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Inhibition of plasminogen suppresses fibrosis and macrophage foaming in a nonalcoholic steatohepatitis mouse model
Get PDF浜松医科大学博士（医学）doctoral医学系研究科thesi
Intra-left ventricular hemodynamics assessed with 4D flow magnetic resonance imaging in patients with left ventricular thrombus
Get PDF浜松医科大学博士（医学）doctoral医学系研究科thesi
YTHDF1 and YTHDF2 are associated with better patient survival and an inflamed tumor-immune microenvironment in non-small-cell lung cancer
Get PDF浜松医科大学博士（医学）doctoral医学系研究科The human YTH domain family (YTHDF) proteins are RNA-binding proteins that recognize N6-methyladenosine (m6A), facilitating various biological processes via m6A RNA modification. How these molecules associate with non-small-cell lung cancer (NSCLC) molecular mechanisms remain unclear. The protein expression levels of YTHDF1 and YTHDF2 in 603 cases of resected NSCLC were evaluated using immunohistochemistry. We analyzed the associations of these attributes with patient characteristics and survival. We also assessed four subsets of lymphocytes (PD-1+, CD8+, Foxp3+, and CD45RO+) as tumorinfiltrating lymphocytes (TILs) in the tumor nest and in the surrounding stroma separately. In addition, we investigated differentially expressed genes and the expression of PD-L1 in YTHDF1- and YTHDF2- deprived lung cancer cells. The expressions of both YTHDF1 and YTHDF2 were less in the advancedstage tumors than in the early-stage tumors. The expressions of both YTHDF1 and YTHDF2 were also independent favorable prognostic factors for recurrence-free survival (HR, 0.745; 95% CI, 0.562-0.984 for YTHDF1; HR, 0.683; 95% CI, 0.503-0.928 for YTHDF2). The TIL densities of almost all four lymphocyte subsets in the stroma were significantly higher in the tumors with high YTHDF1 and YTHDF2 expression. In vitro, YTHDF1 and YTHDF2 knockdown in cells upregulated tumor PD-L1 expression and altered multiple immune-related genes. High expressions of both YTHDF1 and YTHDF2 are associated with a favorable prognostic outcome of NSCLC patients, a greater amount of TILs, and downregulation of PD-L1. YTHDF1 and YTHDF2 could be novel prognostic and druggable targets related to the tumor-immune microenvironment in lung cancers.doctoral thesi
Prostaglandin E-major urinary metabolite predicts relapse in patients with ulcerative colitis in clinical remission
Get PDF浜松医科大学博士（医学）doctoral医学系研究科INTRODUCTION: Prostaglandin E-major urinary metabolite (PGE-MUM) is a novel biomarker reflecting endoscopic activity in ulcerative colitis (UC). However, there are no studies investigating the efficacy of PGE-MUM as a biomarker for predicting relapse. We investigated whether PGE-MUM can predict clinical relapse of UC.
METHODS: The measurement of PGE-MUM and endoscopic evaluation were performed in 70 patients with UC in clinical remission. The optimal cutoff values predicting relapse and relapse-free rate were analyzed.
RESULTS: Sixteen patients (22.9%) relapsed during the 12-month follow-up. The median PGE-MUM value of relapsed patients at entry was significantly higher than that of patients in clinical remission (P=0.008). The cutoff value of PGE-MUM predicting future relapse was 25.2 μg/g Cr by receiver-operating characteristic (ROC) analysis, and the area under the ROC curve was 0.721 (95% confidence interval: 0.556-0.886). The relapse-free rate of patients with PGE-MUM ?25.2 μg/g Cr was significantly lower than that in patients with PGE-MUM <25.2 μg/g Cr (log-rank test: P<0.001). The ROC analysis of UC patients with disease duration more than 1-8 years showed that duration of more than 5 years had the largest area under the ROC curve 0.821 (95% confidence interval: 0.583-1.000) and that the optimal cutoff value was 26.3 μg/g Cr.
DISCUSSION: PGE-MUM is a reliable biomarker for predicting future relapse, particularly in UC patients with longdisease duration.doctoral thesi
Efficacy of long-term adrenocorticotropic hormone therapy for West syndrome: A retrospective multicenter case series
Get PDF浜松医科大学博士（医学）doctoral医学系研究科Objectives: Long-term adrenocorticotropic therapy (LT-ACTH), which consisted of 2-4 weeks of daily injections of adrenocorticotropic hormone (ACTH) and subsequent months of weekly injections, was tried for relapsed West syndrome (WS) or other intractable epilepsies in small case reports. Our aim was to explore the efficacy of LT-ACTH for preventing WS relapse, as well as the prevalence of its adverse events.
Methods: This is a retrospective, nationwide, multicenter case series of patients with WS who underwent LT-ACTH. Clinical information of the patients and protocol of LT-ACTH were collected from participating institutes in this study. We defined clinical response to ACTH as achievement of hypsarrhythmia and epileptic spasms resolution. Patients who responded to daily ACTH injections were identified and assessed whether they experienced WS relapse during/after the weekly ACTH injection period. The outcome was measured by the nonrelapse rate at 24 months after daily ACTH injections using the Kaplan-Meier method.
Results: Clinical information of 16 children with WS was analyzed. The median age at LT-ACTH initiation was 14.5 months (range: 7-68 months). Thirteen (81%) patients had previously undergone conventional ACTH treatment. The LT-ACTH regimens comprised a median of 16 days of daily injections (range: 11-28 days) and 10 months of weekly injections (range: 3-22 months). Seven patients experienced WS relapse during/after subsequent weekly ACTH period, and the nonrelapse rate at 24 months after daily injections was estimated at 60.6% (95% confidence interval: 32.3%-80.0%). Height stagnation, hypertension, and irritability were observed; lethal adverse events were not reported.
Significance: Our study firstly explored the efficacy of LT-ACTH for preventing WS relapse. LT-ACTH might be a treatment option for patients with relapsed or intractable WS; however, we note that our study is limited by its small sample size and the lack of an appropriate control group.doctoral thesi
Potent bystander effect and tumor tropism in suicide gene therapy using stem cells from human exfoliated deciduous teeth
Get PDF浜松医科大学博士（医学）doctoral医学系研究科thesi
Long-term stability of 24 synthetic cannabinoid metabolites spiked into whole blood and urine for up to 168 days, and the comparable study for the 6 metabolites in non-spiked real case specimens stored for several years
Get PDFPurpose The aim of this study is to investigate the stabilities of the 24 synthetic cannabinoid metabolites (SCMs) in blood and urine at various temperatures from –30 to 37℃ stored for 1 to 168 days. In addition, experiments of stabilities at lower temperatures and for much longer duration have been performed as described below.
Methods The quantification was performed by liquid chromatography–tandem mass spectrometry (LC–MS/MS). The blank blood and urine spiked with SCMs and non-spiked real case (authentic) specimens were incubated at 37℃ up to 56 days and at 22, 4 or –30℃ up to 168 days. The non-spiked authentic blood and urine specimens were also stored at –30 or –80℃ for 1, 3 or 5 years to investigate stabilities during very long time frames.
Results All the 24 SCMs were much more stable in urine than in blood at 37, 22 or 4℃. All 24 SCMs spiked into blood or urine were stable at –30℃ for up to 168 days. The 6 SCMs in the authentic specimens exhibited long stabilities at –30 or –80℃ for 3 to 5 years. Some tendencies were observed according to the relation between the structures of SCMs and their stabilities.
Conclusions The long-term stabilities of 24 SCMs in spiked samples and those of 6 SCMs in the authentic specimens were examined using LC–MS/MS. SCMs were largely very stable and usable several years after storage at –30 or –80℃.journal articl
Maternal Uniparental Isodisomy of Chromosome 4 and 8 in Patients with Retinal Dystrophy: SRD5A3-Congenital Disorders of Glycosylation and RP1-Related Retinitis Pigmentosa
Get PDF浜松医科大学博士（医学）doctoral医学系研究科Purpose: Uniparental disomy (UPD) is a rare chromosomal abnormality. We performed whole-exosome sequencing (WES) in cases of early-onset retinal dystrophy and identified two cases likely caused by UPD. Herein, we report these two cases and attempt to clarify the clinical picture of retinal dystrophies caused by UPD. Methods: WES analysis was performed for two patients and their parents, who were not consanguineous. Functional analysis was performed in cases suspected of congenital disorders of glycosylation (CDG). We obtained clinical case data and reviewed the literature. Results: In case 1, a novel c.57G>C, p.(Trp19Cys) variant in SRD5A3 was detected homozygously. Genetic analysis suggested a maternal UPD on chromosome 4, and functional analysis confirmed CDG. Clinical findings showed early-onset retinal dystrophy, intellectual disability, and epilepsy. In case 2, an Alu insertion (c.4052_4053ins328, p.[Tyr1352Alafs]) in RP1 was detected homozygously. Maternal UPD on chromosome 8 was suspected. The clinical picture was consistent with RP1-related retinitis pigmentosa. Although the clinical features of retinal dystrophy by UPD may vary, most cases present with childhood onset. Conclusions: There have been limited reports of retinal dystrophy caused by UPD, suggesting that it is rare. Genetic counseling may be encouraged in pediatric cases of retinal dystrophy.doctoral thesi
