RESUMO
Monovalent Omicron XBB.1.5 mRNA vaccines were newly developed and approved by the FDA in Autumn 2023 for preventing COVID-19. However, clinical efficacy for these vaccines is currently lacking. We previously established the quantification of antigen-specific antibody sequence (QASAS) method to assess the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination at the mRNA level using B-cell receptor (BCR) repertoire assay and the coronavirus antibody database (CoV-AbDab). Here, we used this method to evaluate the immunogenicity of monovalent XBB.1.5 vaccines. We analyzed repeated blood samples of healthy volunteers before and after monovalent XBB.1.5 vaccination (BNT162b2 XBB.1.5 or mRNA-1273.815) for the BCR repertoire to assess BCR/antibody sequences that matched SARS-CoV-2-specific sequences in the database. The number of matched unique sequences and their total reads quickly increased 1 week after vaccination. Matched sequences included those bound to the Omicron strain and Omicron XBB sublineage. The antibody sequences that can bind to the Omicron strain and XBB sublineage revealed that the monovalent XBB.1.5 vaccines showed a stronger response than previous vaccines or SARS-CoV-2 infection before the emergence of XBB sublineage. The QASAS method was able to demonstrate the immunogenic effect of monovalent XBB.1.5 vaccines for the 2023-2024 COVID-19 vaccination campaign.
RESUMO
Complement component 8gamma (C8γ), a member of the lipocalin protein family, is suggested to act as a carrier protein for various chemicals. Although C8γ has been identified in both humans and rodents for some time, our understanding of the species differences in its chemical binding properties remains limited. In the present study, with the aim to elucidate the potential role of C8γ as a carrier protein in both humans and mice, we conducted a radioligand binding assay to examine the chemical binding properties of human C8γ (hC8γ) and mouse C8γ (mC8γ). Scatchard analysis revealed that [14C]TPT bound to hC8γ with an equilibrium dissociation constant (Kd) of 64.2 ± 32.4 nM, comparable to that of [14C]TPT to mC8γ. Competitive ligand-binding assays demonstrated binding of TPT and TBT to hC8γ, while diphenyltin, dibutyltin, monophenyltin, monobutyltin, and tetrabutyltin did not exhibit binding. These results suggest that for effective binding to C8γ, chemicals must possess substituents of appropriate bulkiness. Further analyses with other group 14 compounds with triphenyl substituents revealed that a central metal atom, rather than a central non-metal or semi-metal atom, is crucial for specific binding to both hC8γ and mC8γ. Overall our findings imply that C8γ may play a role in the physiological or toxicological actions of group 14 metal compounds with tributyl or triphenyl substituents by binding to these chemicals in both humans and mice.
Assuntos
Ligação Proteica , Animais , Humanos , Camundongos , Complemento C8/metabolismo , Complemento C8/química , Compostos Organometálicos/química , Compostos Organometálicos/metabolismo , Ligação CompetitivaRESUMO
Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). Early diagnosis of SOS/VOD is associated with improved clinical outcomes. In 2023, the refined European Society for Blood and Marrow Transplantation diagnostic and severity criteria (refined EBMT criteria 2023) have been advocated. The revision has introduced new diagnostic categories, namely; probable, clinical, and proven SOS/VOD. In addition, the Sequential Organ Failure Assessment (SOFA) score has been newly incorporated into the SOS/VOD severity grading. We performed a retrospective analysis to evaluate the utility of these criteria. We analyzed 161 cases who underwent allogeneic HSCT. We identified 53 probable, 23 clinical, and 4 proven SOS/VOD cases. Probable SOS/VOD was diagnosed a median of 5.0 days earlier (interquartile range: 2-13 days, P < 0.001) than that of clinical SOS/VOD. The development of probable SOS/VOD alone was associated with a significantly inferior survival proportion compared to non-SOS/VOD (100-day survival, 86.2% vs. 94.3%, P = 0.012). The SOFA score contributed to the prediction of prognosis. Consequently, the refined EBMT criteria 2023 demonstrated the utility of SOS/VOD diagnosis and severity grading. Further investigations and improvements in these criteria are warranted.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Doenças Vasculares , Humanos , Hepatopatia Veno-Oclusiva/diagnóstico , Hepatopatia Veno-Oclusiva/etiologia , Estudos Retrospectivos , Síndrome , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
Mature B-cell acute lymphoblastic leukemia (ALL) is defined by the expression of light chain-restricted surface immunoglobulin (sIg) and usually has features of the leukemic phase of Burkitt lymphoma including FAB-L3 morphology and MYC rearrangement. Recently, another distinct entity in childhood mature B-cell ALL has been characterized as non-L3 morphology and KMT2A rearrangement. Here we report an unusual case of mature B-cell ALL that presented with RUNX1 rearrangement. A 65-year-old male was admitted to our department for thorough examination of leukocytosis and thrombocytopenia. The patient's bone marrow was hypercellular and infiltrated with 97.8% myeloperoxidase-negative, medium-to-large-sized blasts without cytoplasmic vacuoles. Immunophenotypes were characterized by the presence of light chain-restricted sIg and the lack of immature markers, indicating a diagnosis of mature B-cell ALL with L2 morphology: sIg-κ+, CD19+, CD20+, CD22+, CD79a+, TdT-, and CD34-. G-banding combined with spectral karyotyping showed the following complex karyotype: 45,X,der(Y;10)(p10;q10),del(13)(q?),inv(21)(p13q22.1). Fluorescence in situ hybridization revealed separated signals of RUNX1 at 21q22.1, whereas rearrangements of MYC and KMT2A were not found. To our knowledge, inv(21)(p13q22.1) involving RUNX1 is a novel cytogenetic aberration and this is the first case of mature B-cell ALL that presented with RUNX1 rearrangement. Thus, RUNX1 may be implicated in the pathogenesis of mature B-cell ALL showing non-L3 morphology without MYC rearrangement.
Assuntos
Linfoma de Burkitt , Linfoma de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Masculino , Humanos , Idoso , Linfoma de Burkitt/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Hibridização in Situ Fluorescente , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Linfoma de Células B/diagnóstico , Linfoma de Células B/genéticaRESUMO
Transcranial magnetic stimulation studies have indicated that action observation (AO) modulates corticospinal excitability. Although a few previous studies have shown that the AO of simple motor movements at a slow playback speed facilitates corticospinal excitability more than that at normal playback speed, it is unclear if this effect occurs during the AO of sport-related complex movements. Therefore, we investigated the changes in the motor evoked potential (MEP) amplitudes of the flexor carpi radialis (FCR) and abductor digiti minimi (ADM) muscles during the AO of a basketball free-throw movement at three different playback speeds (100%, 75%, and 50% speeds). Additionally, we evaluated the effects of stimulus timing (holding the ball vs. releasing the ball for shooting) and motor expertise (expert basketball players vs. novices) on the MEP amplitude during the AO. Our results demonstrated that regardless of motor expertise, the MEP amplitude of the FCR muscle was significantly smaller in the 50% speed condition than in the 100% condition. In the ADM muscle, the MEP amplitude was significantly larger when the ball was held after dribbling than when the ball was released. Therefore, it is suggested that corticospinal excitability in specific muscles during the observation of complex whole-body movements is influenced by video playback speed and stimulus timing.
Assuntos
Basquetebol , Movimento/fisiologia , Músculo Esquelético/fisiologia , Potencial Evocado Motor/fisiologia , Estimulação Magnética Transcraniana , Eletromiografia , Tratos Piramidais/fisiologiaRESUMO
Sinusoidal obstruction syndrome (SOS) is a fatal complication of hematopoietic stem cell transplantation (HSCT). Early diagnosis for SOS can improve clinical outcomes significantly. Here, we performed a retrospective study to investigate the Cairo diagnostic criteria, in which SOS was defined as the development of two or more in seven events, including transfusion-refractory thrombocytopenia. Among 154 cases of allogeneic HSCT, 10 cases of SOS using the European Society for Blood and Marrow Transplantation criteria (EBMT16) as the reference standard were identified. The original Cairo criteria could diagnose SOS 5 days earlier than any other established criteria, with some false-positive results (sensitivity = 100.0%; specificity = 72.2%). When the cutoff was set to three events for the Cairo criteria, the diagnosis of SOS could be made 3 days earlier than that using the EBMT16 criteria, with comparable precision (specificity = 86.1%). The accuracy of the Cairo criteria improved further when the cutoff point was set to four (specificity = 93.8%). The fulfillment of the Cairo criteria was associated with high mortality. Based on our results, the Cairo criteria were also considered clinically useful, especially at three or four cutoff points. Further studies are required to validate and refine the criteria.
RESUMO
The use of anti-SARS-CoV-2 antibody products like tixagevimab/cilgavimab represents an important strategy to protect immunocompromised patients with haematological malignancies from COVID-19. Although patients who receive these agents should still be vaccinated, the use of tixagevimab/cilgavimab can mask the production of anti-spike antibody after vaccination, making it hard to assess vaccine response. We have newly established a quantification method to assess the response to SARS-CoV-2 vaccination at the mRNA level using B-cell receptor (BCR) repertoire assay and the Coronavirus Antibody Database (CoV-AbDab). Repeated blood samples before and after vaccination were analysed for the BCR repertoire, and BCR sequences were searched in the database. We analysed the number and percentage frequency of matched sequences. We found that the number of matched sequences increased 2 weeks after the first vaccination and quickly decreased. Meanwhile, the number of matched sequences more rapidly increased after the second vaccination. These results show that the postvaccine immune response can be assessed at the mRNA level by analysing the fluctuation in matching sequences. Finally, BCR repertoire analysis with CoV-AbDab clearly demonstrated the response to mRNA SARS-CoV-2 vaccination even after tixagevimab/cilgavimab administration in haematological malignancy patients who underwent allogeneic haematopoietic stem cell transplantation.
Assuntos
COVID-19 , Neoplasias Hematológicas , Humanos , COVID-19/prevenção & controle , Vacinas contra COVID-19 , SARS-CoV-2 , Vacinação , Anticorpos Antivirais , Neoplasias Hematológicas/tratamento farmacológico , RNA Mensageiro , Receptores de Antígenos de Linfócitos B/genéticaRESUMO
Hyperglycemia in the early days following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-known risk factor for acute graft-versus-host disease (GVHD) and non-relapse mortality. The FreeStyle Libre Pro, a factory calibrated continuous glucose monitoring (CGM) device, has been used for the retrospective analysis of glucose testing in patients with diabetes. We assessed the safety and accuracy of the device in patients undergoing allo-HSCT. We recruited eight patients who underwent allo-HSCT between August 2017 and March 2020. They wore the FreeStyle Libre Pro on the day before or on the day of transplantation until 28 days after transplantation. Adverse events, especially bleeding and infection, were monitored to assess safety, and blood glucose levels were measured and compared with the device values. None of the eight participants experienced bleeding that was difficult to stop from the sensor site or local infection that required antimicrobial administration. The device value was well correlated with blood glucose (correlation coefficient r=0.795, P<0.01); however, the overall mean absolute relative difference was 32.1%±16.0%. Our study demonstrated the safety of FreeStyle Libre Pro in allo-HSCT patients. However, the sensor results tended to be lower than the blood glucose levels.
RESUMO
Global longitudinal strain (GLS), a new cardiac parameter measured by the speckle-tracking method, is reportedly more sensitive than ejection fraction (EF) in detecting slight cardiac dysfunction in heart failure patients. We validated the utility of GLS in allogeneic hematopoietic stem cell transplantation (HSCT) patients during a long-term follow-up. Medical records of patients who underwent allogeneic HSCT between 2013 and 2020 were reviewed retrospectively. We evaluated the last echocardiography performed before transplantation and those performed annually during the 5 years after transplantation. We also investigated newly diagnosed cardiac events, which developed after HSCT. Among 85 patients, 22 used cardioprotective drugs. The median follow-up duration in surviving patients was 54.1 months (range, 2.9-92.6 months). GLS significantly decreased year by year, and patients taking cardioprotective agents tended to have a better GLS at 5 years than at 3 years, while EF did not change. Fifteen patients developed newly diagnosed cardiac events. Multivariate analysis revealed that low GLS and high serum ferritin levels at baseline were independently associated with the development of cardiac events. Therefore, we need a continuous follow-up of cardiac function by GLS and prescription of cardioprotective drugs might be considered for HSCT patients with low GLS. Further research is warranted.
RESUMO
As an uncommon but nonrandom translocation in acute myeloid leukemia (AML) t(5;11)(q31;q23) results in fusion between KMT2A at 11q23 and ARHGAP26 at 5q31. The 5q31 region has another KMT2A partner, AFF4, which was identified in acute lymphoblastic leukemia harboring ins(5;11)(q31;q13q23). We report here a 65-year-old woman with AML M5b. G-banding and spectral karyotyping demonstrated 46,XX,t(5;11)(q31;q23.3). Fluorescence in situ hybridization revealed not only separated 5' and 3' KMT2A signals but a faint 5' KMT2A signal. Reverse transcription polymerase chain reaction (RT-PCR), using a KMT2A sense primer and ARHGAP26 antisense primer, detected no band whereas RT-PCR with a AFF4 antisense primer revealed an amplified band. However, sequence analysis unexpectedly disclosed that KMT2A exon 6 was connected with MLLT10 exons 15 to 18. This may be due to cross-hybridization between MLLT10 exon 18 and AFF4 antisense primer derived from AFF4 exon 10 since both exons had eight identical bases (AAGCAGCT). The MLLT10 gene is located at 10p12.31; a faint 5' KMT2A signal was probably present at this locus. These findings indicate that in AML the 5' KMT2A fragment containing exons 1 to 6 may be cryptically inserted into MLLT10 intron 14 when a reciprocal translocation t(5;11)(q31;q23.3) involving KMT2A occurred.
Assuntos
Leucemia Mieloide Aguda , Fatores de Transcrição , Feminino , Humanos , Idoso , Hibridização in Situ Fluorescente , Fatores de Transcrição/genética , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia Mieloide Aguda/genética , Translocação Genética , Éxons , Fatores de Elongação da Transcrição/genéticaRESUMO
A 68-year-old man was admitted because of a left shoulder mass and swollen right testis. Pathological examinations indicated a diagnosis of diffuse large B-cell lymphoma (DLBCL) with the CD20+BCL6+MUM1+BCL2+CD10-MYC- phenotype in both lesions. G-banding of soft tissue showed 47,XY,+18, whereas testicular cells showed 47,X,+X,-Y,der (4) t (4;18) (p15;?),del (5) (q?),+13. Fluorescence in situ hybridization detected additional MALT1 and BCL2 signals in both lesions. Southern blot demonstrated different IGH rearrangements between the soft tissue and testis. The patient was diagnosed with biclonal DLBCL with different karyotypes but similar immunophenotypes. Partial trisomy 18q involving MALT1 and BCL2 may be commonly involved in the pathogenesis of this biclonal DLBCL.
Assuntos
Linfoma Difuso de Grandes Células B , Trissomia , Masculino , Humanos , Trissomia/genética , Translocação Genética , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genéticaRESUMO
An acute promyelocytic leukemia (APL) patient not demonstrating the retinoic acid receptor α (RARA) translocation is rare. A 76-year-old man was diagnosed with myelodysplastic syndrome (MDS). After a year, abnormal promyelocytes were detected with pancytopenia and disseminated intravascular coagulopathy. Morphologically, the patient was diagnosed with APL; however, a genetic examination failed to detect RARA translocation. Thereafter, whole-genome sequencing revealed an NRAS missense mutation [c.38G>A (p.G13D)]. This mutation was not detected in posttreatment bone marrow aspirate, despite residual MDS. Few reports are available on similar cases. Furthermore, the NRAS c.38G>A mutation may be a novel pathogenic variant exacerbating RARA translocation-negative acute promyelocytic-like leukemia.
Assuntos
Leucemia Promielocítica Aguda , Síndromes Mielodisplásicas , Idoso , Humanos , Masculino , Células Precursoras de Granulócitos/patologia , GTP Fosfo-Hidrolases/genética , Leucemia Promielocítica Aguda/complicações , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Proteínas de Membrana/genética , Mutação/genética , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/genética , Translocação GenéticaRESUMO
BACKGROUND: We developed a novel photoacoustic needle, which emits ultrasound produced by the photoacoustic effect. This study focused on the most common "pitfall" associated with placement during ultrasound-guided vascular access, which is misidentification of the needle tip. METHODS: The study was conducted as a prospective cohort study using a questionnaire. The authors intentionally created two successful and one failed ultrasound-guided central venous catheterization videos using the photoacoustic needle on a simulator. Each of these three videos was then split into two movies for viewing, one with standard ultrasound images only and the second including the images from the photoacoustic needle, for a total of six movies. RESULTS: Participants who were 18 anesthesiologists, 12 residents, and 10 medical students, watched each of the six movies and completed a survey whether the puncture was successful or not. In the results, there was a significant difference in the percentage of correct answers whether the movie depicted successful or failed puncture with and without the photoacoustic ultrasound (p = 0.0001). CONCLUSION: The novel photoacoustic needle improved the ability to identify the needle tip on recorded videos. It may have efficacy to prevent serious mechanical complication during the ultrasound-guided vascular access in clinical practice.
RESUMO
We previously reported that a second dose of BNT162b2 was safe and effective for allogeneic hematopoietic stem cell transplantation (HSCT) patients. Here, we investigated the safety and efficacy of a third dose of COVID-19 mRNA vaccine in allogeneic HSCT patients. Antibody titers against the S1 spike protein were measured using the QuaResearch COVID-19 Human IgM IgG ELISA kit. The previous study included 25 allogeneic HSCT patients who received two doses of BNT162b2. Following the exclusion of three patients because of the development of COVID-19 (n = 2) and loss to follow-up (n = 1), the study evaluated 22 allogeneic HSCT patients who received a third dose of COVID-19 mRNA vaccine (BNT162b2 [n = 15] and mRNA-1273 [n = 7]). Median age at the time of the first vaccination was 56 (range, 23-71) years. Five patients were receiving immunosuppressants at the third vaccination, namely calcineurin inhibitors (CI) alone (n = 1), steroids alone (n = 2), or CI combined with steroids (n = 2). Twenty-one patients (95%) seroconverted after the third dose. None of our patients had serious adverse events, new-onset graft-versus-host disease (GVHD), or GVHD exacerbation after vaccination. A third dose of the BNT162b2 and mRNA-1273 COVID-19 vaccines was safe and effective for allogeneic HSCT patients.
RESUMO
Anti-CD20 antibodies react with CD20 expressed not only on malignant B cells, but also on normal B cells. It has been reported that patients treated with anti-CD20 antibodies had an insufficient response to two-dose mRNA SARS-CoV-2 vaccination. To investigate the efficacy of a third dose in these patients, we investigated serum IgG antibody titers for the S1 protein after a third vaccination in 22 patients treated with the anti-CD20 antibody who failed two-dose vaccination. Results showed that overall, 50% of patients seroconverted. Although no patient who received the third dose within 1 year of the last anti-CD20 antibody administration showed an increase in S1 antibody titer, 69% of patients who received the third dose more than 1 year after the last anti-CD20 antibody administration seroconverted. Our data show that a third dose of vaccination is effective in improving the seroconversion rate in patients treated with the anti-CD20 antibody who failed standard two-dose vaccination.
RESUMO
The photochromic molecules showing wavelength-selective or light intensity-dependent photoresponse are receiving increased attention in recent years. Although a photoswitch with a single chromophore can control the ON and OFF states of a function, that consisting of multi-chromophores would be useful for the specific control in complex systems. Herein, we designed stepwise two-photon induced photochromic molecules (PABI-PIC and PABI-PIC2) consisting of two different photochromic units (PABI and PIC). One-photon absorption reaction in the UV light region of PABI-PIC generates the short-lived transient biradical (BR) that absorbs an additional photon in the visible and UV light region in a stepwise manner to produce the two-photon photochemical product, the quinoidal species (Quinoid). The photochromic properties of these transient species are completely different in color and fading speed. In addition, PABI-PIC also shows the excitation wavelength-dependent photochromism because the excited states of the PABI and PIC units are electronically orthogonal. Therefore, the stepwise photochromic properties of PABI-PIC are easily controlled depending on the excitation light intensity and wavelength. These molecular designs are important for the development of advanced photoresponsive materials.
Assuntos
Processos Fotoquímicos , Fótons , Luz , Raios UltravioletaRESUMO
We investigated the efficacy of BNT162b2 mRNA COVID-19 vaccine in patients with B-cell malignancies treated with anti-CD20 antibody. Although T-cell-mediated immune responses were detected even in patients receiving R-CHOP treatment, the S1 antibody titer following BNT162b2 vaccination remained only marginally increased for more than 3 years after the final dose of anti-CD20 antibody. We found no relationship between the percent of B-cells and S1 antibody titer. The duration of this suppression was much longer than we anticipated. Further protection and treatment strategies against COVID-19 for these patients are warranted.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacina BNT162/uso terapêutico , COVID-19/prevenção & controle , Linfoma de Células B/complicações , Linfoma de Células B/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Formação de Anticorpos , Antígenos CD20/imunologia , COVID-19/imunologia , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma de Células B/imunologia , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Vincristina/uso terapêuticoAssuntos
Subunidade beta de Fator de Ligação ao Core/genética , Cariótipo , Leucemia Mieloide Aguda/genética , Cadeias Pesadas de Miosina/genética , Proteínas de Fusão Oncogênica/genética , Subunidade beta de Fator de Ligação ao Core/metabolismo , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Cadeias Pesadas de Miosina/metabolismo , Proteínas de Fusão Oncogênica/metabolismoRESUMO
We developed a novel technology using the photoacoustic effect that improve needle tip visibility. We evaluated whether this technology improves needle tip visibility when performing a deep peripheral nerve block in a cadaver model. A photoacoustic needle was developed using a conventional echogenic needle with an intraluminal optical fiber. A pulsed laser sends light from a source through the fiber, which is converted to ultrasound at the needle tip using the photoacoustic effect. A nerve block expert performed deep nerve blocks using the photoacoustic needle and the ultrasound views recorded, with or without photoacoustic ultrasound at the needle tip. Needle tip visibility was evaluated by questionnaire (Likert scale 1: very poor, 5: very good) completed by anesthesiologists evaluating recorded images. The score was presented as median [first quartile, third quartile]. Statistical analysis was performed using the Wilcoxon matched-pairs signed rank test. The scores of needle tip visibility with photoacoustic ultrasound from the needle tip (4.3 [4.0, 4.5]) was significantly higher than that without photoacoustic ultrasound (3.5 [3.2, 3.8]) (p < 0.01). Ultrasound emitted at the needle tip using the photoacoustic effect improves needle tip visibility during deep peripheral nerve blocks.Clinical trial number University Hospital Medical Information Network Center Clinical Trials Registration System (UMIN000036974).