Papers by Tomoyuki Sugimoto
Journal of Neuroinflammation, 2021
Background Intractable neuropathic pain is a common symptom of neuromyelitis optica spectrum diso... more Background Intractable neuropathic pain is a common symptom of neuromyelitis optica spectrum disorder (NMOSD). However, the underlying mechanism of NMOSD pain remains to be elucidated. In this study, we focused on ATP, which is one of the damage-associated molecular patterns, and also a well-recognized molecule involved in peripheral neuropathic pain. Methods We assessed the development of pain symptoms by injecting anti-AQP4 recombinant autoantibodies (rAQP4 IgG) into rat spinal cords. We incubated HEK293 cells expressing AQP4 (HEK-AQP4) and rat astrocytes with rAQP4 IgG and assessed the level of ATP in the supernatant. We performed transcriptome analysis of the spinal cords injected with rAQP4 IgG. Pharmacological inhibition was also applied to investigate the involvement of ATP in the development of neuropathic pain in our rat model. The ATP concentration within the cerebrospinal fluid was examined in patients with NMOSD and other neurological diseases. Results Development of mec...
Scientific Reports, 2020
Although recent studies indicate the involvement of monocytes in accelerating the lesion formatio... more Although recent studies indicate the involvement of monocytes in accelerating the lesion formation of neuromyelitis optica spectrum disorder (NMOSD), the precise mechanism of the innate immune system activation remains elusive. Thus, in this study, we aimed to clarify the mechanisms of NMOSD pathogenesis from the viewpoint of innate immunity activation. We established anti-AQP4 recombinant autoantibodies (Ab) from plasmablasts in NMOSD patient’s CSF. Human astrocytes treated with anti-AQP4 Ab produced a significant amount of CCL2 and contributed to the efficient recruitment of monocytes. Moreover, mitochondrial DNA (mtDNA), which activated monocytes via Toll-like receptor 9 (TLR9), was released from astrocytes treated with anti-AQP4 Ab. MtDNA further enhanced CCL2 production by monocytes, and it was demonstrated that mtDNA concentration correlated with the efficiency of monocyte recruitment in the CSF of NMOSD patients. In conclusion, these observations highlight that mtDNA which wa...
Journal of Neuroinflammation, 2020
Background Sema4A is a regulator of helper T cell (Th) activation and differentiation in the prim... more Background Sema4A is a regulator of helper T cell (Th) activation and differentiation in the priming phase, which plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). However, the role of Sema4A in the effector phase remains elusive. We aimed to investigate the role of Sema4A at the effector phase in adoptively transferred EAE model. Clinical features and cytokine profiles of MS patients with high Sema4A levels were also examined in detail to clarify the correlation between Sema4A levels and disease activity of patients with MS. Methods We adoptively transferred encephalitogenic Th1 or Th17 cells to wild type (WT) or Sema4A-deficient (Sema4A KO) mice and assessed severity of symptoms and cellular infiltration within the central nervous system (CNS). In addition, we analyzed clinical and radiological features (n = 201), levels of serum IFN-γ and IL-17A (n = 86), complete remission ratio by IFN-β (n = 38) in all of...
Clinical Cancer Research, 2020
Purpose: Pancreatic cancer remains a disease of high mortality despite advanced diagnostic techni... more Purpose: Pancreatic cancer remains a disease of high mortality despite advanced diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic cancers. MUC1 and MUC4 expression are related to the aggressive behavior of human neoplasms and a poor patient outcome. In contrast, MUC2 is a tumor suppressor, and we have previously reported that MUC2 is a favorable prognostic factor in pancreatic neoplasia. This study investigates whether the methylation status of three mucin genes from postoperative tissue specimens from patients with pancreatic neoplasms could serve as a predictive biomarker for outcome after surgery. Experimental Design: We evaluated the methylation status of MUC1, MUC2, and MUC4 promoter regions in pancreatic tissue samples from 191 patients with various pancreatic lesions using methylation-specific electrophoresis. Then, integrating these results and clinicopathologic features, we used support vector machine-, neural network-...
Journal of Neuroinflammation, 2018
Background: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the cent... more Background: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system. Although complement-dependent astrocyte damage mediated by anti-aquaporin 4 autoantibody (AQP4-Ab) is well acknowledged to be the core of NMOSD pathogenesis, additional inflammatory cascades may contribute to the establishment of lesion formation. Thus, in this study, we investigated the possible pathogenic role of immune-reactive mitochondrial DNA (mtDNA) in cerebrospinal fluid (CSF) of NMOSD patients. Methods: Using quantitative polymerase chain reaction, we measured extracellular mtDNA levels in CSF of NMOSD patients positive for AQP4-Ab. Patients with multiple sclerosis or other neurological diseases were examined as controls. Pre-and post-treatment extracellular mtDNA levels were also compared in the NMOSD group. Extracellular mtDNA release from human astrocytes was analyzed in vitro utilizing NMOSD sera, and interleukin (IL)-1β production was measured in supernatants of mixed glial cells stimulated with DNA fraction of CSF derived from NMOSD patients. Furthermore, specific innate immune pathways mediating the IL-1β production by mtDNA were investigated in peripheral blood mononuclear cells with selective inhibitors of Toll-like receptor 9 (TLR9) and NOD-like receptor protein 3 (NLRP3) inflammasomes. Results: Extracellular mtDNA level was specifically elevated in acute phase of NMOSD CSF. In vitro studies provided the evidence that mtDNA is released from human astrocytes by NMOSD sera. In addition, DNA fraction isolated from NMOSD CSF promoted secretion of IL-1β from mixed glial cells. Selective inhibition of TLR9 and NLRP3 inflammasomes revealed that mtDNA-mediated IL-1β production depends on specific innate immune pathways. Conclusion: Extracellular mtDNA is specifically elevated in the CSF of patients with acute phase NMOSD, and mtDNA released by AQP4-Ab-mediated cellular damage elicits the innate immune cascades via TLR9 and NLRP3 inflammasomes pathways. Our study highlights mtDNA-mediated innate immune pathways as a novel therapeutic target for future treatment of NMOSD patients.
PLOS ONE, 2018
We previously demonstrated that patients with multiple sclerosis (MS) of high serum Sema4A levels... more We previously demonstrated that patients with multiple sclerosis (MS) of high serum Sema4A levels are resistant to IFN-β therapy. To further elucidate the role of serum Sema4A as a biomarker for therapeutic stratification in MS patients, it is important to clarify the efficacy of other disease-modifying drugs (DMD) in those with high serum Sema4A levels. Thus, in this study we investigated whether fingolimod has beneficial effects on MS patients with high Sema4A levels. We retrospectively analyzed annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) change in 56 relapsing-remitting multiple sclerosis (RRMS) patients who had been treated with fingolimod, including those who switched from IFN-β therapy. The levels of Sema4A in the sera were measured by sandwich ELISA. The implications of Sema4A on the efficacy of fingolimod were investigated by administering recombinant Sema4A-Fc and fingolimod to mice with experimental autoimmune encephalomyelitis (EAE). Retrospective analysis of MS cohort (17 high Sema4A and 39 low Sema4A) demonstrated the effectiveness of fingolimod in those with high serum Sema4A levels, showing reduction of ARR (from 1.21 to 0.12) and EDSS progression (from 0.50 to 0.04). Consistent with this observation, improvement in the disease severity of EAE mice receiving recombinant Sema4A-Fc was also observed after fingolimod treatment. These data suggest that fingolimod could serve as a candidate DMD for managing the disease activity of MS patients with high Sema4A levels.
Open Journal of Statistics, 2014
In this paper, we discuss the theoretical validity of the observed partial likelihood (OPL) const... more In this paper, we discuss the theoretical validity of the observed partial likelihood (OPL) constructed in a Coxtype model under incomplete data with two class possibilities, such as missing binary covariates, a cure-mixture model or doubly censored data. A main result is establishing the asymptotic convergence of the OPL. To reach this result, as it is difficult to apply some standard tools in the survival analysis, we develop tools for weak convergence based on partial-sum processes. The result of the asymptotic convergence shown here indicates that a suitable order of the number of Monte Carlo trials is less than the square of the sample size. In addition, using numerical examples, we investigate how the asymptotic properties discussed here behave in a finite sample.
Statistics in medicine, Apr 30, 2017
Clinical trials with multiple primary time-to-event outcomes are common. Use of multiple endpoint... more Clinical trials with multiple primary time-to-event outcomes are common. Use of multiple endpoints creates challenges in the evaluation of power and the calculation of sample size during trial design particularly for time-to-event outcomes. We present methods for calculating the power and sample size for randomized superiority clinical trials with two correlated time-to-event outcomes. We do this for independent and dependent censoring for three censoring scenarios: (i) the two events are non-fatal; (ii) one event is fatal (semi-competing risk); and (iii) both are fatal (competing risk). We derive the bivariate log-rank test in all three censoring scenarios and investigate the behavior of power and the required sample sizes. Separate evaluations are conducted for two inferential goals, evaluation of whether the test intervention is superior to the control on: (1) all of the endpoints (multiple co-primary) or (2) at least one endpoint (multiple primary). Copyright © 2017 John Wiley &...
Biostatistics (Oxford, England), 2016
In the article by Tomoyuki Sugimoto et al. ('A logrank Test-Based Method for Sizing Clinical Tria... more In the article by Tomoyuki Sugimoto et al. ('A logrank Test-Based Method for Sizing Clinical Trials With Two Co-Primary Time-to-Event Endpoints'), there were errors on pages 409-421 of issue 14(3) of Biostatistics. In Section 4.2 on p. 418, the article described "the total sample size is 928 commonly for the three copulas when ρ = 0. When ρ = 0.3, 0.5, and 0.8, they are 928, 926, and 924 for the Clayton copula; 926, 922, and 920 for the Gumbel copula; and 926, 924, and 920 for the Frank copula." However, these numbers were calculated with the two hazard ratios ψ 1 = 1.77 and ψ 2 = 1.39, not ψ −1
Annals of Clinical and Translational Neurology, 2015
Journal of Neuroinflammation, 2014
Background: Accumulating evidence has shown that the inflammatory process participates in the pat... more Background: Accumulating evidence has shown that the inflammatory process participates in the pathogenesis of amyotrophic lateral sclerosis (ALS), suggesting a therapeutic potential of anti-inflammatory agents. Janus kinase 2 (JAK2), one of the key molecules in inflammation, transduces signals downstream of various inflammatory cytokines, and some Janus kinase inhibitors have already been clinically applied to the treatment of inflammatory diseases. However, the efficacy of JAK2 inhibitors in treatment of ALS remains to be demonstrated. In this study, we examined the role of JAK2 in ALS by administering a selective JAK2 inhibitor, R723, to an animal model of ALS (mSOD1 G93A mice). Findings: Orally administered R723 had sufficient access to spinal cord tissue of mSOD1 G93A mice and significantly reduced the number of Ly6c positive blood monocytes, as well as the expression levels of IFN-γ and nitric oxide synthase 2, inducible (iNOS) in the spinal cord tissue. R723 treatment did not alter the expression levels of Il-1β, Il-6, TNF, and NADPH oxidase 2 (NOX2), and suppressed the expression of Retnla, which is one of the markers of neuroprotective M2 microglia. As a result, R723 did not alter disease progression or survival of mSOD1 G93A mice. Conclusions: JAK2 inhibitor was not effective against ALS symptoms in mSOD1 G93A mice, irrespective of suppression in several inflammatory molecules. Simultaneous suppression of anti-inflammatory microglia with a failure to inhibit critical other inflammatory molecules might explain this result.
Annals of clinical and translational neurology, 2015
The intestinal microflora affects the pathogenesis of several autoimmune diseases by influencing ... more The intestinal microflora affects the pathogenesis of several autoimmune diseases by influencing immune system function. Some bacteria, such as lactic acid bacteria, have been reported to have beneficial effects on immune function. However, little is known about the effects of yeasts. Here, we aimed to investigate the effects of various dietary yeasts contained in fermented foods on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), and to elucidate the mechanisms underlying these effects. The effects of eight yeasts selected from 18 types of yeasts contained in fermented foods were examined using an EAE model. Of these, Candida kefyr was investigated by analyzing the intestinal microflora and its effects on intestinal and systemic immune states. Administration of C. kefyr ameliorated the severity of EAE. Reduced numbers of Th17 cells, suppressed interleukin (IL)-6 production by intestinal explants, and increased Tregs and CD103-positive reg...
Gastric Cancer, 2011
Background Bursectomy is regarded as a standard surgical procedure during gastrectomy for serosa-... more Background Bursectomy is regarded as a standard surgical procedure during gastrectomy for serosa-positive gastric cancer in Japan. There is little evidence, however, that bursectomy has clinical benefit. We conducted a randomized controlled trial to demonstrate non-inferiority of treatment with the omission of bursectomy. Methods Between July 2002 and January 2007, 210 patients with cT2-T3 gastric adenocarcinoma were intraoperatively randomized to radical gastrectomy and D2 lymphadenectomy with or without bursectomy. The primary endpoint was overall survival (OS). Secondary endpoints were recurrence-free survival, operative morbidity, and levels of amylase in drainage fluid on postoperative day 1. Two interim analyses were performed, in September 2008 and August 2010. Results Overall morbidity (14.3%) and mortality (0.95%) rates were the same in the two groups. The median levels of amylase in drainage fluid on postoperative day 1 were similar in the two groups (P = 0.543). In the second interim analysis, the 3-year OS rates were 85.6% in the bursectomy group and 79.6% in the non-bursectomy group. The hazard ratio for death without bursectomy was 1.44 (95% confidence interval [CI] 0.79-2.61; P = 0.443 for non-inferiority). Among 48 serosa-positive (pT3-T4) patients, the 3-year OS was 69.8% for the bursectomy group and 50.2% for the non-bursectomy group, conferring a hazard ratio for death of 2.16 (95% CI 0.89-5.22; P = 0.791 for non-inferiority). More patients in the nonbursectomy group had peritoneal recurrences than in the bursectomy group (13.2 vs. 8.7%). Conclusions The interim analyses suggest that bursectomy may improve survival and should not be abandoned as a futile procedure until more definitive data can be obtained.
PLoS ONE, 2014
Background: Activation of glial cells is a cardinal feature in multiple sclerosis (MS) pathology,... more Background: Activation of glial cells is a cardinal feature in multiple sclerosis (MS) pathology, and acetate has been reported to be selectively uptaken by astrocytes in the CNS. The aim of this study was to investigate the efficacy of PET with 11 Cacetate for MS diagnosis. Materials and Methods: Six patients with relapsing-remitting MS and 6 healthy volunteers (HV) were enrolled. The 11 Cacetate brain uptake on PET was measured in patients with MS and HV. Volume-of-interest analysis of cerebral gray and white matter based on the segmentation technique for co-registered MRI and voxel-based statistical parametric analysis were performed. Correlation between 11 C-acetate uptake and the lesion number in T1-and T2-weighted MR images were also assessed. Results: The standardized uptake value (SUV) of 11 C-acetate was increased in both white and gray matter in MS patients compared to HV. Voxel-based statistical analysis revealed a significantly increased SUV relative to that in the bilateral thalami (SUVt) in a broad area of white matter, particularly in the subcortical white matter of MS patients. The numbers of T2 lesions and T1 black holes were significantly correlated with SUV of 11 C-acetate in white and gray matter. Conclusions: The 11 C-acetate uptake significantly increased in MS patients and correlated to the number of MRI lesions. These preliminary data suggest that 11 C-acetate PET can be a useful clinical examination for MS patients.
PLoS ONE, 2011
Background: Certain intestinal microflora are thought to regulate the systemic immune response. L... more Background: Certain intestinal microflora are thought to regulate the systemic immune response. Lactic acid bacteria are one of the most studied bacteria in terms of their beneficial effects on health and autoimmune diseases; one of which is Multiple sclerosis (MS) which affects the central nervous system. We investigated whether the lactic acid bacterium Pediococcus acidilactici, which comprises human commensal bacteria, has beneficial effects on experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Methodology/Principal Findings: P. acidilactici R037 was orally administered to EAE mice to investigate the effects of R037. R037 treatment suppressed clinical EAE severity as prophylaxis and therapy. The antigen-specific production of inflammatory cytokines was inhibited in R037-treated mice. A significant increase in the number of CD4 + Interleukin (IL)-10-producing cells was observed in the mesenteric lymph nodes (MLNs) and spleens isolated from R037-treated naive mice, while no increase was observed in the number of these cells in the lamina propria. Because only a slight increase in the CD4 + Foxp3 + cells was observed in MLNs, R037 may primarily induce Foxp3 2 IL10-producing T regulatory type 1 (Tr1) cells in MLNs, which contribute to the beneficial effect of R037 on EAE. Conclusions/Significance: An orally administered single strain of P. acidilactici R037 ameliorates EAE by inducing IL10producing Tr1 cells. Our findings indicate the therapeutic potential of the oral administration of R037 for treating multiple sclerosis.
Operators and Matrices, 2012
This paper provides an inverse formula freed of determinant expressions for a general tridiagonal... more This paper provides an inverse formula freed of determinant expressions for a general tridiagonal matrix. This is viewed as an alternative version of the Usmani formula, which easily tends to blow up computationally. We discuss a number of different viewpoints regarding the proposed and Usmani's formulas, such as the proof method and the meaning of included terms, although our formula itself may be obtained by a simple transformation of Usmani's. A study of the limit elements based on the inverse formula and a numerical experiment for comparison with the other inverse methods are provided. In addition, we briefly discuss the inverse formula in the case of zero minors, which is illustrated by a numerical example.
Journal of the Japanese Society of Computational Statistics, 2011
We consider power-transformations to obtain stability and invariance of measurement scale. The tr... more We consider power-transformations to obtain stability and invariance of measurement scale. The transformation discussed here is the normalized form of the powertransformation originally suggested by Schlesselman (1971). The original suggestion is a simple modification of the Box and Cox transformation to scale invariance for measurement units. In addition to discussion on the scale invariance, we study (i) the behaviors of Jacobian of the transformation and (ii) the effect of the modification on the estimates. Then, we show that the modification of the scale invariance improves the performance of estimates, especially the mean estimate. A simulation study is performed to evaluate numerically performances of the modified transformation, compared with the normalized Box and Cox transformation.
Journal of the Japanese Society of Computational Statistics, 2007
We consider methods for parameter estimation of the shifted power transformation. The ordinary li... more We consider methods for parameter estimation of the shifted power transformation. The ordinary likelihood function is unbounded and then fails to have a local maximum. This is a non-regular problem in likelihood because the range of observations depends on the unknown shift parameter. To avoid such a difficulty , we discuss the group likelihood method and the maximum product of spacings method, in a univariate case, assuming the power-normal distribution as an underlying distribution for observations. We describe the computational procedures for parameter estimation. To evaluate the performance of the estimates from the two methods, we perform a simulation study. In addition, two examples are given to illustrate some aspects of the two methods. 1.
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Papers by Tomoyuki Sugimoto