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Objective: To evaluate the influence of the combinations of b-values on computed diffusion-weighted images (cDWIs) for prostate cancer (PCa) detection at b = 2000s mm-2. Methods: Diffusion-weighted imaging (DWIs) for 31 patients with PCa (65.2 ±7.1 years) were obtained pre-operatively at different b-values (0,100, 500,1000 and 2000smm-2) on a 3-T MRI. cDWIs at b = 2000 were generated by using six b-value combinations: 0-100 s mm-2 (cDWI0-100); 0-500 s mm-2 (cDWI0-500); 100-500s mm-2 (cDWI100-500);0-1000s mm2 (cDWI-0-1000); 100-1000smm-2 (cDWI100-500)1 and 500-1000 s mm2 (cDWI500-1000). These cDWIs and measured DWIs with b = 2000 s mm-2 (mDWI2000) were evaluated in this setting. To assess image quality for each DWI, contrast ratios (CRs) of cancerous and non-cancerous lesions were evaluated. To compare the detectability of PCa for each DWI, receiver operating characteristic analysis was used. Results: CRs of all cDWIs were significantly higher than those of mDWI2000 (p<0.05). Areas under the curve of cDWI0-0-100 (0.62) and cDWI0-500 (0.65) were significantly smaller (P < 0.05) than those of others (cDWI100-500 0.72; cDWI0-1000, 0.73; cDWI100-1000. 0.71; cDWI500-1000. 0.74; mDWI2000. 0.72). Conclusion: The combinations of b-values influenced imago quality and diagnostic ability of cDWIs for PCa detection. The combinations of b ≥ 100 and b ≥ 500 s mm-2, as well as b = 0 and b = 1000s mm-2, were optimal in this study. Advances in knowledge: For generating the useful cDWI for PCa detection, radiologists should take care of the combination of b-values when including low b-values. [ABSTRACT FROM AUTHOR]

The article defines functional T cell subsets by using monoclonal antibodies to obtain more knowledge of T cell regulatory mechanisms on periodontal lesions. Advanced human periodontitis was presumed to be B cell lesion including many plasma cells, but many T cells were detected in conjunction with plasma cells located subjacent to the pocket epithelium. The activated T cells could serve as effector cells with the release of soluble factors including inflammatory lymphokines as well as immune regulation.

Human periodontitis has been confirmed to be an IgG plasma cell-rich lesion. However, we also detected many T cells, both CD4-positive and CD8-positive cells, in periodontal lesions. Some of these T cells expressed HLA-DR (Ia-like) antigen on their surfaces, and the proportion of HLA-DR+ cells was approximately equal in both CD4+ and CD8+ cell populations (Okada et al., 1983, 1984). Consequently, both helper and suppressor T cells were believed to participate in the establishment of periodontal lesions. On the other hand, B cells were thought to be activated polyclonally in periodontal lesions, because a variety of periodontal florae possessed polyclonal B-cell-activating activity. We demonstrated that Actinomyces viscosus T14V stimulated mouse spleen B cells polyclonally and induced many IgM-producing cells but few IgG-producing cells. Moreover, IgG-producing cells were differentiated from only surface IgG-positive B cells but not from surface IgG-negative B cells - namely, surface IgM- or IgA-positive B cells (Harada et al, 1988). These results suggested that memory B cells, which had already been primed with appropriate antigens, might migrate into periodontal lesions, and then be activated polyclonally and develop into IgG-producing cells. The periodontal lesion could, therefore, be induced by the interactions of immunoregulatory mechanisms of T cells and polyclonal B cell activity of periodontal florae. In fact, L3T4-positive T cells (helper-inducer T cells) enhanced IgG synthesis of mouse spleen B cells which had been activated with T-independent B cell activators such as LPS and A. viscosus preparations (Okada et al, 1987; Ito et al., 1988). We hypothesized from the above results that autoreactive T cells recognized the increasing self-MHC class II(Ia) antigen on B cells which had been activated with polyclonal B cell activators, and then produced soluble factors, which could enhance IgG synthesis of these B cells. Autoreactive T cells as well as PBAs, thus, may play an important role in the establishment of the IgG plasma cell-rich periodontal lesion. [ABSTRACT FROM AUTHOR]

Purpose: Fresh blood imaging (FBI) utilizes physiological blood signal differences between diastole and systole, causing a long acquisition time. The purpose of this study is to develop a fast FBI technique using a centric k y - k z k-space trajectory (cFBI) and an exponential refocusing flip angle (eFA) scheme with fast longitudinal restoration., Methods: This study was performed on 8 healthy subjects and 2 patients (peripheral artery disease and vascular disease) with informed consent, using a clinical 3-Tesla MRI scanner. A numeric simulation using extended phase graph (EPG) and phantom studies of eFA were carried out to investigate the restoration of longitudinal signal by lowering refocusing flip angles in later echoes. cFBI was then acquired on healthy subjects at the popliteal artery station to assess the effect of varying high/low flip ratios on the longitudinal restoration effects. In addition, trigger-delays of cFBI were optimized owing to the long acquisition window in zigzag centric k y - k z k-space trajectory. After optimizations, cFBI images were compared against standard FBI (sFBI) images in terms of scan time, motion artifacts, Nyquist N/2 artifacts, blurring, and overall image quality. We also performed two-way repeated measures analysis of variance., Results: cFBI with eFA achieved nearly a 50% scan time reduction compared to sFBI. The high/low flip angle of 180/2 degrees with lower refocusing pulses shows fast longitudinal restoration with the highest blood signals, yet also more sensitive to the background signals. Overall, 180/30 degrees images show reasonable blood signal recovery while minimizing the background signal artifacts. After the trigger delay optimization, maximum intensity projection image of cFBI after systole-diastole subtraction demonstrates less motion and N/2 artifacts than that of sFBI., Conclusion: Together with eFA for fast longitudinal signal restoration, the proposed cFBI technique achieved a 2-fold reduction in scan time and improved image quality without major artifacts.

3-Nitrotyrosine (3-NT), a byproduct of oxidative and nitrosative stress, is implicated in age-related neurodegenerative disorders. Current literature suggests that free 3-NT becomes integrated into the carboxy-terminal domain of α-tubulin via the tyrosination/detyrosination cycle. Independently of this integration, 3-NT has been associated with the cell death of dopaminergic neurons. Given the critical role of tyrosination/detyrosination in governing axonal morphology and function, the substitution of tyrosine with 3-NT in this process may potentially disrupt axonal homeostasis, although this aspect remains underexplored. In this study, we examined the impact of 3-NT on the axons of cerebellar granule neurons, which is used as a model for non-dopaminergic neurons. Our observations revealed axonal shortening, which correlated with the incorporation of 3-NT into α-tubulin. Importantly, this axonal effect was observed prior to the onset of cellular death. Furthermore, 3-NT was found to diminish mitochondrial motility within the axon, leading to a subsequent reduction in mitochondrial membrane potential. The suppression of syntaphilin, a protein responsible for anchoring mitochondria to microtubules, restored the mitochondrial motility and axonal elongation that were inhibited by 3-NT. These findings underscore the inhibitory role of 3-NT in axonal elongation by impeding mitochondrial movement, suggesting its potential involvement in axonal dysfunction within non-dopaminergic neurons., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

CD4 + T cells induced from human iPSCs (iCD4 + T cells) offer a therapeutic opportunity for overcoming immune pathologies arising from hematopoietic stem cell transplantation. However, most iCD4 + T cells are conventional helper T cells, which secrete inflammatory cytokines. We induced high-level expression of FOXP3, a master transcription factor of regulatory T cells, in iCD4 + T cells. Human iPSC-derived, FOXP3-induced CD4 + T (iCD4 + Treg-like) cells did not secrete inflammatory cytokines upon activation. Moreover, they showed demethylation of the Treg-specific demethylation region, suggesting successful conversion to immunosuppressive iCD4 + Treg-like cells. We further assessed these iCD4 + Treg-like cells for CAR-mediated immunosuppressive ability. HLA-A2 CAR-transduced iCD4 + Treg-like cells inhibited CD8 + cytotoxic T cell (CTL) division in a mixed lymphocyte reaction assay with A2 + allogeneic CTLs and suppressed xenogeneic graft-versus-host disease (GVHD) in NSG mice treated with A2 + human PBMCs. In most cases, these cells suppressed the xenogeneic GvHD progression as much as natural CD25 + CD127 - Tregs did., Competing Interests: Declaration of interests S.K. is a director and shareholder at Shinobi Tx and received research funding from Shinobi Tx, Takeda Pharmaceutical, and Astellas. H.K received research funding from Chugai, Kyowa Kirin, Zenyaku Kogyo, Sumitomo Pharma, Eisai, Daiichi Sankyo, Otsuka Pharmaceutical, Perseus Proteomics, CURED, Astellas Pharma, Asahi Kasei, AbbVie, Nippon Shinyaku, JCR Pharmaceuticals, and Takeda Pharmaceutical. S.K. has patent applications related to the research (patent no. WO/2023/182328). T. Sato., T. Shinohara., K.K., A.M., K.N., M.S., and Y.K. are employees of Takeda Pharmaceutical Co. Ltd., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Differentiation of pancreatic endocrine cells from human pluripotent stem cells (PSCs) has been thoroughly investigated for application in cell therapy against diabetes. In the context of induced pancreatic endocrine cell implantation, previous studies have reported graft enlargement resulting from off-target pancreatic lineage cells. However, there is currently no documented evidence of proliferative off-target cells beyond the pancreatic lineage in existing studies. Here, we show that the implantation of seven-stage induced PSC-derived pancreatic islet cells (s7-iPICs) leads to the emergence of unexpected off-target cells with proliferative capacity via in vivo maturation. These cells display characteristics of both mesenchymal stem cells (MSCs) and smooth muscle cells (SMCs), termed proliferative MSC- and SMC-like cells (PMSCs). The frequency of PMSC emergence was found to be high when 10 8 s7-iPICs were used. Given that clinical applications involve the use of a greater number of induced cells than 10 8 , it is challenging to ensure the safety of clinical applications unless PMSCs are adequately addressed. Accordingly, we developed a detection system and removal methods for PMSCs. To detect PMSCs without implantation, we implemented a 4-wk-extended culture system and demonstrated that putative PMSCs could be reduced by compound treatment, particularly with the taxane docetaxel. When docetaxel-treated s7-iPICs were implanted, the PMSCs were no longer observed. This study provides useful insights into the identification and resolution of safety issues, which are particularly important in the field of cell-based medicine using PSCs., Competing Interests: Competing interests statement:T.W. and T.T. are scientific advisers for Orizuru Therapeutics. The remaining authors declare no competing interests.

Purpose: Fatty acid composition of the orbit makes it challenging to achieve complete fat suppression during orbit MR imaging. Implementation of a fat suppression technique capable of suppressing signals from saturated (aliphatic) and unsaturated (olefinic or protons at double-bonded carbon sites) fat would improve the visualization of an optical nerve. Furthermore, the ability to semi-quantify the fractions of aliphatic and olefinic fat may potentially provide valuable information in assessing orbit pathology., Methods: A phantom study was conducted on various oil samples on a clinical 3 Tesla scanner. The imaging protocol included three 2D fast spin echo (FSE) sequences: in-phase, polarity-altered spectral and spatial selective acquisition (PASTA), and a combination of PASTA with opposed phase in olefinic and aliphatic chemical shift. The results were validated against high-resolution 11.7T NMR and compared with images acquired with spectral attenuated inversion recovery (SPAIR) and chemical shift selective (CHESS) fat suppression techniques. In-vivo data were acquired on eight healthy subjects and were compared with the prior histological studies., Results: PASTA with opposed phase achieved complete suppression of fat signals in the orbits and provided images of well-delineated optical nerves and muscles in all subjects. The olefinic fat fraction in the olive, walnut, and fish oil phantoms at 3T was found to be 5.0%, 11.2%, and 12.8%, respectively, whereas 11.7T NMR provides the following olefinic fat fractions: 6.0% for olive, 11.5% for walnut, and 12.6% for fish oils. For the in-vivo study, on average, olefinic fat accounted for 9.9% ± 3.8% of total fat while the aliphatic fat fraction was 90.1% ± 3.8%, in the normal orbits., Conclusion: We have introduced a new fat suppression technique using PASTA with opposed phase and applied it to human orbits. The purposed method achieves an excellent orbital fat suppression and the quantification of aliphatic and olefinic fat signals.

Introduction: T cells induced from induced pluripotent stem cells(iPSCs) derived from antigen-specific T cells (T-iPS-T cells) are an attractive tool for T cell immunotherapy. The induction of cytotoxic T-iPS-T cells is well established in feeder-free condition for the aim of off-the-shelf production, however, the induction of helper T-iPS-T cells remains challenging., Methods: We analyzed T-iPS-T cells matured in 3D organoid culture at different steps in the culture process at the single-cell level. T-iPS-T cell datasets were merged with an available human thymocyte dataset based in single-cell RNA sequencing (scRNA-seq). Particularly, we searched for genes crucial for generation CD4+ T-iPS-T cells by comparing T-iPS-T cells established in 2D feeder-free or 3D organoid culture., Results: The scRNA-seq data indicated that T-iPS-T cells are similar to T cells transitioning to human thymocytes, with SELENOW, GIMAP4, 7, SATB1, SALMF1, IL7R, SYTL2, S100A11, STAT1, IFITM1, LZTFL1 and SOX4 identified as candidate genes for the 2D feeder-free induction of CD4+ T-iPS-T cells., Discussion: This study provides single cell transcriptome datasets of iPS-T cells and leads to further analysis for CD4+ T cell generation from T-iPSCs., Competing Interests: YK, SuA and TS are employees of Takeda Pharmaceutical Co. Ltd. ShA is an employee of Axcelead Drug Discovery Partners, Inc. SK is a founder, shareholder, and director at Thyas Co., Ltd. and received research fundings from Takeda Pharmaceutical Co., Ltd., Astellas Co., Ltd., Terumo Co., Ltd., Mitsui-soko Co., Ltd., Kotai Bio Co., Ltd.,and Thyas Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ishiguro, Iriguchi, Asano, Shinohara, Shiina, Arima, Kassai, Sakai, Obama and Kaneko.)

Purpose: For biochemical evaluation of soft tissues of the knee, T1rho magnetic resonance imaging (MRI) has been proposed. Purpose of this study was to compare three T1rho sequences based on fast advanced spin echo (FASE), ultrashort echo time (UTE), and magnetization-prepared angle-modulated partitioned k-space spoiled gradient echo snapshots (MAPSS) acquisitions for the knee evaluation., Materials and Methods: We developed two T1rho sequences using 3D FASE or 3D radial UTE acquisitions. 3D MAPSS T1rho was provided by the manufacturer. Agarose phantoms with varying concentrations were imaged. Additionally, bilateral knees of asymptomatic subjects were imaged sagittally. T1rho values of the phantoms and 4 regions of interest (ROI) of the knees (i.e., anterior and posterior meniscus, femoral and tibial cartilage) were determined., Results: In phantoms, all T1rho values monotonically decreased with increasing agarose concentration. 3D MAPSS T1rho values of 51, 34, and 38 ms were found for 2, 3, and 4% agarose, respectively, similar to published values on another platform. In the knee, the raw images were detailed with good contrast. Cartilage and meniscus T1rho values varied with the pulse sequence, being the lowest in the 3D UTE T1rho sequence. Comparing different ROIs, menisci generally had lower T1rho values compared to cartilage, as expected in healthy knees., Conclusion: We have successfully developed and implemented the new T1rho sequences and validated them using agarose phantoms and volunteer knees. All sequences were optimized to be clinically feasible (~ 5 min or less) and yielded satisfactory image quality and T1rho values consistent with the literature., (© 2023. The Author(s) under exclusive licence to Japan Radiological Society.)

Background: MRI relaxometry mapping and proton density fat fraction (PDFF) have been proposed for the evaluation of hepatic fibrosis. However, sex-specific relationships of age and body fat with these MRI parameters have not been studied in detail among adults without clinically manifest hepatic disease. We aimed to determine the sex-specific correlation of multiparametric MRI parameters with age and body fat and to evaluate their interplay associations., Methods: 147 study participants (84 women, mean age 48±14 years, range 19-85 years) were prospectively enrolled. 3 T MRI including T1, T2 and T1ρ mapping and PDFF and R2* map were acquired. Visceral and subcutaneous fat were measured on the fat images from Dixon water-fat separation sequence., Results: All MRI parameters demonstrated sex difference except for T1ρ. PDFF was more related to visceral than subcutaneous fat. Per 100 ml gain of visceral or subcutaneous fat is associated with 1 or 0.4% accretion of liver fat, respectively. PDFF and R2* were higher in men (both P = 0.01) while T1 and T2 were higher in women (both P < 0.01). R2* was positively but T1 and T2 were negatively associated with age in women (all P < 0.01), while T1ρ was positively related to age in men (P < 0.05). In all studies, R2* was positively and T1ρ was negatively associated with PDFF (both P <0.0001)., Conclusion: Visceral fat plays an essential role in the elevated liver fat. When using MRI parametric measures for liver disease evaluation, the interplay between these parameters should be considered., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

T cells play important roles in autoimmune diseases, but it remains unclear how to optimally manipulate them. We focused on the T cell immunoreceptor with Ig and ITIM domains (TIGIT), a coinhibitory molecule that regulates and is expressed in T cells. In autoimmune diseases, the association between TIGIT-expressing cells and pathogenesis and the function of human-TIGIT (hu-TIGIT) signalling modification have not been fully elucidated. Here we generated anti-hu-TIGIT agonistic monoclonal antibodies (mAbs) and generated hu-TIGIT knock-in mice to accurately evaluate the efficacy of mAb function. Our mAb suppressed the activation of CD4 + T cells, especially follicular helper T and peripheral helper T cells that highly expressed TIGIT, and enhanced the suppressive function of naïve regulatory T cells. These results indicate that our mAb has advantages in restoring the imbalance of T cells that are activated in autoimmune diseases and suggest potential clinical applications for anti-hu-TIGIT agonistic mAbs as therapeutic agents., (© 2023. The Author(s).)

Objective: To evaluate the diagnostic equivalency between an ultrafast (1 min 53 s) lumbar MRI protocol using deep learning-based reconstruction and a conventional lumbar MRI protocol (12 min 31 s)., Materials and Methods: This study included 58 patients who underwent lumbar MRI using both conventional and ultrafast protocols, including sagittal T1-weighted, T2-weighted, short-TI inversion recovery, and axial T2-weighted sequences. Compared with the conventional protocol, the ultrafast protocol shortened the acquisition time to approximately one-sixth. To compensate for the decreased signal-to-noise ratio caused by the acceleration, deep learning-based reconstruction was applied. Three neuroradiologists graded degenerative changes and analyzed for presence of other pathologies. For the grading of degenerative changes, interprotocol intrareader agreement was assessed using kappa statics. Interchangeability between the two protocols was also tested by calculating the individual equivalence index between the intraprotocol interreader agreement and interprotocol interreader agreement. For the detection of other pathologies, interprotocol intrareader agreement was assessed., Results: For the grading of degenerative changes, the kappa values for interprotocol intrareader agreement of all three readers ranged from 0.707 to 0.804, indicating substantial to almost perfect agreement. Except for foraminal stenosis and disc contour on axial images, the 95% confidence interval of the individual equivalence index was < 5%, indicating the two protocols were interchangeable. For the detection of other pathologies, the interprotocol intrareader agreement rates were > 98% for each individual pathology., Conclusions: Our proposed ultrafast lumbar spine MRI protocol provided almost equivalent diagnostic results to that of the conventional protocol, except for some degenerative changes., (© 2022. The Author(s), under exclusive licence to International Skeletal Society (ISS).)

Signal intensity (SI) drop has been proposed as an indirect stenosis assessment in non-contrast coronary MRA (NC-MRCA) but it uses unproven assumptions. We aimed to clarify the mechanisms that govern the SI in vitro and develop a stenosis detection method in vivo. Flow phantom tubes with/without stenosis were scanned under two spatial resolutions (0.5/1.0 mm 3 ) on a 3.0 T MRI. Thirty-two coronary arteries from 11 volunteers were prospectively scanned with an EKG- and respiratory-gated 3D NC-MRCA with a resolution of 1.0 mm 3 , with coronary computed tomography angiography (CTA) as reference. The normalized SI along the centerline of the tubes or the coronary arteries was assessed against the distance from the orifice using a linear regression model. Its coefficient (SI decay slope) and goodness-of-fit (R2) were extracted to assess the effect of flow velocity and stenosis on the SI profile curve. The R2 was utilized for the stenosis detection. Phantom study: A slow flow velocity caused a steep SI decay slope. The SI drop revealed only at the inlet and outlet of stenosis due to the flow turbulence/vortex and yielded low R2, in which shape changed by the resolution. Clinical study: The R2 cutoff to detect ≥ 50% stenosis for the left and right coronary arteries were 0.64 and 0.20 with a sensitivity/specificity of 71.5/71.5 and 66.7/100 (%), respectively. The SI drop did not reflect the actual stenosis position and not suitable for the stenosis localization. The R2 cutoff represents an alternative method to detect stenoses on NC-MRCA at vessel level.Trial registration: ClinicalTrials.gov; NCT03768999, registered on December 7, 2018., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Computed diffusion-weighted imaging (cDWI) is a mathematical computation technique that generates DWIs for any b-value by using actual DWI (aDWI) data with at least two different b-values and may improve differentiation of metastatic from nonmetastatic lymph nodes., Purpose: To determine the appropriate b-value for cDWI to achieve a better diagnostic capability for lymph node staging (N-staging) in non-small cell lung cancer (NSCLC) patients compared to aDWI, short inversion time (TI) inversion recovery (STIR) imaging, or positron emission tomography with 2-[fluorine-18] fluoro-2-deoxy-d-glucose combined with computed tomography (FDG-PET/CT)., Study Type: Prospective., Subjects: A total of 245 (127 males and 118 females; mean age 72 years) consecutive histopathologically confirmed NSCLC patients., Field Strength/sequence: A 3 T, half-Fourier single-shot turbo spin-echo sequence, electrocardiogram (ECG)-triggered STIR fast advanced spin-echo (FASE) sequence with black blood and STIR acquisition and DWI obtained by FASE with b-values of 0 and 1000 sec/mm 2 ., Assessment: From aDWIs with b-values of 0 and 1000 (aDWI 1000 ) sec/mm 2 , cDWI using 400 (cDWI 400 ), 600 (cDWI 600 ), 800 (cDWI 800 ), and 2000 (cDWI 2000 ) sec/mm 2 were generated. Then, 114 metastatic and 114 nonmetastatic nodes (mediastinal and hilar lymph nodes) were selected and evaluated with a contrast ratio (CR) for each cDWI and aDWI, apparent diffusion coefficient (ADC), lymph node-to-muscle ratio (LMR) on STIR, and maximum standard uptake value (SUV max )., Statistical Tests: Receiver operating characteristic curve (ROC) analysis, Youden index, and McNemar's test., Results: Area under the curve (AUC) of CR 600 was significantly larger than the CR 400 , CR 800 , CR 2000 , aCR 1000 , and SUV max . Comparison of N-staging accuracy showed that CR 600 was significantly higher than CR 400 , CR 2000 , ADC, aCR 1000 , and SUV max , although there were no significant differences with CR 800 (P = 0.99) and LMR (P = 0.99)., Data Conclusion: cDWI with b-value at 600 sec/mm 2 may have potential to improve N-staging accuracy as compared with aDWI, STIR, and PET/CT., Evidence Level: 2 TECHNICAL EFFICACY: Stage 2., (© 2022 International Society for Magnetic Resonance in Medicine.)

Background: The effect of hepatic steatosis on the gradient-echo (GRE) based Modified Look-Locker Inversion Recovery (MOLLI) technique for T1 mapping has not been evaluated. The purpose of this study was to evaluate a GRE based MOLLI technique for hepatic T1 mapping and determine the relationship of T1 differences (ΔT1) on in-phase (IP) and out-of-phase (OP) to fat fraction (FF) measurement., Materials and Methods: 3 T MRI included MOLLI T1 mapping with TE = 1.3 (OP), 2.4 (IP), and 1.8 ms, and chemical-shift-encoded sequence with spectral modeling of fat to generate FF map as a reference. Bloch simulations and oil/water phantoms were used to characterize the response of the MOLLI T1 in various FF < 30% since MOLLI T1 estimation was erratic beyond this limit. Curve fit between ΔT1 and FF from simulation was applied to validate the phantom and the in-vivo results. Thirty-eight normal volunteers were included (16 women, Age 44 ± 12 years, BMI 27 ± 5.3 kg/m 2 ). MOLLI water images were reconstructed by the average of OP and IP images, and the T1 values on water images served as the reference for T1 bias calculation defined as the percent difference between OP, IP, TE = 1.8 ms and the referenced water T1. Linear regression was performed to correlate the FF quantified by the reference and MOLLI methods., Results: Phantom results were consistent with the Bloch simulations. The simulated relationship between FF (0-30%) and ΔT1 could be modeled precisely by a cubic equation with R2 = 1. In-vivo MOLLI ΔT1 and estimated FF were correlated to the reference FF (both R2 ≥ 0.96 and P < 0.001). TE = 1.8 ms demonstrated less T1 bias (-1.34%) compared to TE = OP (5.32%) or IP (-3.8%, both P < 0.001)., Conclusion: At 3 T, TE of 1.8 ms can be used to reduce the T1 bias and deliver consistent T1 values when FF is <30%., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: We sought to clarify the presence of radiographic thymus variants using a scoring system, and their association with clinical and immunological features in RA patients., Methods: A total of 387 RA patients were randomly selected from all patients visiting our department who underwent chest CT scanning, with exclusion of patients with thymoma or thymic cyst, or age < 30 years. Thymus size and attenuation score in axial CT images were quantitatively interpreted and assessed. Associations between immunophenotype data and clinical and serological features were analysed in a subset of patients., Results: Thymic enlargement was found in 76 (19.6%) patients, and a thymus attenuation score ≥ 2 was found in 50 (12.9%) patients. The score was significantly associated with antibodies to ACPA positivity. Thymic enlargement was significantly associated with the proportions of CD4+ effector memory T cells., Conclusion: Radiographic thymus variants were frequently observed in RA patients and may reflect an abnormal immune response involved in the pathogenesis of RA., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

While numerous disease-modifying anti-rheumatic drugs (DMARDs) have brought about a dramatic paradigm shift in the management of rheumatoid arthritis (RA), unmet needs remain, such as the small proportion of patients who achieve drug-free status. The aim of this study was to explore key molecules for remission at the T cell level, which are known to be deeply involved in RA pathogenesis, and investigate the disease course of patients who achieved molecular remission (MR). We enrolled a total of 46 patients with RA and 10 healthy controls (HCs). We performed gene expression profiling and selected remission signature genes in CD4 + T cells and CD8 + T cells from patients with RA using machine learning methods. In addition, we investigated the benefits of achieving MR on disease control. We identified 9 and 23 genes that were associated with clinical remission in CD4 + and CD8 + T cells, respectively. Principal component analysis (PCA) demonstrated that their expression profiling was similar to those in HCs. For the remission signature genes in CD4 + T cells, the PCA result was reproduced using a validation cohort, indicating the robustness of these genes. A trend toward better disease control was observed during 12 months of follow-up in patients treated with tocilizumab in deep MR compared with those in non-deep MR, although the difference was not significant. The current study will promote our understanding of the molecular mechanisms necessary to achieve deep remission during the management of RA., (© 2021. The Author(s).)

Background: Several deep learning-based methods have been proposed for addressing the long scanning time of magnetic resonance imaging. Most are trained using brain 3T magnetic resonance images, but is unclear whether performance is affected when applying these methods to different anatomical sites and at different field strengths., Purpose: To validate the denoising performance of deep learning-based reconstruction method trained by brain and knee 3T magnetic resonance images when applied to lumbar 1.5T magnetic resonance images., Material and Methods: Using a 1.5T scanner, we obtained lumber T2-weighted sequences in 10 volunteers using three different scanning times: 228 s (standard), 119 s (double-fast), and 68 s (triple-fast). We compared the images obtained by the standard sequence with those obtained by the deep learning-based reconstruction-applied faster sequences., Results: Signal-to-noise ratio values were significantly higher for deep learning-based reconstruction-double-fast than for standard and did not differ significantly between deep learning-based reconstruction-triple-fast and standard. Contrast-to-noise ratio values also did not differ significantly between deep learning-based reconstruction-triple-fast and standard. Qualitative scores for perceived signal-to-noise ratio and overall image quality were significantly higher for deep learning-based reconstruction-double fast and deep learning-based reconstruction-triple-fast than for standard. Average scores for sharpness, contrast, and structure visibility were equal to or higher for deep learning-based reconstruction-double-fast and deep learning-based reconstruction-triple-fast than for standard, but the differences were not statistically significant. The average scores for artifact were lower for deep learning-based reconstruction-double-fast and deep learning-based reconstruction-triple-fast than for standard, but the differences were not statistically significant., Conclusion: The deep learning-based reconstruction method trained by 3T brain and knee images may reduce the scanning time of 1.5T lumbar magnetic resonance images by one-third without sacrificing image quality., Competing Interests: Declaration of Conflicting Interests: The authors “Yuichi Yamashita” and “Yoshimori Kassai” are employees of Canon Medical Systems Corporation. Other authors have no conflict of interest., (© The Foundation Acta Radiologica 2021.)

Current contrast-enhanced magnetic resonance angiography (MRA) and non-contrast-enhanced balanced steady-state free precession (bSSFP) MRA cause susceptibility artifacts from metallic devices in assessing endovascular visceral-artery interventions. The aims of this study are to investigate and compare image quality (IQ) and susceptibility artifacts of three-dimensional (3D) ultrashort echo time (UTE) time-spatial labeling inversion pulse (Time-SLIP) with those of 3D bSSFP Time-SLIP and to assess denoising deep learning reconstruction (dDLR) for the improvement of the signal-to-noise ratio (SNR) in 3D UTE with sparse sampling in phantoms and human subjects. This is a prospective type of study. Pulsatile glycerin-water flow phantom with platinum-tungsten-alloy coil, stainless-steel, nitinol, and cobalt-alloy stents were used. Ten healthy volunteers (seven males) and three patients (two males) were included in this study. 3D UTE Time-SLIP and 3D bSSFP Time-SLIP at 3T were used. The phantom-based study compared the signal-intensity ratio of the device levels (SR device ) and distal segments (SR distal ) to the proximal segments. The volunteer-based study measured SNR, contrast ratio (CR), and IQ. The patient study evaluated local artifacts from metallic devices. Statistical tests included paired t-tests, Wilcoxon-signed rank tests, and Kruskal-Wallis tests. In the phantom-based study, SR device was small with UTE Time-SLIP, except the stainless-steel stent. SR distal was greater (49.1%-90.4%) on bSSFP images than UTE images (-11.1% to 9.6%). Among volunteers, dDLR in UTE images improved SNR (p < 0.05) and IQ (p < 0.05), but CR was unaffected. UTE Time-SLIP showed inferior SNR and IQ than bSSFP Time-SLIP in images with and without dDLR (p < 0.05 for each). However, among patients, UTE Time-SLIP showed reduced metal artifacts compared to bSSFP Time-SLIP. Irrespective of the lower SNR and IQ of 3D UTE Time-SLIP than those of 3D bSSFP Time-SLIP, the former appeared to better depict flow after stenting or coiling. This indicates the potential of 3D UTE Time-SLIP to provide suitable diagnostic images of target vessels. dDLR improved SNR with reducing artifacts related to radial sampling, while maintaining the contrast. LEVEL OF EVIDENCE: 2. TECHNICAL EFFICACY STAGE: 2., (© 2020 International Society for Magnetic Resonance in Medicine.)

Background: Oxygen (O 2 )-enhanced MRI is mainly performed by a 2D sequence using 1.5T MR systems but trying to be obtained by a 3D sequence using a 3T MR system., Purpose: To compare the capability of 3D O 2 -enhanced MRI and that of thin-section computed tomography (CT) for pulmonary functional loss assessment and clinical stage classification of chronic obstructive pulmonary disease (COPD) in smokers., Study Type: Prospective study., Population: Fifty six smokers were included., Field Strength/ Sequence: 3T, 3D O 2 -enhanced MRIs were performed with a 3D T 1 -weighted fast field echo pulse sequence using the multiple flip angles., Assessments: Smokers were classified into four stages ("Without COPD," "Mild COPD," "Moderate COPD," "Severe or very severe COPD"). Maps of regional changes in T 1 values were generated from O 2 -enhanced MR data. Regions of interest (ROIs) were then placed over the lung on all slices and averaged to determine mean T 1 value change (ΔT 1 ). Quantitative CT used the percentage of low attenuation areas within the entire lung (LAA%)., Statistical Tests: ΔT 1 and LAA% were correlated with pulmonary functional parameters, and compared for four stages using Tukey's Honestly Significant Difference test. Discrimination analyses were performed and McNemar's test was used for a comparison of the accuracy of the indexes., Results: There were significantly higher correlations between ΔT 1 and pulmonary functional parameters (-0.83 ≤ r ≤ -0.71, P < 0.05) than between LAA% and the same pulmonary functional parameters (-0.76 ≤ r ≤ -0.69, P < 0.05). ΔT 1 and LAA% of the "Mild COPD" and "Moderate COPD" groups were significantly different from those of the "Severe or Very Severe COPD" group (P < 0.05). Discriminatory accuracy of ΔT 1 (62.5%) and ΔT1 with LAA% (67.9%) was significantly greater than that of LAA% (48.2%, P < 0.05)., Data Conclusion: Compared with thin-section CT, 3D O 2 -enhanced MRI has a similar capability for pulmonary functional assessment but better potential for clinical stage classification in smokers., Level of Evidence: 2 TECHNICAL EFFICACY STAGE: 1., (© 2020 International Society for Magnetic Resonance in Medicine.)

Clinical successes demonstrated by chimeric antigen receptor T-cell immunotherapy have facilitated further development of T-cell immunotherapy against wide variety of diseases. One approach is the development of "off-the-shelf" T-cell sources. Technologies to generate T-cells from pluripotent stem cells (PSCs) may offer platforms to produce "off-the-shelf" and synthetic allogeneic T-cells. However, low differentiation efficiency and poor scalability of current methods may compromise their utilities. Here we show improved differentiation efficiency of T-cells from induced PSCs (iPSCs) derived from an antigen-specific cytotoxic T-cell clone, or from T-cell receptor (TCR)-transduced iPSCs, as starting materials. We additionally describe feeder-free differentiation culture systems that span from iPSC maintenance to T-cell proliferation phases, enabling large-scale regenerated T-cell production. Moreover, simultaneous addition of SDF1α and a p38 inhibitor during T-cell differentiation enhances T-cell commitment. The regenerated T-cells show TCR-dependent functions in vitro and are capable of in vivo anti-tumor activity. This system provides a platform to generate a large number of regenerated T-cells for clinical application and investigate human T-cell differentiation and biology.

Coronary magnetic resonance angiography (coronary MRA) is advantageous in its ability to assess coronary artery morphology and function without ionizing radiation or contrast media. However, technical limitations including reduced spatial resolution, long acquisition times, and low signal-to-noise ratios prevent it from clinical routine utilization. Nonetheless, each of these limitations can be specifically addressed by a combination of novel technologies including super-resolution imaging, compressed sensing, and deep-learning reconstruction. In this paper, we first review the current clinical use and motivations for non-contrast coronary MRA, discuss currently available coronary MRA techniques, and highlight current technical developments that hold unique potential to optimize coronary MRA image acquisition and post-processing. In the final section, we examine the various research-based coronary MRA methods and metrics that can be leveraged to assess coronary stenosis severity, physiological function, and atherosclerotic plaque characterization. We specifically discuss how such technologies may contribute to the clinical translation of coronary MRA into a robust modality for routine clinical use.

Background: The aim of this study was to identify the molecular mechanism of dysregulation of B cell subpopulations of primary Sjögren's syndrome (pSS) at the transcriptome level., Methods: We enrolled patients with pSS (n = 6) and healthy controls (HCs) (n = 6) in the discovery cohort using microarray and pSS (n = 14) and HCs (n = 12) in the validation cohort using quantitative PCR (qPCR). Peripheral B cells acquired from these subjects were separated by cell sorting into four subsets: CD38 - IgD + (Bm1), CD38 + IgD + (naive B cells), CD38 high IgD + (pre-germinal centre B cells) and CD38 ± IgD - (memory B cells). We performed differentially expressed gene (DEG) analysis and weighted gene co-expression network analysis (WGCNA)., Results: Expression of the long non-coding RNA LINC00487 was significantly upregulated in all B cell subsets, as was that of HLA and interferon (IFN) signature genes. Moreover, the normalized intensity value of LINC00487 significantly correlated with the disease activity score of all pSS B cell subsets. Studies of human B cell lines revealed that the expression of LINC00487 was strongly induced by IFNα. WGCNA revealed six gene clusters associated with the B cell subpopulation of pSS. Further, SOX4 was identified as an inter-module hub gene., Conclusion: Our transcriptome analysis revealed key genes involved in the dysregulation of B cell subpopulations associated with pSS., Trial Registration: Not required.

Increased collagen, or fibrosis, is an important marker of disease and may improve identification of patients at risk. In addition, fibrosis imaging may play an increasing role in guiding therapy and monitoring its effectiveness. MRI is the most frequently used modality to detect, visualize and quantify fibrosis non-invasively. However, standard MRI techniques used to phenotype cardiac fibrosis such as delayed enhancement and extracellular volume determination by T 1 mapping, require the administration of gadolinium-based contrast and are particularly difficult to use in patients with cardiac devices such as pacemakers and automatic defibrillators. Therefore, such methods are limited in the serial evaluation of cardiovascular fibrosis as part of chronic disease monitoring. A method to directly measure collagen amount could be of great clinical benefit. In the current review we will discuss the potential of a novel MR technique, ultrashort echo time (UTE) MR, for fibrosis imaging. Although UTE imaging is successfully applied in other body areas such as musculoskeletal applications, there is very limited experience so far in the heart. We will review the established methods and currently available literature, discuss the technical considerations and challenges, show preliminary in vivo images and provide a future outlook on potential applications of cardiovascular UTE.

Objectives: Rheumatoid arthritis (RA) is an autoimmune disease accompanied by lymphocyte infiltration into joint synovium. While T cells are considered to be important for its pathogenesis, the features that are the most relevant to disease and how they change after treatment remain unclear. The aim of this study was to clarify the characteristics of T cells in RA, comprehensively., Methods: We enrolled a total of 311 patients with RA and 73 healthy participants, and carefully classified them by disease state, constructed multiple cohorts and analysed clinical samples from them in a stepwise manner. We performed immunophenotyping with multiple evaluation axes, and two independent transcriptome analyses complementary to each other., Results: We identified that 'effector memory-Tfh' subset was specifically expanded in the peripheral blood (PB) of patients with RA in correlation with disease activity, and reverted after treatment. Besides, we revealed distinct features of T cells in synovial fluid (SF) that the expression of Tfh/Tph-related genes and pro-inflammatory cytokines and chemokines, including CXCL13 , were significantly enriched, whereas these phenotype were Th1-like. Finally, we identified specific pathways, such as mTORC1, IL-2-stat5, E2F, cell cycle and interferon-related genes, that were significantly enriched in SF, in particular, as well as PB of untreated patients with RA, and notably, these features reverted after treatment., Conclusion: Our multi-dimensional investigation identified disease relevant T-cell subsets and gene signatures deeply involved in pathogenesis of RA. These findings could aid in our understanding of essential roles of T cells in RA and will facilitate to development better diagnostic and therapeutic interventions., Competing Interests: Competing interests: YO, KK, YK, KG, MT, RK, HM and YE are employees of Takeda Pharmaceutical Company Limited. KS has received research grants from Eisai, Bristol-Myers Squibb, Kissei Pharmaceutical, and Daiichi Sankyo, and speaking fees from Abbie Japan, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Fuji Film Limited, Janssen Pharmaceutical, Kissei Pharmaceutical, Mitsubishi Tanabe Pharmaceutical, Pfizer Japan, Shionogi, Takeda Pharmaceutical, and UCB Japan, consulting fees from Abbie, and Pfizer Japan. AY has received speaking fees from Chugai Pharmaceutical, Mitsubishi Tanabe Pharmaceutical, Pfizer Japan, Ono Pharmaceutical, Maruho, and Novartis, and consulting fees from GSK Japan. TT has received research grants from Astellas Pharma Inc, Bristol-Myers KK, Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd, Takeda Pharmaceutical Co. Ltd, Teijin Pharma Ltd, AbbVie GK, Asahikasei Pharma Corp, Mitsubishi Tanabe Pharma Co, Pfizer Japan Inc, and Taisho Toyama Pharmaceutical Co. Ltd, Eisai Co. Ltd, AYUMI Pharmaceutical Corporation, and Nipponkayaku Co. Ltd, and speaking fees from AbbVie GK, Bristol-Myers KK, Chugai Pharmaceutical Co. Ltd, Mitsubishi Tanabe Pharma Co, Pfizer Japan Inc, and Astellas Pharma Inc, and Diaichi Sankyo Co. Ltd, and consultant fees from Astra Zeneca KK, Eli Lilly Japan KK, Novartis Pharma KK, Mitsubishi Tanabe Pharma Co, Abbivie GK, Nipponkayaku Co. Ltd, Janssen Pharmaceutical KK, Astellas Pharma Inc, and Taiho Pharmaceutical Co. Ltd., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Ultrasonography (US) can directly demonstrate joint inflammation, including grayscale (GS) signs of synovial hypertrophy and power Doppler (PD) techniques to demonstrate increased blood flow and vascularization. Recently, echogenicity, especially hypoechoic synovium, has also been associated with local inflammatory activity. However, only a few studies have demonstrated correlation between histopathologic and immunopathologic evaluation and US findings. The aim of this study was to clarify whether joint US findings including synovial hypertrophy, vascularity, and echogenicity can accurately characterize synovial pathophysiology in patients with active rheumatoid arthritis (RA)., Methods: A total of 44 patients with RA were included, both treated (n = 25) and untreated (n = 19) and scheduled for US examination of the knee joint with synovial fluid (SF) aspiration and two treated patients also underwent synovial biopsy. US images were quantitatively analyzed using grayscale assessment of synovial hypertrophy and PD for vascularity and echogenicity. Levels of nine SF cytokines and growth factors were also measured., Results: Both US synovial hypertrophy and PD vascularity significantly correlated with SF inflammatory cytokine levels such as IL-6, IL-8, IL-1β and IL-10 in untreated patients. Angiogenic factors, including vascular endothelial growth factor (VEGF), only correlated with PD vascularity. In the treated patients, the associations between synovial hypertrophy and any cytokines were diminished, although synovial vascularity and echogenicity correlated with IL-6 and VEGF (p < 0.05). Histopathologic analysis revealed that hypoechogenicity of the synovium correlated with marked infiltration of lymphocytes and hypervascularity., Conclusions: We demonstrated the pathophysiological origins of US findings in the joint. The degree of US vascularity of the synovium correlated with local inflammatory cytokine levels and angiogenetic factors in patients with active RA. Synovial echogenicity, and not hypertrophy, correlated with inflammation, especially in treated patients with RA.

Limited T cell availability and proliferative exhaustion present major barriers to successful T cell-based immunotherapies and may potentially be overcome through the use of "rejuvenated" induced pluripotent stem cells derived from antigen-specific T cells (T-iPSCs). However, strict antigen specificity is essential for safe and efficient T cell immunotherapy. Here, we report that CD8αβ T cells from human T-iPSCs lose their antigen specificity through additional rearrangement of the T cell receptor (TCR) α chain gene during the CD4/CD8 double positive stage of in vitro differentiation. CRISPR knockout of a recombinase gene in the T-iPSCs prevented this additional TCR rearrangement. Moreover, when CD8αβ T cells were differentiated from monocyte-derived iPSCs that were transduced with an antigen-specific TCR, they showed monoclonal expression of the transduced TCR. TCR-stabilized, regenerated CD8αβ T cells effectively inhibit tumor growth in xenograft cancer models. These approaches could contribute to safe and effective regenerative T cell immunotherapies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Sustained clinical remission (CR) without drug treatment has not been achieved in patients with rheumatoid arthritis (RA). This implies a substantial difference between CR and the healthy state, but it has yet to be quantified. We report a longitudinal monitoring of the drug response at multi-omics levels in the peripheral blood of patients with RA. Our data reveal that drug treatments alter the molecular profile closer to that of HCs at the transcriptome, serum proteome, and immunophenotype level. Patient follow-up suggests that the molecular profile after drug treatments is associated with long-term stable CR. In addition, we identify molecular signatures that are resistant to drug treatments. These signatures are associated with RA independently of known disease severity indexes and are largely explained by the imbalance of neutrophils, monocytes, and lymphocytes. This high-dimensional phenotyping provides a quantitative measure of molecular remission and illustrates a multi-omics approach to understanding drug response.

Purpose: To compare the diagnostic performance of positron emission tomography with [18F] fluoro-2-deoxy-glucose (FDG-PET) coregistered with magnetic resonance imaging (FDG-PET/MRI), MRI with and without diffusion-weighted imaging (DWI), FDG-PET fused with computed tomography (FDG-PET/CT) with brain contrast-enhanced (CE-) MRI, and routine radiological examination for assessment of postoperative recurrence in nonsmall-cell lung cancer (NSCLC) patients., Materials and Methods: 96 consecutive postoperative NSCLC patients (52 men, 44 women; mean age 72 years) prospectively underwent whole-body 3T MRI with and without DWI; PET/CTs and routine radiological examinations consisted of CE-brain MRI, whole-body CE-CT, and bone scintigraphy. The patients were divided into a recurrence (n = 17) and a nonrecurrence (n = 79) group based on pathological and follow-up examinations. All coregistered PET/MRIs were generated by proprietary software. The probability of recurrence was visually assessed on a per-patient basis. Receiver operating characteristic analyses were used to compare the diagnostic performance of all methods. Finally, diagnostic capabilities were compared by means of McNemar's test., Results: Areas under the curves (Azs) were significantly larger for PET/MRI and whole-body MRI with DWI (Az = 0.99) than for PET/CT (Az = 0.92, P < 0.05) and conventional radiological examination (Az = 0.91, P < 0.05). Specificity and accuracy of PET/MRI and MRI with and without DWI were significantly higher than those of PET/CT (P < 0.05) and routine radiological examination (P < 0.05)., Conclusion: Whole-body FDG-PET/MRI and MRI with DWI were found to be more specific and accurate than FDG-PET/CT and routine radiological examinations for assessment of recurrence in NSCLC patients, although MRI with and without DWI demonstrated slightly lower sensitivity than PET/CT., Level of Evidence: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:1707-1717., (© 2017 Wiley Periodicals, Inc.)