for measurement of reticulocytes as an IHP-compliant MP. First, TO/CD235a-MP was validated as an IHP-compliant MP by comparing it with NMB-IHP. Then TO/CD41a/CD61-MP was compared with TO/CD235a-MP. The practical utility of TO/CD41a/CD61-MP was evaluated using XN-2000™(Sysmex) and Celltac G + ™(Nihon Kohden) hematology analyzers to assess the accuracy of different nucleic acid staining methods. We first confirmed that TO/CD235a-MP was consistent with NMB-IHP, then evaluated TO/CD41a/CD61-MP using TO/CD235a-MP. Regression analysis demonstrated consistency between TO/CD41a/CD61-MP and TO/CD235a-MP, thereby establishing TO/CD41a/CD61-MP as IHP-compliant MP. In the accuracy assessment, the correlation coefficients to TO/CD41a/CD61-MP were observed to be 0.97 for both hematology analyzers with %Retic ranging from 0.0 to 8.2. TO/CD41a/CD61-MP serves effectively as an IHP-compliant MP. This study provides the first empirical validation of FCM-based MPs.

LC-MS/MS in Clinical Diagnostics: Opportunities, Technical Hurdles, and Implementation Challenges

Nakagawa T, Wakui M

Medical Mass Spectrometry 8 （ 2 ） 65 - 73 2024年11月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り

CWAの基礎

涌井昌俊

Thrombosis Medicine 14 （ 3 ） 61 - 65 2024年09月

研究論文（学術雑誌）, 単著, 筆頭著者, 最終著者, 責任著者

Modeling and predicting individual variation in COVID-19 vaccine-elicited antibody response in the general population

Nakamura N, Kobashi Y, Kim KS, Park H, Shimazu Y, Zhao T, Nishikawa Y, Omata F, Yoshida M, Abe T, Saito Y, Senoo Y, Takita M, Yamamoto C, Kawamura T, Sugiyama A, Nakayama A, Kaneko Y, eong YD, Tatematsu D, Sato Y, Iwanami S, Fujita Y, Wakui M, Aihara K, Kodama T, Shibuya K, Tani Y, Kawashima M, Nonaka S, Akao M, Iwami S*, Tsubokura M*

PLOS Digit Health 3 （ 5 ） e0000497 2024年05月

研究論文（学術雑誌）, 共著, 査読有り

As we learned during the COVID-19 pandemic, vaccines are one of the most important tools in infectious disease control. To date, an unprecedentedly large volume of high-quality data on COVID-19 vaccinations have been accumulated. For preparedness in future pandemics beyond COVID-19, these valuable datasets should be analyzed to best shape an effective vaccination strategy. We are collecting longitudinal data from a community-based cohort in Fukushima, Japan, that consists of 2,407 individuals who underwent serum sampling two or three times after a two-dose vaccination with either BNT162b2 or mRNA-1273. Using the individually reconstructed time courses of the vaccine-elicited antibody response based on mathematical modeling, we first identified basic demographic and health information that contributed to the main features of the antibody dynamics, i.e., the peak, the duration, and the area under the curve. We showed that these three features of antibody dynamics were partially explained by underlying medical conditions, adverse reactions to vaccinations, and medications, consistent with the findings of previous studies. We then applied to these factors a recently proposed computational method to optimally fit an “antibody score”, which resulted in an integer-based score that can be used as a basis for identifying individuals with higher or lower antibody titers from basic demographic and health information. The score can be easily calculated by individuals themselves or by medical practitioners. Although the sensitivity of this score is currently not very high, in the future, as more data become available, it has the potential to identify vulnerable populations and encourage them to get booster vaccinations. Our mathematical model can be extended to any kind of vaccination and therefore can form a basis for policy decisions regarding the distribution of booster vaccines to strengthen immunity in future pandemics.

Diminished neutralizing activity against the XBB1.5 strain in 55.9% of individuals post 6 months COVID-19 mRNA booster vaccination: Insights from a pseudovirus assay on 1,353 participants in the Fukushima Vaccination Community Survey, Japan

Zhao T, Tani Y, Makino-Okamura C, Takita M, Yamamoto C, Kawahara E, Abe T, Sugiura S, Yoshimura H, Uchiyama T, Yamazaki I, Ishigame H, Wakui M, Fukuyama H, Tsubokura M

Front Immunol （Frontiers in Immunology） 15 1337520 2024年03月

研究論文（学術雑誌）, 共著, 査読有り

This study investigates the neutralizing activity against the XBB1.5 variant and the ancestral strain in a population post-bivalent vaccination using a pseudo virus assay validated with authentic virus assay. While bivalent booster vaccination and past infections enhanced neutralization against the XBB 1.5 strain, individuals with comorbidities showed reduced responses. The study suggests the need for continuous vaccine updates to address emerging SARS-CoV-2 variants and highlights the importance of monitoring real-world immune responses.

特集：血栓・塞栓症の臨床　血液検査

涌井昌俊

日本臨床（日本臨床社） 82 （ 2 ） 148 - 154 2024年02月

研究論文（学術雑誌）, 単著, 筆頭著者, 責任著者

ホットトピックス：凝固（出血）分野

涌井昌俊、長江千愛、武山雅博

血栓止血誌 35 （ 1 ）印刷中 2024年

研究論文（学術雑誌）, 筆頭著者, 責任著者

PRMT1 methylates PHGDH to sustain de novo fatty acid synthesis for the acquisition of chemoresistance in triple-negative breast cancer cells

Yamamoto T *, Hayashida T#, Masugi Y, Oshikawa K, Hayakawa N, Itoh M, Nishime C, Suzuki M, Nagayama A, Kawai Y, Hishiki T, Matsuura T, Naito Y, Kubo A, Yamamoto A, Yoshioka Y, Kurahori T, Nagasaka M, Takizawa M, Takano N, Kawakami K, Sakamoto M, Wakui M, Yamamoto T, Kitagawa Y, Kabe Y, Horisawa K, Suzuki A, Matsumoto M, Suematsu M *

Cancer Res （Cancer Research） 84 （ 7 ） 1065 - 1083 2024年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00085472

Triple-negative breast cancer (TNBC) chemoresistance hampers the ability to effectively treat patients. Identification of mechanisms driving chemoresistance can lead to strategies to improve treatment. Here, we revealed that protein arginine methyltransferase-1 (PRMT1) simultaneously methylates D-3-phosphoglycerate dehydrogenase (PHGDH), a critical enzyme in serine synthesis, and the glycolytic enzymes PFKFB3 and PKM2 in TNBC cells. 13C metabolic flux analyses showed that PRMT1-dependent methylation of these three enzymes diverts glucose toward intermediates in the serine-synthesizing and serine/glycine cleavage pathways, thereby accelerating the production of methyl donors in TNBC cells. Mechanistically, PRMT1-dependent methylation of PHGDH at R54 or R20 activated its enzymatic activity by stabilizing 3-phos-phoglycerate binding and suppressing polyubiquitination. PRMT1-mediated PHGDH methylation drove chemoresistance independently of glutathione synthesis. Rather, activation of the serine synthesis pathway supplied a-ketoglutarate and citrate to increase palmitate levels through activation of fatty acid synthase (FASN). Increased palmitate induced protein S-palmitoylation of PHGDH and FASN to further enhance fatty acid synthesis in a PRMT1-dependent manner. Loss of PRMT1 or pharmacologic inhibition of FASN or protein S-palmitoyltransferase reversed chemoresistance in TNBC. Furthermore, IHC coupled with imaging MS in clinical TNBC specimens substantiated that PRMT1-mediated methylation of PHGDH, PFKFB3, and PKM2 correlates with chemoresistance and that metabolites required for methylation and fatty acid synthesis are enriched in TNBC. Together, these results suggest that enhanced de novo fatty acid synthesis mediated by coordinated protein arginine methylation and protein S-palmitoylation is a therapeutic target for overcoming chemoresistance in TNBC. Significance: PRMT1 promotes chemoresistance in TNBC by methylating metabolic enzymes PFKFB3, PKM2, and PHGDH to augment de novo fatty acid synthesis, indicating that targeting this axis is a potential treatment strategy.

古くて新しい包括的凝固関連検査〜凝固波形解析の現状と展望〜

涌井昌俊

日本臨床検査医学会誌（旧・臨床病理） 72 （ 1 ） 29 - 34 2024年

研究論文（学術雑誌）, 単著, 筆頭著者, 責任著者

MMP-3測定用改良試薬「マトリックスメタロプロテイナーゼ-3キット LZ’栄研’ MMP-3」の基礎的検討

豊田咲希、青木絵美、中川央充、酒井昭子、野口昌代、大野明美、横田浩充、涌井昌俊、松下弘道

医療検査と自動化（日本医療検査科学会雑誌） 49 （ 1 ） 48 - 53 2024年

研究論文（学術雑誌）, 共著, 査読有り

Group of longitudinal adverse event patterns after the fourth dose of COVID-19 vaccination with a latent class analysis

Yamamoto C, Kobashi Y, Kawamura T, Nishikawa Y, Saito H, Oguro F, Zhao T, Takita M, Sawano T, Ozaki A, Abe T, Ito N, Kaneko Y, Nakayama A, Wakui M, Kodama T, Tsubokura M

Frontiers in Public Health in press 2024年

研究論文（学術雑誌）, 共著, 査読有り

Introduction: Vaccination has been implemented as a useful measure to combat the COVID-19 pandemic. However, there is a tendency for individuals to avoid vaccination due to the possibility of adverse events, making it important to investigate the relationship between COVID-19 vaccines and their adverse events. This study explored longitudinal adverse event patterns and factors that influence adverse events following the second to fourth doses of the COVID-19 vaccine through a latent class analysis. Methods: Participants were recruited from the Fukushima Prefecture and included individuals who had completed four doses of the COVID-19 mRNA vaccine. This study utilized data from questionnaire surveys and blood collection conducted between September 2021 and November 2022. In the questionnaire, factors such as sex, age, medical history, medication, type of vaccine administered, and adverse events following vaccination were recorded. Additionally, in the blood data, serological tests [IgG(S)] and cellular immune responses (T-spot) were measured. Descriptive statistics, latent class analysis, multivariable logistic regression, and multiple regression analyses were performed to identify the longitudinal adverse event patterns and influencing factors. By analyzing adverse events over time, we identified two distinct groups: those less prone to experiencing adverse events (Group 1) and those more susceptible (Group 2) to latent class analysis. Results: A total of 1,175 participants were included after excluding those without any adverse events. The median age of the participants in Group 1 was 70 years, and in Group 2 it was 51 years. The proportion of female participants was 298 in Group 1 and 353 in Group 2. Patients in Group 2 were significantly younger (p < 0.001) and more likely to be female (p < 0.001) than those in Group 1. Furthermore, the median IgG(S) value after the fourth vaccination was 3,233 AU/mL in Group 1 and 4,059.39 AU/mL in Group 2. The median T-spot value was 15.4 in Group 1 and 28.5 in Group 2. Group 2 showed significantly higher IgG(S) and T-spot values after the fourth vaccination (p < 0.001). Discussion: Our findings suggest that factors other than age, particularly sex and a history of allergies, significantly influence the likelihood of experiencing adverse events. Groups categorized by latent class analysis for longitudinal adverse events are expected to be valuable for optimizing vaccination strategies and formulating public health measures.

SARS-CoV-2 spike protein antibody titers after the fourth dose of BNT162b2 vaccine among Japanese patients undergoing hemodialysis: a single-center study

Watanabe S, Sawano T, Saito H, Ozaki A, Wakui M, Zhao T, YamamotoC, Kobashi Y, Kawamura T, Sugiyama A, Nakayama A, Kaneko Y, Shimmura H, Tsubokura M

Front Immuno in press 2024年

研究論文（学術雑誌）, 共著, 査読有り

Comparison of clot waveform analysis with or without adjustment between prothrombin time and activated partial thromboplastin time assays to assess in vitro effects of direct oral anticoagulants

Wakui M, Fujimori Y, Ozaki Y, Oka S, Ziparo M, Osada E, Kondo Y, Nakagawa T, Nakamura S, Matsushita H

Clin Chim Acta 562 119887 2024年

研究論文（学術雑誌）, 共著, 筆頭著者, 責任著者, 査読有り, ISSN 00098981

Background: Clot waveform analysis (CWA) reportedly enhances the interpretation of clotting time measurement. This study aimed to compare CWA between prothrombin time (PT) and activated partial thromboplastin time (APTT) assays for better understanding how to apply CWA for assessing effects of direct oral anticoagulants (DOACs). Methods: Samples were prepared by spiking plasma with rivaroxaban, apixaban, edoxaban, or dabigatran. To compensate the influence of fibrinogen, CWA parameters were adjusted by unifying maximum changes in transmittance in clotting reaction curves detected by the optical system. Results: Non-adjusted PT-CWA parameters unexpectedly rose at low drug concentrations but declined at high drug concentrations while adjusted PT-CWA parameters exhibited dose-dependent decrease. Both non-adjusted and adjusted APTT-CWA parameters showed dose-dependent decrease. Adjusted CWA parameters were applicable to Hill plot analysis. All DOACs exhibited Hill coefficients indicating positively cooperative effects regarding most adjusted PT-CWA parameters. Regarding adjusted APTT-CWA parameters, rivaroxaban, apixaban, and edoxaban exhibited Hill coefficients indicating no or negatively cooperative effects. The observed differences between PT-CWA and APTT-CWA suggested the implication of thrombin positive feedback in DOAC effects. Conclusion: The results revealed distinct features of DOAC effects in extrinsic and intrinsic pathways. To ascertain the clinical implication, further studies using clinical samples are needed.

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論文 - 涌井　昌俊