Papers - Wakui, Masatoshi

全領域をコンプリート！超進化！AI時代の臨床検査：血液学検査 [凝固]

涌井昌俊

検査と技術 印刷中 2025

Research paper (scientific journal), Single Work, Lead author, Last author, Corresponding author

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

Research paper (scientific journal), Joint Work, Accepted

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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.

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

Nakagawa T, Wakui M

Medical Mass Spectrometry 8 ( 2 ) 65 - 73 2024.11

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted

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CWAの基礎

涌井昌俊

Thrombosis Medicine 14 ( 3 ) 61 - 65 2024.09

Research paper (scientific journal), Single Work, Lead author, Last author, Corresponding author

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 2024.05

Research paper (scientific journal), Joint Work, Accepted

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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.

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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 2024.03

Research paper (scientific journal), Joint Work, Accepted

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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.

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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 2024.02

Research paper (scientific journal), Single Work, Lead author, Corresponding author

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

Research paper (scientific journal), Lead author, Corresponding author

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

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00085472

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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.

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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

Research paper (scientific journal), Single Work, Lead author, Corresponding author

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

Research paper (scientific journal), Joint Work, Accepted

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

Research paper (scientific journal), Joint Work, Lead author, Corresponding author, Accepted,  ISSN  00098981

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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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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

Research paper (scientific journal), Joint Work, Accepted

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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.

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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

Research paper (scientific journal), Joint Work, Accepted

Kinetics of Humoral and Cellular Immune Responses 5 Months Post-COVID-19 Booster Dose by Immune Response Groups at the Peak Immunity Phase: An Observational Historical Cohort Study Using the Fukushima Vaccination Community Survey

Kobashi Y, Kawamura T, Shimazu Y, Kaneko Y, Nishikawa Y, SugiyamaA, Tani Y, Nakayama A, Yoshida M, Zho T, Yamamoto C, Saito H, Takita M, Wakui M, Kodama T, Tsubokura M

Vaccine X in press 2024

Research paper (scientific journal), Joint Work, Accepted

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Background: Understanding the waning of immunity after booster vaccinations is important to identify which immune-low populations should be prioritized. Methods: We investigated longitudinal cellular and humoral immunity after the third vaccine dose in both high- and low-cellular and humoral immunity groups at the peak immunity phase after the booster vaccination in a large community-based cohort. Blood samples were collected from 1045 participants at peak (T1: median 54 days post-third dose) and decay (T2: median 145 days post-third dose) phases to assess IgG(S), neutralizing activity, and ELISpot responses. Participants were categorized into high/low ELISpot/IgG(S) groups at T1. Cellular and humoral responses were tracked for approximately five months after the third vaccination. Results: In total, 983 participants were included in the cohort. IgG(S) geometric mean fold change between timepoints revealed greater waning in the >79 years age group (T2/T1 fold change: 0.27) and higher IgG(S) fold change in the low-ELISpot group at T1 (T2/T1 fold change: 0.32–0.33) than in the other groups, although ELISpot geometric mean remained stable. Conclusions: Antibody level of those who did not respond well to third dose vaccination waned rapidly than those who responded well. Evidence-based vaccine strategies are essential in preventing potential health issues caused by vaccines, including side-effects.

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Amino acid catabolite markers for early prognostication of pneumonia in patients with COVID-19

Maeda R, Seki Kimizuka N, Uwamino Y, Wakui M, Nakagama Y, Kido Y, Sasai M, Matsuura Y, Uchiyama J, Kim Y-Gi, Mishima M, Suematsu M, Sugiura Y

Nat Commun (Nature Communications)  14 ( 1 ) 8469 2023.12

Research paper (scientific journal), Joint Work, Accepted

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Effective early-stage markers for predicting which patients are at risk of developing SARS-CoV-2 infection have not been fully investigated. Here, we performed comprehensive serum metabolome analysis of a total of 83 patients from two cohorts to determine that the acceleration of amino acid catabolism within 5 days from disease onset correlated with future disease severity. Increased levels of de-aminated amino acid catabolites involved in the de novo nucleotide synthesis pathway were identified as early prognostic markers that correlated with the initial viral load. We further employed mice models of SARS-CoV2-MA10 and influenza infection to demonstrate that such de-amination of amino acids and de novo synthesis of nucleotides were associated with the abnormal proliferation of airway and vascular tissue cells in the lungs during the early stages of infection. Consequently, it can be concluded that lung parenchymal tissue remodeling in the early stages of respiratory viral infections induces systemic metabolic remodeling and that the associated key amino acid catabolites are valid predictors for excessive inflammatory response in later disease stages.

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Effects of DOAC-Stop on clot waveform analysis of plasma spiked with antithrombin-dependent and antithrombin-independent anticoagulants

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

Int J Lab Hematol (International Journal of Laboratory Hematology)  45 ( 6 ) 979 - 983 2023.12

Research paper (scientific journal), Joint Work, Lead author, Corresponding author, Accepted,  ISSN  17515521

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Antibody profiling of microbial antigens in the blood of COVID-19 mRNA vaccine recipients using microbial protein microarrays

Saito H, Yoshimura H, Yshida M, Tani Y, Kawashima M, Uchiyama T, Tianchen Z, Yamamoto C, Kobashi Y, Wakui M, Tianchen Z, Yamamoto C, Kawashima M, Sawano T, Kawamura T, Imoto S, Pak H, Nakamura N Iwami S, Kaneko Y, Nakayama A, , Kodama T, Wakui M, Kawamura T, Tsubokura M

Vaccines (Vaccines)  11 ( 11 ) 1694 2023.11

Research paper (scientific journal), Joint Work, Accepted

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Although studies have demonstrated that infections with various viruses, bacteria, and parasites can modulate the immune system, no study has investigated changes in antibodies against microbial antigens after the COVID-19 mRNA vaccination. IgG antibodies against microbial antigens in the blood of vaccinees were comprehensively analyzed using microbial protein microarrays that carried approximately 5000 microbe-derived proteins. Changes in antibodies against microbial antigens were scrutinized in healthy participants enrolled in the Fukushima Vaccination Community Survey conducted in Fukushima Prefecture, Japan, after their second and third COVID-19 mRNA vaccinations. Antibody profiling of six groups stratified by antibody titer and the remaining neutralizing antibodies was also performed to study the dynamics of neutralizing antibodies against SARS-CoV-2 and the changes in antibodies against microbial antigens. The results showed that changes in antibodies against microbial antigens other than SARS-CoV-2 antigens were extremely limited after COVID-19 vaccination. In addition, antibodies against a staphylococcal complement inhibitor have been identified as microbial antigens that are associated with increased levels of neutralizing antibodies against SARS-CoV-2. These antibodies may be a predictor of the maintenance of neutralizing antibodies following the administration of a COVID-19 mRNA vaccine.

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Association of systemic adverse reaction patterns with long-term dynamics of humoral and cellular immunity after coronavirus disease 2019 third vaccination

Yoshida M, Kobashi Y, Kawamura T, Shimazu Y, Nishikawa Y, Omata F, Saito H, Yamamoto C, Zhao T, Takita M, Ito N, Tatsuno K, Kaneko Y, Nakayama A, Kodama T, Wakui M, Takahashi K, Tsubokura M

Sci Rep (Scientific Reports)  13 ( 1 ) 9264 2023.06

Research paper (scientific journal), Joint Work, Accepted

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The objective of this study was to clarify the impact of adverse reactions on immune dynamics. We investigated the pattern of systemic adverse reactions after the second and third coronavirus disease 2019 (COVID-19) vaccinations and their relationship with immunoglobulin G against severe acute respiratory syndrome coronavirus 2 spike 1 protein titers, neutralizing antibody levels, peak cellular responses, and the rate of decrease after the third vaccination in a large-scale community-based cohort in Japan. Participants who received a third vaccination with BNT162b2 (Pfizer/BioNTech) or mRNA-1273 (Moderna), had two blood samples, had not had COVID-19, and had information on adverse reactions after the second and third vaccinations (n = 2198) were enrolled. We collected data on sex, age, adverse reactions, comorbidities, and daily medicine using a questionnaire survey. Participants with many systemic adverse reactions after the second and third vaccinations had significantly higher humoral and cellular immunity in the peak phase. Participants with multiple systemic adverse reactions after the third vaccination had small changes in the geometric values of humoral immunity and had the largest geometric mean of cellar immunity in the decay phase. Systemic adverse reactions after the third vaccination helped achieve high peak values and maintain humoral and cellular immunity. This information may help promote uptake of a third vaccination, even among those who hesitate due to adverse reactions.

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Varying cellular immune response against SARS-CoV-2 after the booster vaccination: A cohort study from Fukushima Vaccination Community Survey, Japan

Tani Y, Takita M, Kobashi Y, Wakui M, Tianchen Z, Yamamoto C, Saito H, Kawashima M, Sugiura S, Nishikawa Y, Omata F, Shimazu Y, Kawamura T, Sugiyama A, Nakayama A, Kaneko Y, Kodama T, Kami M, Tsubokura M

Vaccines (Vaccines)  11 ( 5 ) 920 2023.04

Research paper (scientific journal), Joint Work, Accepted

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Booster vaccination reduces the incidence of severe cases and mortality related to COVID-19, with cellular immunity playing an important role. However, little is known about the proportion of the population that has achieved cellular immunity after booster vaccination. Thus, we conducted a Fukushima cohort database and assessed humoral and cellular immunity in 2526 residents and healthcare workers in Fukushima Prefecture in Japan through continuous blood collection every 3 months from September 2021. We identified the proportion of people with induced cellular immunity after booster vaccination using the T-SPOT.COVID test, and analyzed their background characteristics. Among 1089 participants, 64.3% (700/1089) had reactive cellular immunity after booster vaccination. Multivariable analysis revealed the following independent predictors of reactive cellular immunity: age < 40 years (adjusted odds ratio: 1.81; 95% confidence interval: 1.19–2.75; p-value: 0.005) and adverse reactions after vaccination (1.92, 1.19–3.09, 0.007). Notably, despite IgG(S) and neutralizing antibody titers of ≥500 AU/mL, 33.9% (349/1031) and 33.5% (341/1017) of participants, respectively, did not have reactive cellular immunity. In summary, this is the first study to evaluate cellular immunity at the population level after booster vaccination using the T-SPOT.COVID test, albeit with several limitations. Future studies will need to evaluate previously infected subjects and their T-cell subsets.

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Clot waveform analysis for perioperative hemostatic monitoring in a hemophilia A patient on emicizumab undergoing liver transplantation

Awane M, Wakui M, Ozaki Y, KondoY, Oka S, Fujimori Y, Yatabe Y, Arai T, Yamada Y, Hori S, Obara H, Hasegawa Y, Matsushita H

Clin Chim Acta (Clinica Chimica Acta)  544   117339 2023.04

Research paper (scientific journal), Joint Work, Lead author, Corresponding author, Accepted,  ISSN  00098981

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How to optimize perioperative factor VIII (FVIII) replacement through hemostatic monitoring is critically important to manage hemophilia A patients. The bispecific antibody emicizumab binds activated FIX (FIXa) and FX to functionally mimic FVIIIa. While being used for hemostatic control in hemophilia A, this therapeutic antibody inconveniently interferes with coagulation tests using human FIXa and FX, such as activated partial thromboplastin time (APTT) and FVIII activity measurement based on one-stage clotting assays. Clot waveform analysis (CWA) extends the interpretation of measurement curves for coagulation time to provide global information. We performed APTT-CWA to monitor perioperative hemostasis in a hemophilia A patient on emicizumab undergoing liver transplantation. Plasma samples were treated with anti-idiotype monoclonal antibodies against emicizumab to enable accurate coagulation assays. Kinetics of maximum coagulation velocity and acceleration mimicked that of FVIII activity. These CWA parameters better correlated with FVIII activity than APTT. The plateaus of them were observed at FVIII activity of 100% or more, supporting the protocol for perioperative FVIII replacement. Thus, CWA may measure coagulation potential in hemophilia A patients undergoing liver transplantation, aiding in optimizing perioperative hemostasis.

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凝固カスケード反応の本質に迫る！　凝固波形解析

涌井昌俊

臨床検査専門医会誌（Laboratory and Clinical Practice; Lab Clin Pract） 40 ( 2 ) 36 - 41 2023.03

Research paper (scientific journal), Single Work

COVID-19のAPTT凝固波形解析

蔵野信、志村拓也、涌井昌俊、矢冨裕

血栓止血誌 34 ( 1 ) 29 - 35 2023.02

Research paper (scientific journal), Joint Work

Antibody and T cell responses against SARS-CoV-2 after booster vaccination in patients on dialysis: a prospective observational study

Kawashima M, Saito H, Nishiuchi T, Yoshimura H, Wakui M, Tani Y, Nishikawa Y, Omata F, Takita M, Zhao T, Yamamoto C, Kobashi Y, Kawamura T, Sugiyama A, Nakayama A, Kaneko Y, Sawano T, Shibuya K, Kazama JJ, Shineha R, Tsubokura M

Vaccines (Vaccines)  11 ( 2 ) 260 2023.01

Research paper (scientific journal), Joint Work, Accepted

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Intensive vaccination is recommended for populations more vulnerable to COVID-19 infection, although data regarding the built of immunity after vaccination for dialysis patients are lacking. This prospective, observational cohort study of maintenance hemodialysis patients examined IgG antibody levels against the SARS-CoV-2 spike (S1) protein, neutralizing activity, and interferon gamma levels after the third dose of the BNT162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna) vaccine. Humoral immunity was repeatedly measured for up to two months. The study includes 58 patients on hemodialysis. Median neutralizing antibodies reached a maximum at 56 and 9 days after booster vaccination with BNT162b2 and mRNA-1273, respectively. The median IgG antibody titer reached a maximum of 3104.38 and 7209.13 AU/mL after 16 days of booster dose, and cellular immunity was positive in 61.9% and 100% of patients with BNT162b2 and mRNA-1273 vaccination, respectively. By repeating the measurements over a period of two months, we clarified the chronological aspects of the acquisition of humoral immunity in dialysis patients after a booster COVID-19 vaccination; most dialysis patients acquired not only humoral immunity, but also cellular immunity against SARS-CoV-2. Future research should investigate the continued long-term dynamics of antibody titers and cellular immunity after the third or further vaccinations, evaluating the need for additional vaccinations for hemodialysis patients.

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Polysulfide serves as a hallmark of desmoplastic reaction to differentially diagnose ductal carcinoma in situ and invasive breast cancer by SERS imaging

Kubo A, Masugi Y, Hase T, Nagashima K, Kawai Y, Takizawa M, Hishiki T, Shiota M, Wakui M, Kitagawa Y, Kabe Y, Sakamoto M, Yachie A, Hayashida T, Suematsu M

Antioxidant (Antioxidants)  12 ( 2 ) 240 2023.01

Research paper (scientific journal), Joint Work, Accepted

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Pathological examination of formalin-fixed paraffin-embedded (FFPE) needle-biopsied samples by certified pathologists represents the gold standard for differential diagnosis between ductal carcinoma in situ (DCIS) and invasive breast cancers (IBC), while information of marker metabolites in the samples is lost in the samples. Infrared laser-scanning large-area surface-enhanced Raman spectroscopy (SERS) equipped with gold-nanoparticle-based SERS substrate enables us to visualize metabolites in fresh-frozen needle-biopsied samples with spatial matching between SERS and HE staining images with pathological annotations. DCIS (n = 14) and IBC (n = 32) samples generated many different SERS peaks in finger-print regions of SERS spectra among pathologically annotated lesions including cancer cell nests and the surrounding stroma. The results showed that SERS peaks in IBC stroma exhibit significantly increased polysulfide that coincides with decreased hypotaurine as compared with DCIS, suggesting that alterations of these redox metabolites account for fingerprints of desmoplastic reactions to distinguish IBC from DCIS. Furthermore, the application of supervised machine learning to the stroma-specific multiple SERS signals enables us to support automated differential diagnosis with high accuracy. The results suggest that SERS-derived biochemical fingerprints derived from redox metabolites account for a hallmark of desmoplastic reaction of IBC that is absent in DCIS, and thus, they serve as a useful method for precision diagnosis in breast cancer.

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Time course of adverse reactions following BNT162b2 vaccination in healthy and allergic disease individuals aged 5–11 years and comparison with individuals aged 12–15 years: an observational and historical cohort study

Yoshida M, Kobashi Y, Shimazu Y, Saito H, Yamamoto C, Kawamura T, Wakui M, Takahashi K, Ito N, Nishikawa Y, Zhao T, Tsubokura M

Eur J Pediatr (European Journal of Pediatrics)  182 ( 1 ) 123 - 133 2023

Research paper (scientific journal), Joint Work, Accepted,  ISSN  03406199

　View Summary

We aimed to investigate the type and frequency of adverse events over 7 days following the first and second BNT162b2 vaccination. This observational and historical cohort study included patients aged 5–11 years who received two doses of BNT162b2 and provided consent along with their guardians. We collected data on sex, age, height, weight, blood type, history of Bacille Calmette-Guerin vaccination, allergic disease, medication, history of coronavirus disease 2019 (COVID-19), and adverse reactions 7 days following the first and second BNT162b2 vaccination using a questionnaire. Our results were compared with previously reported results for individuals aged 12–15 years. A total of 421 participants were eligible for this study. Among the 216 patients with allergic disease, 48 (22.2%) had experienced worsening of their chronic diseases, and the frequency of fatigue and dizziness after the second dose was higher than that of healthy individuals. The experience of systemic adverse reactions was associated with asthma. The frequency of headache, diarrhea, fatigue, muscle/joint pain, and fever after the second BNT162b2 vaccination was lower in individuals aged 5–11 years than in those aged 12–15 years. Fever was the only systemic adverse reaction that lasted longer than 5 days (1.0% of participants). Conclusions: Individuals with allergic diseases, who are potentially susceptible to COVID-19, may experience worsening of their chronic diseases and more frequent adverse reactions after BNT162b2 vaccination than healthy individuals. To ensure that children with allergic diseases receive the vaccine safely, further information needs to be collected.What is Known:• Adverse reactions afterBNT162b2 vaccination among individuals aged 5–11 years are generallynonserious, more common after second vaccination, and substantially less commoncompared to those observed among individuals aged 12–15 years.What is New:• Individuals with allergic diseasesexperienced worsening of their chronic diseases and more frequent adversereactions after BNT162b2 vaccination than healthy individuals.• Systemic adverse reactions were associatedwith asthma. Fever was the only systemic adversereaction that lasted longer than 5 days.

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Humoral and cellular immune response dynamics in Japanese healthcare workers up to six months after receiving a third dose of BNT162b2 monovalent vaccine

Uwamino Y, Yokoyama T, Sato Y, Shibata A, Kurafuji T, Tanabe A, Noguchi M, Arai T, Ohno A, Yokota H, Namkoong H, Nishimura T, Kosaki K, Hasegawa N, Wakui M, Murata M, Matsushita H

Vaccine (Vaccine)  41 ( 9 ) 1545 - 1549 2023

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0264410X

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Longitudinal data on the immune response from the first dose to several months after the third dose of COVID-19 vaccine are limited. We analyzed the immune response in 406 Japanese healthcare workers who received at least three doses of vaccine. The geometric mean anti-receptor binding domain IgG antibody titers and antigen-stimulated T-cell interferon-gamma levels after 6 months after receiving a third dose were similar to those 8 weeks after receiving a second dose. Humoral and cellular immunity induced by the third dose was more durable than that induced by the second dose. UMIN Clinical Trials Registry ID: UMIN000043340.

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APTT

涌井昌俊

検査と技術 (医学書院)  51 ( 9 ) 956 - 960 2023

Research paper (scientific journal), Single Work, Lead author, Corresponding author

PT

涌井昌俊

検査と技術 (医学書院)  51 ( 9 ) 951 - 955 2023

Research paper (scientific journal), Single Work, Lead author, Corresponding author

Estimating immunity with mathematical models for SARS-CoV-2 after COVID-19 vaccination

Uwamino Y, Nagashima K, Yoshifuji A, Suga S, Nagao M, Fujisawa T, Ryuzaki M, Takemoto Y, Namkoong H, Wakui M, Matsushita H, Hasegawa N, Sato Y, Murata M

NPJ Vaccines (npj Vaccines)  8 ( 1 ) 33 2023

Research paper (scientific journal), Joint Work, Accepted

　View Summary

Tools that can be used to estimate antibody waning following COVID-19 vaccinations can facilitate an understanding of the current immune status of the population. In this study, a two-compartment-based mathematical model is formulated to describe the dynamics of the anti-SARS-CoV-2 antibody in healthy adults using serially measured waning antibody concentration data obtained in a prospective cohort study of 673 healthcare providers vaccinated with two doses of BNT162b2 vaccine. The datasets of 165 healthcare providers and 292 elderly patients with or without hemodialysis were used for external validation. Internal validation of the model demonstrated 97.0% accuracy, and external validation of the datasets of healthcare workers, hemodialysis patients, and nondialysis patients demonstrated 98.2%, 83.3%, and 83.8% accuracy, respectively. The internal and external validations demonstrated that this model also fits the data of various populations with or without underlying illnesses. Furthermore, using this model, we developed a smart device application that can rapidly calculate the timing of negative seroconversion.

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Five doses of the mRNA vaccination potentially suppress ancestralstrain stimulated SARS-CoV2-specific cellular immunity: A cohort study from the Fukushima Vaccination Community Survey, Japan

Tani Y, Takita M, Wakui M, Saito H, Tianchen Z, Yamamoto C, Kawamura T, Sugiyama A, Nakayama A, Kaneko Y, Kodama T, Tsubokura M

Front Immunol (Frontiers in Immunology)  14   10.3389/fimmu.2023 2023

Research paper (scientific journal), Joint Work, Accepted

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The bivalent mRNA vaccine is recommended to address coronavirus disease variants, with additional doses suggested for high-risk groups. However, the effectiveness, optimal frequency, and number of doses remain uncertain. In this study, we examined the long-term cellular and humoral immune responses following the fifth administration of the mRNA severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in patients undergoing hemodialysis. To our knowledge, this is the first study to monitor long-term data on humoral and cellular immunity dynamics in high-risk populations after five doses of mRNA vaccination, including the bivalent mRNA vaccine. Whereas most patients maintained humoral immunity throughout the observation period, we observed reduced cellular immune reactivity as measured by the ancestral-strain-stimulated ELISpot assay in a subset of patients. Half of the individuals (50%; 14/28) maintained cellular immunity three months after the fifth dose, despite acquiring humoral immunity. The absence of a relationship between positive controls and T-Spot reactivity suggests that these immune alterations were specific to SARS-CoV-2. In multivariable analysis, participants aged ≥70 years showed a marginally significant lower likelihood of having reactive results. Notably, among the 14 individuals who received heterologous vaccines, 13 successfully acquired cellular immunity, supporting the effectiveness of this administration strategy. These findings provide valuable insights for future vaccination strategies in vulnerable populations. However, further research is needed to evaluate the involvement of immune tolerance and exhaustion through repeated vaccination to optimize immunization strategies.

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Assessing anti-SARS-CoV-2 cellular immunity in 571 vaccinees by using an interferon-gamma release assay

Wakui M, Uwamino Y, Yatabe Y, Nakagawa T, Sakai A, Kurafuji T, Shibata A, Tomita Y, Noguchi M, Tanabe A, Arai T, Ohno A, Yokota H, Uno S, Yamasawa W, Sato Y, Ikeda M, Yoshimura A, Hasegawa N, Saya H, Murata M

Eur J Immunol (European Journal of Immunology)  52 ( 12 ) 1961 - 1971 2022.12

Research paper (scientific journal), Joint Work, Lead author, Corresponding author, Accepted,  ISSN  00142980

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Memory T cell responses have been analyzed only in small cohorts of COVID-19 vaccines. Herein, we aimed to assess anti-SARS-CoV-2 cellular immunity in a large cohort using QuantiFERON assays, which are IFN-γ release assays (IGRAs) based on short-term whole blood culture. The study included 571 individuals receiving the viral spike (S) protein-expressing BNT162b2 mRNA vaccine. QuantiFERON assays revealed antigen-specific IFN-γ production in most individuals 8 weeks after the second dose. Simultaneous flow cytometric assays to detect T cells expressing activation-induced markers (AIMs) performed for 28 randomly selected individuals provided data correlating with the QuantiFERON data. Simultaneous IFN-γ enzyme-linked immunospot and AIM assays for another subset of 31 individuals, based on short-term peripheral blood mononuclear cell culture, also indicated a correlation between IFN-γ production and AIM positivity. These observations indicated the acquisition of T cell memory responses and supported the usability of IGRAs to assess cellular immunity. The QuantiFERON results were weakly correlated with serum IgG titers against the receptor-binding domain of the S protein and were associated with pre-vaccination infection and adverse reactions after the second dose. The present study revealed cellular immunity after COVID-19 vaccination, providing insights into the effects and adverse reactions of vaccination.

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Memory B cells and memory T cells induced by SARS-CoV-2 booster vaccination or infection show different dynamics and responsiveness to the omicron variant

Mise-Omata S, Ikeda M, Takeshita M, Uwamino Y, Wakui M, Arai T, Yoshifuji A, Murano K, Siomi H, Nakagawara K, Ohyagi M, Ando M, Hasegawa N, Saya H, Murata M, Fukunaga K, Namkoong H, Lu X, Yamasaki S, Yoshimura A

J Immunol (Journal of immunology (Baltimore, Md. : 1950))  209 ( 11 ) 2104 - 2113 2022.12

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00221767

　View Summary

Although the immunological memory produced by BNT162b2 vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been well studied and established, further information using different racial cohorts is necessary to understand the overall immunological response to vaccination. We evaluated memory B and T cell responses to the severe acute respiratory syndrome coronavirus 2 spike protein before and after the third booster using a Japanese cohort. Although the Ab titer against the spike receptor-binding domain (RBD) decreased significantly 8 mo after the second vaccination, the number of memory B cells continued to increase, whereas the number of memory T cells decreased slowly. Memory B and T cells from unvaccinated infected patients showed similar kinetics. After the third vaccination, the Ab titer increased to the level of the second vaccination, and memory B cells increased at significantly higher levels before the booster, whereas memory T cells recovered close to the second vaccination levels. In memory T cells, the frequency of CXCR5+CXCR3+CCR6- circulating follicular Th1 was positively correlated with RBD-specific Ab-secreting B cells. For the response to variant RBDs, although 60-80% of memory B cells could bind to the omicron RBD, their avidity was low, whereas memory T cells show an equal response to the omicron spike. Thus, the persistent presence of memory B and T cells will quickly upregulate Ab production and T cell responses after omicron strain infection, which prevents severe illness and death due to coronavirus disease 2019.

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Clot waveform analysis for perioperative hemostatic monitoring in a hemophilia A patient on emicizumab undergoing liver transplantation (preprint)

Awane M, Wakui M, Ozaki Y, KondoY, Oka S, Fujimori Y, Yatabe Y, Arai T, Yamada Y, Hori S, Obara H, Hasegawa Y, Matsushita H

Research Square preprint 2022.12

Research paper (scientific journal), Joint Work, Lead author, Corresponding author

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プロトロンビン時間（PT）の試薬特性

涌井昌俊

検査と技術 (医学書院)  50 ( 7 ) 728 - 734 2022.07

Research paper (scientific journal), Single Work

メタクロマジー核酸染色によるRNP法TMを用いたCelltac G+TM試作機.の網赤血球算定の基礎的性能

荒井智子、片桐尚子、近藤直美、谷田部陽子、横田浩充、永井豊、三ツ橋雄之、涌井昌俊、村田満

日本検査血液学会雑誌 23 ( 2 ) 265 - 273 2022.07

Research paper (scientific journal), Joint Work, Accepted

COVID-19の免疫とワクチン

涌井昌俊

The Lipid 33 ( 1 ) 14 - 22 2022.04

Research paper (scientific journal), Single Work

Response kinetics of different classes of antibodies to SARS-CoV2 infection in the Japanese population: the IgA and IgG titers increased earlier than the IgM titers

KuranoM, Morita Y, Nakano Y, Yokoyama R, Shimura T, Qian C, Xia F, He F, Zheng L, Ohmiya H, Kishi Y, Okada J, Yoshikawa N, Nakajima K, Nagura Y, Okazaki H, Jubishi D, Moriya K, Seto Y, Yasui F, Kohara M, Wakui M, Kawamura T, Kodama T, Yatomi Y

Int Immunopharmacol (International Immunopharmacology)  103   1089491 2022.02

Research paper (scientific journal), Joint Work, Accepted,  ISSN  15675769

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To better understand the immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with COVID-19, it is important to investigate the kinetics of the antibody responses and their associations with the clinical course in different populations, since there seem to be considerable differences between Western and Asian populations in the clinical features and spread of COVID-19. In this study, we serially measured the serum titers of IgM, IgG and IgA antibodies generated against the nucleocapsid protein (NCP), S1 subunit of the spike protein (S1), and receptor-binding domain in the S1 subunit (RBD) of SARS-CoV-2 in Japanese individuals with COVID-19. Among the IgM, IgG, and IgA antibodies, IgA antibodies against all of the aforementioned viral proteins were the first to appear after the infection, and IgG and/or IgA seroconversion often preceded IgM seroconversion. In regard to the timeline of the antibody responses to the different viral proteins (NCP, S1 and RBD), IgA against NCP appeared than IgA against S1 or RBD, while IgM and IgG against S1 appeared earlier than IgM/IgG against NCP or RBD. The IgG responses to all three viral proteins and responses of all three antibody classes to S1 and RBD were sustained for longer durations than the IgA/IgM responses to all three viral proteins and responses of all three antibody classes to NCP, respectively. The seroconversion of IgA against NCP occurred later and less frequently in patients with mild COVID-19. These results suggest possible differences in the antibody responses to SARS-CoV-2 antigens between the Japanese and Western populations.

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Young age, female sex, and presence of systemic adverse reactions are associated with high post-vaccination antibody titer after two doses of BNT162b2 mRNA SARS-CoV-2 vaccination: An observational study of 646 Japanese healthcare workers and university staff

Uwamino Y, Kurafuji T, Sato Y, Tomita Y, Shibata A, Tanabe A, Yatabe Y, Noguchi M, Sakai A, Noguchi M, Arai T, Ohno A, Yokota H, Yamasawa W, Uno S, Nishimura T, Hasegawa N, Saya H, Wakui M*, Murata M

Vaccine (Vaccine)  40 ( 7 ) 1019 - 1025 2022.02

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0264410X

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Background: SARS-CoV-2 vaccination has started worldwide, including Japan. Although high rates of vaccine response and adverse reactions of BNT162b2 vaccine have been reported, knowledge about the relationship between sex differences and antibody response is limited. Furthermore, it is uncertain whether adverse reactions are associated with the vaccine response. Methods: This prospective observational study included 673 Japanese participants working in a medical school and its affiliated hospital in Tokyo, Japan (UMIN000043340). Serum samples were collected before the first dose and three weeks after the second dose of BNT162b2 vaccine, and antibody titers against the receptor-binding domain of the spike protein of SARS-CoV-2 were measured. Answers to questionnaires about background characteristics and adverse reactions were obtained at the time of sample collection, and the relationship between antibody titers was analyzed. Results: After excluding participants who did not complete receiving two doses of vaccination or two series of serum sample collection, 646 participants were analyzed. Although all participants became sero-positive after vaccination, antibody titers were highly variable among individuals (260.9–57,399.7A U/mL), with a median titer of 13478.0AU/mL. Mean titer was higher in females than in males and higher in young (≤45 years old) participants than in aged (>45 years old) participants. Participants who experienced adverse reactions demonstrated a higher antibody titer after vaccination than those without adverse reactions. Multivariable analysis demonstrated that young age, female sex, and adverse reactions after the second dose were independently related to higher antibody titers after the second dose. Discussion: A favorable antibody response was observed after two doses of BNT162b2 vaccination among mostly healthy Japanese participants, especially among female and young participants. Although further investigation is essential, our results imply that the systemic adverse reactions (i.e., fever and general fatigue) are associated with a higher antibody response that indicates the acquisition of humoral immunity.

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凝固波形解析

涌井昌俊

血栓止血誌 33 ( 1 ) 69 - 74 2022.02

Research paper (scientific journal), Single Work

Dynamics of antibody response and cellular immunity after two doses of BNT162b2 mRNA vaccine over 6 months among Japanese healthcare providers and breakthrough infections (preprint)

Uwamino Y*, Kurafuji T, Takato K, Sakai A, Tanabe A, Noguchi M, Yatabe Y, Arai T, Ohno A, Tomita Y, Shibata A, Yokota H, Yamasawa W, Namkoong H, Sato Y, Hasegawa N, Wakui M, Murata M

medRxi preprint 2022.01

Research paper (scientific journal), Joint Work

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The effect of the E484K mutation of SARS-CoV-2 on the neutralizing activity of antibodies from BNT162b2 vaccinated individuals

Uwamino Y, Yokoyama T#, ShimamuraT, Nishimura T, Sato Y, Wakui M, Kosaki K, Hasegawa N, Murata M

Vaccine (Vaccine)  40 ( 13 ) 1928 - 1931 2022

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0264410X

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The reduced vaccine efficacy against the SARS-CoV-2 variant lineage B. 1.351 (beta variant) containing the E484K and N501Y mutations is well known. The E484K mutation in SARS-CoV-2 is thought to be responsible for weakened humoral immunity. Vaccine efficacy against the R.1 lineage, which contains the E484K mutation but not the N501Y mutation, is uncertain. Serum samples were collected from 100 healthy Japanese participants three weeks after receiving the second dose of the BNT162b2 vaccine, and serum neutralization antibody titers were measured against five SARS-CoV-2 variants. The geometric mean neutralization titers measured for the original and R.1 lineages were equivalent (91.90 ± 2.40 and 102.67 ± 2.28, respectively), whereas a low titer was measured for the beta variant (18.03 ± 1.92). Although further investigations with other variant strains and serum samples are essential, our results imply that the weakened humoral response is not caused solely by the E484K mutation. (UMIN000043340).

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Dynamics of antibody titers and cellular immunity among Japanese healthcare workers during the 6 months after receiving two doses of BNT162b2 mRNA vaccine

Uwamino Y, Kurafuji T, Takato K, Sakai A, Tanabe A, Noguchi M, Yatabe Y, Arai T, Ohno A, Tomita Y, Shibata A, Yokota H, Yamasawa W, Namkoong H, Sato Y, Hasegawa N, Wakui M, Murata M

Vaccine (Vaccine)  40 ( 32 ) 4538 - 4543 2022

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0264410X

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Background: The antibody titer is known to wane within months after receiving two doses of the Pfizer-BioNTech BNT162b2 mRNA SARS-CoV-2 vaccine. However, knowledge of the cellular immune response dynamics following vaccination is limited. This study to aimed to determine antibody and cellular immune responses following vaccination, and the incidence and determinants of breakthrough infection. Methods: This prospective cohort study a 6-month follow-up period was conducted among Japanese healthcare workers. All participants received two doses of BNT162b2 vaccine. Anti-SARS-CoV-2 antibody titers and T-cell immune responses were measured in serum samples collected at several timepoints before and after vaccination. Results: A total of 608 participants were included in the analysis. Antibody titers were elevated 3 weeks after vaccination and waned over the remainder of the study period. T-cell immune responses showed similar dynamics. Six participants without predisposing medical conditions seroconverted from negative to positive on the IgG assay for nucleocapsid proteins, indicating breakthrough SARS-CoV-2 infection. Five of the six breakthrough infections were asymptomatic. Conclusions: Both humoral and cellular immunity waned within 6 months after BNT162b2 vaccination. The incidence of asymptomatic breakthrough infection within 6 months after vaccination was approximately one percent. UMIN Clinical Trials Registry ID: UMIN000043340.

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Performance evaluation of a novel reticulocyte identification method using metachromatic nucleic acid staining based on a crossover analysis of emission DNA/RNA light (RNP DeterminationTM) in hematology analyzer Celltac G+

Yahagi K, Arai T, Katagiri H, Yatabe Y, Yokota H, Nagai Y, Mitsuhashi T, Wakui M, Murata M

Int J Lab Hematol (International Journal of Laboratory Hematology)  44 ( 6 ) 1050 - 1059 2022

Research paper (scientific journal), Joint Work, Accepted,  ISSN  17515521

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Introduction: Assessing the percentage of reticulocytes (%Retic) is useful for diagnosing and treating blood diseases that present with anaemia. The Celltac G+™ hematology analyzer (HA) uses a novel reticulocyte identification method that involves metachromatic nucleic acid staining with acridine orange and crossover analysis of emission light of DNA/RNA (determination of red cells, nucleic acid-containing cells, and platelets, RNP Determination™). The red and green fluorescence generated by stained single-stranded RNA and double-stranded DNA express immaturity and morphological abnormality of erythrocytes by detecting erythrocyte RNA and DNA content. Methods: The basic performance of the test automated analyzer (TAA) Celltac G+ was evaluated and compared with the flow cytometry reference method and the comparative automated analyzer (CAA) XN-1000/2000™. In addition, its precision, limit of quantity (LoQ), linearity, analytical measurement interval (AMI), accuracy, and comparability and the effects of interfering substances were evaluated. Results: Evaluation of %Retic by the TAA demonstrated good precision and linearity. The AMI was confirmed from 0.02 to 8.23, and the LoQ in %Retic as the coefficient of variation within an 11% limit (SD, within a 0.01 limit) was 0.14. TAA correlated well with the reference method and routine HA (CAA). Some deviations were found between TAA and CAA in DNA measurements of erythrocytes from abnormal samples. Conclusion: Celltac G+ uses a novel measurement principle and can assess erythrocyte immaturity independent of DNA contents. It represents a new HA that provides novel, useful information on immaturity and morphological abnormality of erythrocytes.

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Time course of adverse reactions after BNT162b2 vaccination in healthy and allergic disease individuals aged 5–11 years: an observational and historical cohort study (preprint)

Yoshida M, Kobashi Y, Shimazu Y, Saito H, Yamamoto C, Kawamura T, Wakui M, Takahashi K, Ito N, Nishikawa Y, Zhao T, Tsubokura M

Research Square  2022

Research paper (scientific journal), Joint Work

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What proportion of population is induced cellular immunity against SARS-CoV-2 after booster vaccination: a cross-sectional study (preprint)

Tani Y, Takita M, Kobashi Y, Wakui M, Tianchen Z, Yamamoto C, Saito H, Kawashima M, Sugiura S, Nishikawa Y, Omata F, Shimazu Y, Kawamura T, Sugiyama A, Nakayama A, Kaneko Y, Kodama T, Kami M, Tsubokura M

Research Square  2022

Research paper (scientific journal), Joint Work

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Anti-SARS-CoV-2 cellular immunity in 571 vaccinees assessed using an interferon-gamma release assay (preprint)

Uwamino Y, Wakui M, Yatabe Y, Nakagawa T, Sakai A, Kurafuji T, Shibata A, Tomita Y, Noguchi M, Tanabe A, Arai T, Ohno A, Yokota H, Uno S, Yamasawa W, Sato Y, Ikeda M, Yoshimura A, Hasegawa N, Saya H, Murata M

medRxiv  2021.12

Research paper (other academic), Joint Work

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How clinical laboratory physicians should stand and go on in near future: Their individuality and cooperativity expected for medical practice and science— Chairpersons’ remarks —

Wakui M, Tabe Y

Rinsho Byori (日本臨床検査医学会)  69 ( 12 ) 943 - 944 2021.12

Research paper (scientific journal)

Alinity hq platelet results are equivalent with the international reference method in thrombocytopenic samples

Lifson MA, Wakui M, Arai T, Mitsuhashi T, Lakos G, Murata M

Int J Lab Hematol (International Journal of Laboratory Hematology)  43 ( 6 ) 1357 - 1362 2021.12

Research paper (scientific journal), Joint Work, Accepted,  ISSN  17515521

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Introduction: Accurate and precise platelet (PLT) count is critical for the appropriate management of patients with thrombocytopenia. This study evaluated the performance of PLT counting with the Abbott Alinity hq hematology analyzer, which utilizes multi-dimensional optical technology. Methods: Imprecision, linearity, and accuracy were assessed per CLSI guidelines. Alinity hq PLT results were compared to the international flow cytometry reference method (IRM) in the concentration range of 6.3 to 103.0 × 109/L. Additional comparisons were made with Sysmex XN-3000 PLT counts: impedance (PLT-I), optical (PLT-O), and optical fluorescent (PLT-F) methods. Results: The average within-run %CV was 4.7% on patient samples with PLT concentrations ranging from 13.1 to 41.7 × 109/L, and the within-laboratory %CV was 3.6% at the level of 68.2 × 109/L. Linearity evaluation indicated a maximum deviation of 3.1% from the linear fit in the range of 0.1 to 316.8 × 109/L. Comparison between Alinity hq and the IRM PLT counts yielded a correlation coefficient of 0.99 and predicted bias of 0.0 and −0.5 × 109/L at 10.0 and 20.0 × 109/L transfusion thresholds, respectively. Alinity hq PLT counts also correlated well with Sysmex PLT counts, with strongest correlation obtained with PLT-F and PLT-O (r =.99) methods. Conclusion: This study demonstrated excellent analytical performance of Alinity hq PLT counting in thrombocytopenic samples, equivalency with the IRM and strong agreement with Sysmex PLT-F and PLT-O methods. The Alinity hq multi-dimensional optical PLT count is available with every CBC without additional reagents and may help promote efficiency in clinical laboratories.

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コロナ抗体検査の現況　～ワクチン接種後のコロナ抗体価の動態、データの見方～

涌井昌俊

臨床検査支援協会機関紙ASCL LETTER (臨床検査支援協会)   ( 2 ) 11 - 11 2021.12

Research paper (other academic), Single Work

抗体検査と免疫学

涌井昌俊

診断と治療 (診断と治療社)  109 ( 11 ) 1521 - 1525 2021.11

Research paper (scientific journal), Single Work

Characterization of antithrombin-dependent anticoagulants through clot waveform analysis to potentially distinguish them from antithrombin-independent inhibitors targeting activated coagulation factors

Wakui M, Fujimori Y, Nakamura S, Oka S, Ozaki Y, Kondo Y, Nakagawa T, Katagiri H, Murata M

Journal of Clinical Pathology (Journal of Clinical Pathology)  74 ( 4 ) 251 - 256 2021

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00219746

　View Summary

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ. Aims: While antithrombin (AT)-independent inhibitors targeting thrombin or activated factor X have been assessed through clot waveform (CWA), there are no reports on assessment with respect to AT-dependent anticoagulants. The present study aims to characterise AT-dependent anticoagulants through CWA to distinguish them from AT-independent inhibitors. Methods: CWA was applied to the activated partial thromboplastin time (APTT) assay of plasma samples spiked with each of AT-dependent drugs (unfractionated heparin, enoxaparin and fondaparinux) and AT-independent drugs (rivaroxaban, apixaban, edoxaban, dabigatran, argatroban, hirudin and bivalirudin), which was performed using the CS-5100 or CN-6000 (Sysmex). The APTT-CWA data were automatically gained by the analyser program. The positive mode of clotting reaction curves was defined as the direction towards fibrin generation. Results: Regarding dose-response curves in AT-dependent anticoagulants, the maximum positive values of the first and secondary derivatives (Max1 and Maxp2, respectively) and the maximum negative values of the secondary derivative (Maxn2) seemed to drop to zero without making an asymptotic line, consistent with the irreversibility. Such a feature was observed also in hirudin, as reported previously. Notably, the symmetric property of Max1 peaks in the waveforms was distorted dose dependently in AT independent but not AT-dependent drugs. A plot of Maxp2 logarithm versus Maxn2 logarithm was linear. The slope was about 1 in AT-dependent drugs while that was more than 1 in AT-independent drugs. These features made it possible to distinguish AT-dependent and AT-independent drugs. Conclusions: The results aid in further understanding of the pharmacological aspects of anticoagulation and in screening of candidates for novel anticoagulants.

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Evaluation of usability of various rapid antibody tests in diagnostic application for COVID-19

Uwamino Y, Wakui M*#, Aoki W, Kurafuji T, Yanagita E, Morita M, Nagata M, nose R, Noguchi M, Yokota H, Hasegawa N, Saya H, Murata M and for the Keio Donner Project Team

Annal Clin Biochem ({SAGE} Publications)  58 ( 3 ) 174 - 180 2021

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00045632

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© The Author(s) 2021. Background: The usability of laboratory tests related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critically important for the world undergoing the COVID-19 pandemic. The present study aimed to assess the diagnostic usability of rapid tests for the detection of antibody against SARS-CoV-2 through comparison of their results with the results of reverse transcription polymerase chain reaction (RT-PCR) test for the detection of SARS-CoV-2 genomic RNA and with the results of a quantitative test for antibody detection. Methods: Serum samples were collected from 18 patients undergoing RT-PCR testing for SARS-CoV-2. Twelve patients were RT-PCR positive while six were negative. A quantitative test based on chemiluminescent immunoassay and three rapid tests based on immunochromatography were performed to detect anti-SARS-CoV-2 IgG and IgM. Results: All the antibody tests exhibited poor sensitivity at the timing of initial RT-PCR diagnosis. IgG responses occurring prior to or simultaneously with IgM responses were observed through not only the quantitative test but also the three rapid tests. Based on concordance with the quantitative test results, the large variance among the three rapid tests was revealed. Conclusions: All antibody tests were unsatisfactory to replace RT-PCR for the early diagnosis of COVID-19. Rapid antibody tests as well as a quantitative antibody test were useful in the assessment of immune responses in COVID-19. The obvious variance among the three rapid tests suggested limited accuracy and difficult standardization. Diagnostic usability of rapid antibody tests for COVID-19 should be investigated rigorously.

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Assessment of humoral responses in COVID-19 using various quantitative antibody tests

Wakui M, Uwamino Y, Kurafuji T, Noguchi M, Ohno A, Yokota H, Kikuchi H, Hasegawa N, Saya H, Murata M and for the Keio Donner Project Team

Ann Clin Biochem ({SAGE} Publications)  58 ( 4 ) 368 - 376 2021

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00045632

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Background: Quantitative antibody tests are expected to be useful in diagnostics of COVID-19 and investigation of herd immunity against SARS-CoV-2. To make it proper to perform them, understanding of the immunological aspects is critically important. The present study aimed to assess humoral responses in COVID-19 using various quantitative antibody tests. Methods: Four quantitative antibody tests that are different in targeted antigens, detectable immunoglobulin classes and avidity were used. Diagnosis was confirmed by RT-PCR for SARS-CoV-2 detection. Antibody titres of 117 samples collected from 24 COVID-19 patients and 23 non-COVID-19 patients were measured to evaluate correlations between different tests. For 24 COVID-19 patients, antibody titres measured at various time points after the onset or the RT-PCR diagnosis were subjected to assessment of humoral responses. Results: Correlations between tests were observed to some degree, although there were discrepancies putatively due to differences in measurement principle. Seronegative COVID-19 was diagnosed for some patients, in whom antibody titres were less than the cut-off value in each test throughout the time courses. IgG seroconversion without prior IgM seroconversion most frequently occurred, while predominance of IgM responses over IgG responses was observed in some severe cases. Viral burdens estimated according to threshold cycle values at the RT-PCR seemed to impact antibody responses. Conclusions: The results provide insights into the nature of humoral responses to SARS-CoV-2 and diagnostic performance of antibody tests.

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In vitro unexpected effects of polyphosphates observed through activated partial thromboplastin time-based clot waveform analysis

Ozaki Y, Wakui M*#, Fujimori Y, Oka S, Nakamura S, Kondo Y, Nakagawa T, Katagiri H, Murata M

Int J Lab Hematol (International Journal of Laboratory Hematology)  43 ( 4 ) O234 - O237 2021

Research paper (scientific journal), Joint Work, Accepted,  ISSN  17515521

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各種検査領域における緊急検査　3) 血液検査 (3) 凝固・線溶検査

涌井昌俊

Medical Technology 臨時増刊号 『必携！日当直の緊急検査マニュアル』 (医歯薬出版)  49 ( 13 ) 1417 - 1423 2021

Research paper (other academic)

増刊号：よくある質問にパッと答えられる—見開き！ 検査相談室 “血液疾患以外におけるフローサイトメトリーの活用について教えてください”

谷田部陽子、涌井昌俊

臨床検査 65 ( 4 ) 332 - 333 2021

Research paper (scientific journal), Joint Work, Last author

先天性副腎過形成症におけるGC/MS尿ステロイドプロフィル検査の意義

中川央充、本間桂子、涌井昌俊、村田　満、長谷川奉延

糖尿尿・内分泌代謝科 53 ( 1 ) 111 2021

Research paper (scientific journal), Joint Work

血栓性素因（Thrombophilia）

涌井昌俊

HemosIL News (アイ・エル・ジャパン)  16 2020.12

Research paper (other academic), Single Work

Expertises required in laboratory medicine that contributes to medical research and care becoming diversified

Masatoshi Wakui

Rinsho Byori (日本臨床検査医学会)  68 ( 6 ) 535 - 540 2020.06

Research paper (scientific journal), Single Work

Application of clot-fibrinolysis waveform analysis to assessment of in vitro effects of direct oral anticoagulants on fibrinolysis

Oka S, Wakui M, Fujimori Y, Kuroda Y, Nakamura S, Kondo Y, Nakagawa T, Katagiri H, Murata M

Int J Lab Hematol (International Journal of Laboratory Hematology)  42 ( 3 ) 292 - 298 2020.06

Research paper (scientific journal), Joint Work, Accepted,  ISSN  17515521

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© 2020 John Wiley & Sons Ltd Introduction: Acceleration of fibrinolysis by direct oral anticoagulants (DOACs) has been reported by several groups, suggesting contribution of not only anticoagulant but also fibrinolytic effects to the therapeutic efficacy. The present study aims to evaluate the usability of clot-fibrinolysis waveform analysis (CFWA) for assessment of in vitro effects of DOACs on fibrinolysis. Methods: The experimental conditions were optimized according to how t-PA concentrations and a time length after t-PA adjustment affect parameters of CFWA. Addition of the activated partial thromboplastin time (APTT) reagent followed by that of calcium and t-PA was done to obtain clotting and fibrinolytic reaction curves which were mathematically differentiated for CFWA (APTT-CFWA). The positive and negative modes of waveforms were defined as the direction toward fibrin generation and that toward fibrin degradation, respectively. The maximum positive and negative values (Maxp1 and Maxn1) correspond to the maximum coagulation velocity and the maximum fibrinolysis velocity, respectively. Plasma spiked with each of DOACs (rivaroxaban, apixaban, edoxaban, and dabigatran) was subjected to APTT-CFWA. Results: Optimization of t-PA use was based on Maxn1. Roughly biphasic effects of rivaroxaban and dabigatran but not apixaban or edoxaban on fibrinolysis were observed through Maxn1 and the fibrinolysis peak time, which was defined as a time length from the time when Maxp1 (Maxp1 time) to the time when Maxn1 appears (Maxn1 time). Conclusion: The results suggest the usability of CFWA for assessment of DOAC effects and provide insights into relevance of anticoagulation to therapeutic efficacy and bleeding risk from the perspective of fibrinolysis.

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CWAによる基礎的検討

涌井昌俊

Thrombosis Medicine (先端医学社)  10 ( 1 ) 45 - 54 2020.03

Research paper (other academic), Single Work

Effect of refrigeration of blood samples in lithium-heparin tubes on QuantiFERON TB Gold Plus test result

Uwamino Y, Sakai A, Nishimura T, Noguchi M, Uno S, Fujiwara H Mori M, Wakui M, Murata M, Hasegawa N

J Infect Chemother (Journal of Infection and Chemotherapy)  26 ( 3 ) 312 - 314 2020.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1341321X

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© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases The QuantiFERON TB Gold Plus (QFT-Plus) test is a newly approved interferon-gamma releasing assay test for detecting latent tuberculosis. Although blood samples for QFT test can be refrigerated for 48 h in lithium-heparin tubes according to package inserts, no published data are available on the effects of sample refrigeration on the test results. We conducted a clinical study that aimed to elucidate whether sample refrigeration for 48 h affects QFT-Plus test results. We collected 2 blood samples each from 40 participants for QFT-Plus; one sample was refrigerated before incubation for QFT-Plus assay, while the other sample was incubated soon after collection and treated as control. After comparing QFT-Plus test results of refrigerated samples and control samples, the concordance rate and kappa coefficient between them were 95% and 0.90, respectively. Thus, blood samples for QFT-Plus test can be refrigerated for 48 h in lithium-heparin tubes without influencing the test results.

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臨床検査における質量分析法の可能性と落とし穴

涌井昌俊、中川央充

臨床検査 (医学書院)  64 ( 3 ) 262 - 271 2020.03

Research paper (scientific journal), Joint Work

Distinct features of bivalent direct thrombin inhibitors, hirudin and bivalirudin, revealed by clot waveform analysis and enzyme kinetics in coagulation assays

Wakui M, Fujimori Y, Nakamura S, Kondo Y, Kuroda Y, Oka S, Nakagawa T, Katagiri H, Murata M

J Clin Pathol (Journal of Clinical Pathology)  72 ( 12 ) 817 - 824 2019.12

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00219746

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© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. Aims Bivalent direct thrombin inhibitors (DTIs), hirudin and bivalirudin, bind to the active site and exosite 1 of thrombin irreversibly and reversibly, respectively. The present study aims to assess in vitro effects of hirudin and bivalirudin through clot waveform analysis (CWA) and enzyme kinetics in coagulation assays. Methods The pooled normal plasma and its dilutions were spiked with hirudin or bivalirudin. The activated partial thromboplastin time (APTT) assay and the Clauss fibrinogen assay were performed using the CS-5100 (Sysmex). The APTT-CWA data were automatically gained by the CS-5100 programme. Results In APTT-CWA, the maximum coagulation velocity, acceleration and deceleration were decreased dependently on the drug concentrations, demonstrating evidence for the blockade of thrombin-positive feedback by hirudin or bivalirudin. The Hill plot analysis was applied to the dose-dependent curves in bivalirudin. The Hill coefficients were greater than 1, showing positive anticoagulant cooperativity. Regarding the dose-dependent curves in hirudin, all the parameters dropped to almost zero without making an asymptotic line. In the Clauss fibrinogen assay, the Lineweaver-Burk plots demonstrated that both drugs exhibit mixed inhibition mimicking uncompetitive binding. The Dixon plots in bivalirudin were linear and supported the inhibition type described above. The Dixon plots in hirudin were non-linear and inappropriate to use for determination of the inhibition type. In addition, the inverse function of the clotting time appeared to drop to zero without making an asymptotic line, suggesting complete loss of thrombin activity by irreversible binding. Conclusions The results provide insights into anticoagulation with bivalent DTIs.

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Intensive optimization and evaluation of global DNA methylation quantification using LC-MS/MS

Nakagawa T, Wakui M, Hayashida T, Nishime C, Murata M

Anal Bioanal Chem (Analytical and Bioanalytical Chemistry)  411 ( 27 ) 7221 - 7231 2019.11

Research paper (scientific journal), Joint Work, Accepted,  ISSN  16182642

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© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. DNA methylation is a typical epigenetic phenomenon. Numerous methods for detecting global DNA methylation levels have been developed, among which LC-MS/MS has emerged as an excellent method from the viewpoint of sensitivity, reproducibility, and cost. However, LC-MS/MS methods have limitations due to a lack of the stability and the standardization required for a laboratory assay. The present study aimed to establish a robust assay that guarantees highly accurate measurements of global DNA methylation levels. There are at least three facets of the developed method. The first is discovery of the solvent conditions to minimize sodium adducts. The second is improvement of separation of nucleosides by LC using the columns that had not been used in previous similar studies. The third is success in reduction of the uncertainty of the measurement results, which was achieved by the calibration using the ratio of mdC but not the absolute amount in the presence of internal standards. These facets represent the advantage over methods reported previously. Our developed method enables quantification of DNA methylation with a short time length (8 min) for one analysis as well as with the high reproducibility of measurements that is represented by the inter-day CV% being less than 5%. In addition, data obtained from measuring global DNA methylation levels in cultured cell lines, with or without pharmacological demethylation, support its use for biomedical research. This assay is expected to allow us to conduct initial screening of epigenetic alterations or aberration in a variety of cells.

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Clot waveform analysis applied to assessment of in vitro effects of anticoagulants

Wakui M, Fujimori Y, Oka S, Katagiri H

Rinsho Byori (日本臨床検査医学会)  67 ( 10 ) 1046 - 1058 2019.10

Research paper (scientific journal), Joint Work

血小板機能異常、凝固異常時に使用する検査とその解釈

片桐尚子、涌井昌俊

Hospitalist (メディカル・サイエンス・インターナショナル)  7 ( 3 ) 537 - 550 2019.09

Research paper (other academic), Joint Work, Accepted

第65回日本臨床検査医学会学術集会シンポジウム2：質量分析検査診断学 2018 update－マーカー探索から検査室における活用まで－:司会のことば

野村文夫、涌井昌俊

臨床病理 67 ( 8 ) 820 - 822 2019.08

Research paper (scientific journal), Joint Work

LC-MS/MSの臨床検査への可能性と課題

中川央充*、涌井昌俊

臨床病理 67 ( 8 ) 835 - 842 2019.08

Research paper (scientific journal), Joint Work

GC-MSを用いた臨床検査における留意点　―尿ステロイドプロフィル検査の経験から―

本間桂子*、涌井昌俊.

臨床病理 67 ( 8 ) 824 - 833 2019.08

Research paper (scientific journal), Joint Work

第65回日本臨床検査医学会学術集会Reversed Clinico-pathological Conference 2 (RCPC2) ：意識レベルが低下し入院した70歳代の女性

本田孝行 松本剛、涌井昌俊、一色美和

臨床病理 67 ( 6 ) 625 - 632 2019.06

Research paper (scientific journal), Joint Work

リンパ球サブセットにおけるCD3陽性とCD4陽性+CD8陽性の乖離に関する解析（2020年度日本臨床検査医学会優秀論文賞）

谷田部陽子、荒井智子、片桐尚子、清水長子、柴田綾子、三ツ橋雄之、涌井昌俊、村田満

臨床病理 67 ( 5 ) 443 - 448 2019.05

Research paper (scientific journal), Joint Work, Accepted

尿蛋白分画測定装置の比較検討

青木絵美、酒井昭子、堀井康司、太田敦美、野口昌代、大野明美、柴田綾子、涌井昌俊、菊池春人、村田　満

臨床病理 67 ( 4 ) 309 - 314 2019.04

Research paper (scientific journal), Joint Work, Accepted

Assessment of in vitro effects of direct thrombin inhibitors and activated factor X inhibitors through clot waveform analysis

Wakui M, Fujimori Y, Katagiri H, Nakamura S, Kondo Y, Kuroda Y, Nakagawa T, Shimizu N, Murata M

J Clin Pathol (Journal of Clinical Pathology)  72 ( 3 ) 244 - 250 2019.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00219746

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© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. Aims Clot waveform analysis (CWA) has been reported to extend the interpretation of clotting time measurement. The parameters obtained from successive derivatives of the clotting reaction curves reflect the rates of activation of individual coagulation factors, theoretically dissecting the cascade pathway. This study aims to assess the in vitro effects of direct thrombin inhibitors (DTIs) and activated factor X (FXa) inhibitors. Methods CWA was applied to the activated partial thromboplastin time (APTT) assay of plasma samples spiked with each drug. For CWA of APTT measurement curves (APTT-CWA), the positive mode of clotting reaction curves was defined as the direction towards fibrin generation. Results All the maximum positive values in the successive derivatives were decreased dependently on the concentrations of each drug. Moreover, the negative values in the second and third derivatives appeared putatively due to consumption of thrombin and factor FXa, respectively, to form complexes with plasma serine protease inhibitors. The decrease of the maximum negative values observed dependently on the concentrations of each drug appeared to be consistent with the decreased generation of thrombin and factor FXa. The analysis of Hill coefficients of each drug in the dose-response of changes in the APTT-CWA parameters revealed a difference in anticoagulant cooperativity between DTIs versus FXa inhibitors. Conclusions The APTT-CWA demonstrated evidence for the blockade of thrombin-positive feedback by DTIs and FXa inhibitors and that for the differences in anticoagulant cooperativity between them. The results demonstrate the usability of CWA for assessment of anticoagulation and provide insights into direct anticoagulants.

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Fatty acid β-oxidation dependent and independent responses and tumor aggressiveness acquired under mild hypoxia

Wakui M, Kawai K, Mizushima T, Nishime C, Serizawa A, Suemizu H, Asakura K, Yamauchi Y, Hayashida T, Suematsu M, Murata M

Anticancer Res (Anticancer Research)  39 ( 1 ) 191 - 200 2019.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  02507005

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© 2019 International Institute of Anticancer Research. All Rights Reserved. Background/Aim: The present study assessed whether and how tumor cells undergoing hypoxia contribute to disease progression after moving to areas with different oxygen conditions. Materials and Methods: Human colorectal carcinoma HCT116 cells cultured under mild hypoxia were subjected to in vivo experiments using transfer to immunodeficient murine recipients and to in vitro experiments using pharmacological inhibition of fatty acid β-oxidation (FAO). Results: Bone involvement and hepatic metastases were accelerated in transfer models of hypoxically cultured HCT116 cells. Hypoxic HCT116 cells exhibited FAO-dependent glycogen synthesis. FAO-dependent and -independent induction of gene expression also occurred under hypoxia. The distribution of glucose transporter 1 expression compared with heme oxygenase 1 expression in HCT116 cell spheroids seemed consistent with differential dependence of hypoxic expression of these molecules on FAO. Conclusion: These results provide insights into the contribution of hypoxia to tumor progression and the relevance of FAO.

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Methodology in a new era for clinical laboratories – Potential and pitfalls of mass spectrometer

Terumichi Nakagawa, Masatoshi Wakui, MD, PhD

Rinsho Byori (the official journal of Japanese Society of Laboratory Medicine) (Japanese Society of Laboratory Medicine)  66 ( 4 ) 398 - 407 2018.04

Research paper (scientific journal), Joint Work

Increased levels of prostaglandin E-major urinary metabolite (PGE-MUM) in active mesenteric panniculitis patients: A case report

Mizuno S, Wakui M, Machida Y, Hosoe N, Hisamatsu T, Ishida T, Kameyama K, Naganuma M, Kanai T

Medicine 96 ( 51 ) e9237 - e9240 2017.12

Research paper (scientific journal), Joint Work, Accepted

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Potential utility and limitations of prothrombin time (PT), activated partial thromboplastin time (APTT), and anti-Xa assays for monitoring of Xa inhibitors

Ohira K, Fujimori Y, Katagiri H, Shimizu N, Mitsuhashi T, Wakui M, Murata M

Journal of The Japanese Society for Laboratory Hematology (日本検査血液学会)  18 ( 1 ) 24 - 29 2017

Research paper (scientific journal), Joint Work, Accepted

Validation of chemiluminescent enzyme immunoassay in detection of autoantibodies in pemphigus and pemphigoid

Fujio Y, Kojima K, Hashiguchi M, Wakui M, Murata M, Amagai M, Yamagami J

J Dermatol Sci 85 ( 3 ) 208 - 215 2017

Research paper (scientific journal), Joint Work, Accepted

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Understanding of coagulation tests from the perspective of chemistry

Masatoshi Wakui, Yuta Fujimori, Hisako Katagiri

Japanese Journal of Clinical Chemistry (日本臨床化学会)  46 ( 2 ) 95 - 104 2017

Research paper (scientific journal), Joint Work

免疫学的測定法の不正確さと質量分析法の落とし穴

WAKUI Masatoshi

臨床化学 (日本臨床化学会)  45 ( 4 ) 369 - 370 2016.12

Research paper (scientific journal), Joint Work, Accepted

Potential application of fibrinogen measurement based on the Clauss assay to monitoring of dabigatran

Fujimori Y, Wakui M, Katagiri H, Ohira K, Shimizu N, Mitsuhashi T, Murata M

Rinsho Byori (日本臨床検査医学会)  64 ( 7 ) 765 - 770 2016.07

Research paper (scientific journal), Joint Work, Accepted

Evaluation of anticoagulant effects of direct thrombin inhibitors, dabigatran and argatroban, based on the Lineweaver-Burk plot applied to the Clauss assay

Fujimori Y, Wakui M*#, Katagiri H, Ohira K, Shimizu N, Murata M

J Clin Pathol 69 ( 4 ) 370 - 372 2016.04

Research paper (scientific journal), Joint Work, Accepted

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Innate Response to Human Cancer Cells with or without IL-2 Receptor Common γ-Chain Function in the NOD Background Mice Lacking Adaptive Immunity.

Nishime C, Kawai K, Yamamoto T, Katano I, Monnai M, Goda N, Mizushima T, Suemizu H, Nakamura M, Murata M, Suematsu M, Wakui M*.

J. Immunol. 195 ( 4 ) 1883 - 1890 2015

Research paper (scientific journal), Joint Work, Accepted

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Basis examination of direct thrombin inhibitor monitoring using two fibrinogen reagents containing different thrombin unit

Fujimori Y, Katagiri H, Wakui M, Shimizu N, Sakata T, Mitsuhashi T, Murata M

Journal of The Japanese Society for Laboratory Hematology 16 ( 3 ) 247 - 252 2015

Research paper (scientific journal), Joint Work, Accepted

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平成28年度日本検査血液学会学術賞受賞論文
https://www.keio.ac.jp/ja/research/researchers/award.html

酸ホスファターゼ.

WAKUI Masatoshi

medicina 52 ( 4 ) 228 - 230 2015

Research paper (scientific journal), Single Work

アデノシンデアミナーゼ.

WAKUI Masatoshi

medicina 52 ( 4 ) 226 - 227 2015

Research paper (scientific journal), Single Work

Discordance between Two Interferon-Gamma Release Assays in the Diagnosis of Latent Tuberculosis Infection in Healthcare Workers

Fujiwara H, Nishimura T, Iketani O, Takano Y, Sakai A, Kondo N, Ohtake K, Oguchi S, Shimizu N, Shibata A, Wakui M, Murata M, Mori M, Iwata S, Hasegawa N

J Infect Dis Ther 2 2014

Research paper (scientific journal), Joint Work,  ISSN  2332-0877

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Bevacizumab terminates homeobox B9-induced tumor proliferation by silencing microenvironmental communication.

Hoshino Y, Hayashida T, Hirata A, Takahashi H, Chiba N, Ohmura M, Wakui M, Jinno H, Hasegawa H, Maheswaran S, Suematsu M, Kitagawa Y.

Mol Cancer 13 ( 1 ) 102 2014

Research paper (scientific journal), Joint Work, Accepted

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Lewis Lung Carcinoma Progression Is Facilitated by TIG-3 Fibroblast Cells.

Yamauchi Y, Izumi Y, Asakura K, Kawai K, Wakui M, Ohmura M, Suematsu M, Nomori H.

Anticancer Res. 33 ( 9 ) 3791 - 3798 2013

Research paper (scientific journal), Joint Work, Accepted

Analysis of single nucleotide polymorphisms (SNPs)

Wakui M

Rinsho Byori 61 ( 11 ) 1008 - 1017 2013

Research paper (scientific journal), Single Work, Accepted

フィブリノゲン測定試薬を用いたアルガトロバンモニタリングの検討

Fujimori Yuta

第2回　血栓止血検査研究会－Tokyo  2012.07

Single Work

重症肝疾患患者で重要となる凝固・線溶マーカー.

WAKUI Masatoshi

Thrombosis Medicine 2 ( 3 ) 219 - 226 2012

Research paper (scientific journal), Single Work

Overexpression of the miR-34 family suppresses invasive growth of malignant melanoma with the wild-type p53 gene.

Yamazaki H, Chijiwa T, Inoue Y, Abe Y, Suemizu H, Kawai K, Wakui M, Furukawa D, Mukai M, Kuwao S, Saegusa M, Nakamura M.

Exp Ther Med. 3 ( 5 ) 793 - 796 2012

Research paper (scientific journal), Joint Work, Accepted

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質量分析によるがんの分子イメージング

WAKUI Masatoshi

最新医学 66 ( 10 ) 2321-2329 2011.10

Research paper (scientific journal), Single Work

Lovastatin and valproic acid additively attenuate cell invasion in ACC-MESO-1 cells.

Yamauchi Y, Izumi Y, Asakura K, Fukutomi T, Serizawa A, Kawai K, Wakui M, Suematsu M, Nomori H.

Biochem. Biophys. Res. Commun. 410 ( 2 ) 382-332 2011.07

Research paper (scientific journal), Joint Work, Accepted

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The reconstituted ‘humanized liver’ in TK-NOG mice is mature and functional.

Hasegawa M, Kawai K, Mitsui T, Taniguchi K, Monnaoi M, Wakui M, Ito M, Suematsu M, Peltz G, Nakamura M, Suemizu1 M.

Biochem. Biophys. Res. Commun. 405 ( 3 ) 405-410 2011.02

Research paper (scientific journal), Joint Work, Accepted

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エステラーゼ染色

荒井 智子、谷田部　陽子、片桐　尚子、清水　長子、三ツ橋　雄之、涌井　昌俊、村田　満

Journal of The Japanese Society for Laboratory Hematology 12 ( 3 ) 472-480 2011

Research paper (scientific journal), Joint Work

Development of imaging mass spectrometry (IMS) dataset extract software, IMS convolution.

Hayasaka T, Goto-Inoue N, Ushijima M, Yao I, Yuba-Kubo A, Wakui M, Shigeki Kajihara S, Matsuura M, Setou M.

Anal. Bioanal. Chem. 401   183-193 2011

Research paper (scientific journal), Joint Work, Accepted

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The influence of donor age on liver regeneration and hepatic progenitor cell populations.

Ono Y, Kawachi S, Hayashida T, Wakui M, Tanabe M, Itano O, Obara H, Shinoda M, Hibi T, Oshima G, Tani N, Mihara K, Kitagawa Y.

Surgery 150 ( 2 ) 154-161 2011

Research paper (scientific journal), Joint Work, Accepted

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The cytostatic effects of lovastatin on ACC-MESO-1 cells.

Asakura K, Izumi Y, Yamamoto M, Yamauchi Y, Kawai K, Serizawa A, Mizushima, T, Ohmura M, Kawamura M, Wakui M, Adachi T, Nakamura M, Suematsu M, Nomori H.

J. Surg. Res. 170   197-209 2011

Research paper (scientific journal), Joint Work, Accepted

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Semi-quantitative analyses of metabolic systems of human colon cancer metastatic xenografts in livers of superimmunodeficient NOG mice.

Kubo A, Ohmura M, Wakui M, Takeshita K, Harad T, Kajihara S, Ogawa K, Suemizu H, Nakamura M, Setou M, Suematsu M.

Anal. Bioanal. Chem 400 ( 7 ) 1895 - 1904 2011

Research paper (scientific journal), Joint Work, Accepted

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日常業務におけるWHO分類の活用とその問題点

Shimizu Nobuko

日本検査血液学会雑誌 11 ( 3 ) 389-400 2010.11

Research paper (scientific journal), Joint Work

生命科学・医学領域における質量分析イメージングの展開：臨床検査への応用の可能性.

WAKUI Masatoshi

日本臨床検査自動化学会会誌 35   269-286 2010.06

Research paper (scientific journal), Single Work

Reduced CD73 expression and its association with altered purine nucleotide metabolism in colorectal cancer cells robustly causing liver metastases.

Matsuyama M, Wakui M, Monnai M, Mizushima T, Nishime C, Kawai K, Ohmura M, Suemizu H, Hishiki T, Suematsu M, Murata M, Chijiwa T, Furukawa D, Ogoshi K, Makuuchi H, Nakamura M.

Oncol. Lett. 1 ( 3 ) 431-436 2010.05

Research paper (scientific journal), Single Work, Accepted

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NOGマウスを用いたヒト化動物モデルの研究展開.

WAKUI Masatoshi

生化学 82   314-318 2010.04

Research paper (scientific journal), Joint Work

Phosphorescence-assisted microvascular O2 measurements reveal alterations of oxygen demand in human metastatic colon cancer in the liver of superimmunodeficient NOG mice.

Handa K, Ohmura M, Nishime C, Hishiki T, Nagahata Y, Kawai K, Suemizu H, Nakamura M, Wakui M, Kitagawa Y, Suematsu M*, Tsukada K.

Adv. Exp. Med. Biol. 1 ( 662 ) 423-429 2010.03

Research paper (scientific journal), Joint Work, Accepted

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Visualization of volatile substances in different organelles with an atmospheric-pressure Mass Microscope

Harada T, Yuba-Kubo A, Sugiura Y, Zaima N, Hayasaka T, Goto-Inoue N, Wakui M, Suematsu M, Takeshita K, Ogawa K, Yoshida Y, Setou M

Anal Chem 81 ( 21 ) 9153 - 9157 2009

Research paper (scientific journal), Joint Work, Accepted

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Thrombospondin 2 inhibits metastasis of human malignant melanoma through microenvironment-modification in NOD/SCID/γCnull (NOG) mice

Chijiwa T, Abe Y, Ikoma N, Yamazaki H, Tsukamoto H, Suemizu H, Kawai K, Wakui M, Nishime C, Matsumoto H, Matsuyama M, Mukai M, Ueyama Y, Nakamura M.

Int. J. Oncol. 34 ( 1 ) 259 - 262 2009

Research paper (scientific journal), Single Work, Accepted

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Establishment of a humanized model of liver using NOD/Shi-scid IL2Rgnull mice.

Suemizu H, Hasegawa M, Kawai K, Taniguchi K, Monnai M, Wakui M, Suematsu M, Ito M, Peltz G, Nakamura M.

Biochem Biophys Res Commun 377 ( 1 ) 248-252 2008.11

Research paper (scientific journal), Joint Work, Accepted

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Evaluation of adjuvant activities using human antigen presenting cells in vitro.

Higashi T, Wakui M, Nakano K, Hashimoto K, Takagi R, Tanaka Y, Matsushita S

Allergol. Int. 57   219-222 2008

Research paper (scientific journal), Joint Work, Accepted

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Notch ligand mRNA levels of human APCs predict Th1/Th2-promoting activities.

Wakui M, Nakano K, Matsushita S.

Biochem Biophys Res Commun 358 ( 2 ) 596-601 2007.06

Research paper (scientific journal), Single Work, Accepted

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樹状細胞が発現するNotchリガンドアイソフォームとTh1/Th2分化

WAKUI Masatoshi

臨床免疫・アレルギー科 46 ( 2 ) 129 - 135 2006

Research paper (scientific journal), Joint Work

樹状細胞による自然免疫と獲得免疫のクロストーク

WAKUI Masatoshi

肝胆膵 52 ( 4 ) 529 - 536 2006

Joint Work

Genetic dissection of SLE pathogenesis: partial functional complementation between Sle1 and Sle3/5 demonstrates requirement for intracellular co-expression for full phenotypic expression of lupus

Wakui M, Morel L, Butfiloski EJ, Kim C, Sobel ES

J. Immunol. 175 ( 2 ) 1337 - 1345 2005

Research paper (scientific journal), Joint Work, Accepted

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Adjuvants that enhance Th2 or Tr responses

Matsushita S*, Liu T, Wakui M, Uemura Y

Allergol. Int. 54 ( 4 ) 507 - 513 2005

Research paper (scientific journal), Joint Work, Accepted

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Genetic dissection of lupus pathogenesis: Sle3/5 impacts IgH CDR3 sequences, somatic mutations, and receptor editing

Wakui M, Kim J, Butfiloski EJ, Morel L, Sobel ES

J. Immunol. 173 ( 12 ) 7368 - 7376 2004

Research paper (scientific journal), Joint Work, Accepted

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Highly specific and quantitative gene expression profiling based on DNA computing

Nishida N, Wakui M, Tokunaga K, Suyama A

Genome Informatics 12   259 - 260 2001

Research paper (international conference proceedings), Joint Work, Accepted

Genes highly expressed in the early phase of murine graft-versus-host reaction

Wakui M, Yamaguchi A, Sakurai D, Ogasawara K, Yokochi T, Tsuchiya N, Ikeda Y, Tokunaga K

Biochem. Biophys. Res. Commun. 282 ( 1 ) 200 - 206 2001

Research paper (scientific journal), Joint Work, Accepted

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Furosemide投与による急速な低カリウム血症がメシル酸ナファモスタット投与によって改善した急性骨髄性白血病患者の一症例

WAKUI Masatoshi

臨床体液 28 ( 1 ) 13 - 18 2001

Research paper (scientific journal), Joint Work, Accepted

Tumor necrosis factor alpha 5-flanking region, tumor necrosis factor receptor II, and HLA-DRB1 polymorphisms in Japanese patients with rheumatoid arthritis

Shibue T, Tsuchiya N*, Komata T, Matsushita M, Shiota M, Ohashi J, Wakui M, Matsuta K, Tokunaga K

Arthritis Rheum. 43 ( 4 ) 753 - 757 2000

Research paper (scientific journal), Joint Work, Accepted

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Risk-adapted pre-emptive therapy for cytomegalovirus disease in patients undergoing allogeneic bone marrow transplantation

Mori T, Okamoto S*, Matsuoka S, Yajima T, Wakui M, Watanabe R, Ishida A, Iwao Y, Mukai M, Hibi T, Ikeda Y

Bone Marrow Transplant. 25 ( 7 ) 765 - 769 2000

Research paper (scientific journal), Joint Work, Accepted

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Treatment of advanced myelodysplastic syndrome with a regimen including recombinant human granulocyte colony-stimulating factor preceding allogeneic bone marrow transplantation

Okamoto S*, Takahashi S, Wakui M, Ishida A, Tanosaki R, Ikeda Y, Asano

Br J Haematol. 104 ( 3 ) 569 - 573 1999

Research paper (scientific journal), Joint Work, Accepted

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Dry eye after haematopoietic stem cell transplantation

Ogawa Y, Okamoto S, Wakui M, Watanabe R, Yamada M, Yoshino M, Ono M, Yang HY, Mashima Y, Oguchi Y, Ikeda Y, Tsubota

Br J Ophthalmol. 83 ( 10 ) 1125 - 1130 1999

Research paper (scientific journal), Joint Work, Accepted

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Prospective evaluation for upper gastrointestinal tract acute graft-versus-host disease after hematopoietic stem cell transplantation

Wakui M, Okamoto S*, Ishida A, Kobayashi H, Watanabe R, Yajima T, Iwao Y, Hisamatsu T, Hibi T, Ikeda Y

Bone Marrow Transplant. 23 ( 6 ) 573 - 578 1999

Research paper (scientific journal), Joint Work, Accepted

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造血幹細胞移植後に認められる上部消化管急性GVHDの臨床的意義に関する研究

WAKUI Masatoshi

今日の移植 11 ( 5 ) 579 - 584 1998

Research paper (scientific journal), Joint Work

Thrombopoietin induces association of Crkl with STAT5 but not STAT3 in human platelets

Ozaki K, Oda A*, Wakao H, Rhodes J, Druker BJ, Ishida A, Wakui M, Okamoto S, Morita K, Handa M, Komatsu N, Ohashi H, Miyajima A Ikeda Y

Blood 92 ( 12 ) 4652 - 4662 1998

Research paper (scientific journal), Joint Work, Accepted

Clinical factors influencing posttransfusion platelet increment in patients undergoing hematopoietic progenitor cell transplantation: a prospective analysis

Ishida A, Handa M*, Wakui M, Okamoto S, Kamakura M, Ikeda Y

Transfusion 38 ( 9 ) 839 - 847 1998

Research paper (scientific journal), Joint Work, Accepted

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Trichomonas foetus meningoencephalitis after allogeneic peripheral blood stem cell transplantation

Okamoto S*, Wakui M, Kobayashi H, Sato N, Ishida A, Tanabe M, Takeuchi T, Fukushima S, Yamada T, Ikeda

Bone Marrow Transplant. 21 ( 1 ) 89 - 91 1998

Research paper (scientific journal), Joint Work, Accepted

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保存的治療のみで軽快後、遅発性再燃を認めた重症型VOD

WAKUI Masatoshi

臨床血液 39 ( 2 ) 139 - 145 1998

Research paper (scientific journal), Joint Work, Accepted

Acquired dysfibrinogenemia following allogeneic bone marrow transplantation

Mori T, Murata M*, Wakui M, Muto A, Ishida A, Tanosaki R, Okamoto S, Ikeda Y

Am J Hematol. 56 ( 4 ) 294 - 295 1997

Research paper (scientific journal), Joint Work, Accepted

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Circulating endogenous thrombopoietin, interleukin-3, interlerkin-6 and interleukin-11 levels in patients undergoing allogeneic bone marrow transplantation

Ishida A, Miyakawa Y, Tanosaki R, Wakui M, Ueno H, Watanabe R, Awaya N, Tahara T, Kato T, Miyazaki H, Oda A, Kizaki M, Okamoto S, Ikeda Y

Int J Hematol. 65   61 - 69 1996

Research paper (scientific journal), Joint Work, Accepted

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Crkl is constitutively tyrosine phosphorylated in platelets from chronic myelogenous leukemia patients and inducibly phosphorylated in normal platelets stimulated by thrombopoietin

Oda A*, Miyakawa Y, Druker BJ, Ishida A, Ozaki K, Ohashi H, Wakui M, Handa M, Watanabe K, Okamoto S, Ikeda Y

Blood 88 ( 11 ) 4304 - 4313 1996

Research paper (scientific journal), Joint Work, Accepted

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Durable molecular remission in a patient with chronic myelogenous leukemia and host-derived hematopoiesis after allogeneic bone　marrow transplantation

Wakui M, Okamoto S*, Ishida A, Tanosaki R, Mori T, Kawai Y, Ohshima S, Ikeda Y

Bone Marrow Transplant 18 ( 4 ) 801 - 804 1996

Research paper (scientific journal), Joint Work, Accepted

Prolonged thrombocytopenia after administration of granulocyte colony-stimulating factor and leukapheresis in a donor for allogeneic peripheral blood stem cell transplantation

Okamoto S*, Ishida A, Wakui M, Tanosaki R, Oda A, Ikeda Y

Bone Marrow Transplant. 18 ( 2 ) 482 - 483 1996

Research paper (scientific journal), Joint Work, Accepted

慢性関節リウマチと貧血

WAKUI Masatoshi

リウマチ科 13 ( 5 ) 413 - 418 1995

Research paper (scientific journal), Joint Work

MLCとその他の検査

WAKUI Masatoshi

臨床検査 39 ( 3 ) 280 - 284 1995

Research paper (scientific journal), Joint Work

骨髄移植の検査

WAKUI Masatoshi

臨床病理 97   394 - 397 1994

Research paper (scientific journal), Joint Work

A 75-year-old woman with longstanding hypertension, resulting in congestive heart failure and renal failure

Handa S*, Yoshikawa T, Kondoh T, Wakui M, Suzuki H, YuasaY, Kameyama K, Hata J

Keio J Med. 41 ( 1 ) 33 - 39 1992

Research paper (scientific journal), Joint Work, Accepted

Incidence and mortality patterns of malignancy and factors affecting the risk of malignancy in dialysis patients

Inamoto H*, Ozaki R, Matsuzaki T, Wakui M, Saruta T, Osawa A

Nephron 59 ( 4 ) 611 - 617 1991

Research paper (scientific journal), Joint Work, Accepted

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