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Toru Kimura

Publications and source records attributed to Toru Kimura.

At least 19 recordsLinked to original sources
PubMed2026

Development and validation of a plasma miRNA-CEA biomarker panel for early detection of lung cancer.

Lung cancer remains a leading cause of cancer-related mortality worldwide, underscoring the critical need for early detection to improve patient outcomes. This study aimed to develop and validate a plasma microRNA biomarker panel for the early detection of non-small cell lung cancer in a Japanese cohort. We enrolled 525 participants, comprising 261 LC cases and 264 non-LC controls, divided into optimization and validation cohorts. A 12-miRNA panel was optimized and further combined with CEA to enhance diagnostic performance. The miRNA-alone model demonstrated robust performance in both the optimization (AUC = 77.0%) and validation cohorts (AUC = 77.9%). Integration with CEA significantly improved accuracy, achieving AUCs of 86.2% in optimization and 84.9% in validation, with particularly high performance in late-stage cancers (AUC = 94.4%) and squamous cell carcinoma (AUC = 90.7%). Sensitivity and specificity thresholds were evaluated, enabling model customization for diverse clinical scenarios. These findings highlight the potential of the miRNA-CEA panel as a minimally invasive tool for early LC detection, especially in non-smoking populations.

Humans↗
PubMed2006

A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord.

Axons in the adult mammalian central nervous system (CNS) exhibit little regeneration after injury. It has been suggested that several axonal growth inhibitors prevent CNS axonal regeneration. Recent research has demonstrated that semaphorin3A (Sema3A) is one of the major inhibitors of axonal regeneration. We identified a strong and selective inhibitor of Sema3A, SM-216289, from the fermentation broth of a fungal strain. To examine the effect of SM-216289 in vivo, we transected the spinal cord of adult rats and administered SM-216289 into the lesion site for 4 weeks. Rats treated with SM-216289 showed substantially enhanced regeneration and/or preservation of injured axons, robust Schwann cell-mediated myelination and axonal regeneration in the lesion site, appreciable decreases in apoptotic cell number and marked enhancement of angiogenesis, resulting in considerably better functional recovery. Thus, Sema3A is essential for the inhibition of axonal regeneration and other regenerative responses after spinal cord injury (SCI). These results support the possibility of using Sema3A inhibitors in the treatment of human SCI.

Animals↗
PubMed2006

RNA interference in immune cells by use of osmotic delivery of siRNA.

Delivery of siRNA to immune cells has been one of the major obstacles to widespread application of RNAi in the immunology field. Here, we report that osmotic delivery of siRNA can be used to silence genes in macrophage RAW264.7 without incurring either cytotoxic or immunomodulatory activity. We also showed usefulness of the osmotic delivery in other types of cells including T cell DO11.10. By repeated osmotic delivery of siRNA, long-term gene silencing was readily achieved. When TLR4 was disrupted in RAW264.7 cells for 48 h and the cells were stimulated with the TLR4 ligand LPS, a significant decrease in TNFalpha production was observed. DNA microarray-based gene expression profile analysis showed that gene silencing by osmotic delivery of siRNA was target-specific and the delivery method itself had little influence on overall gene expression.

Animals↗
PubMed2006

Bezafibrate may attenuate biliary damage associated with chronic liver diseases accompanied by high serum biliary enzyme levels.

BACKGROUND: Bezafibrate is a commonly used medicine for hyperlipidemia, and recently several reports have suggested the efficacy of bezafibrate for the treatment of primary biliary cirrhosis (PBC). To assess its efficacy for other liver diseases, we administered bezafibrate to patients with various categories of hepatobiliary impairment. METHODS: Bezafibrate (400 mg/day) was orally administered to 67 patients with chronic liver disease [22 with PBC, six with primary sclerosing cholangitis (PSC), 20 with chronic liver disease associated with hepatitis C virus (HCV) infection (CLD-C), seven with auto immune hepatitis (AIH), ten with alcoholic liver injury, and two with drug-induced liver injury]. RESULTS: The levels of biliary enzymes, such as alkaline phosphatase and gamma-glutamyltranspeptidase, decreased promptly and dramatically. The abnormally high level of alanine aminotransferase also showed a gradual decrease over 6 months in five of the eight PBC patients, all three PSC patients, eight of the 17 CLD-C patients, and all seven alcoholic liver injury patients. The level of immunoglobulin M showed a gradual decrease in 17 of the 22 PBC patients. CONCLUSIONS: Bezafibrate significantly reduced the level of biliary enzymes in various chronic liver diseases and may be useful for the treatment of certain liver disease subsets.

Aged↗
PubMed2006

Overexpression of the transcription factor GATA-3 enhances the development of pulmonary fibrosis.

Recent studies have demonstrated that Th2 cytokines, such as interleukin-4 and interleukin-13, enhance fibrotic processes by activating fibroblast proliferation and collagen production, whereas interferon-gamma, a Th1 cytokine, inhibits these processes. Th1 and Th2 cells both differentiate from common T precursor cells, with transcription factor GATA-3 a key regulator of Th2 differentiation. In the present study, therefore, we examined the effects of GATA-3 overexpression on the development of pulmonary fibrosis in a mouse model. Wild-type C57BL/6 mice and GATA-3-overexpressing (GATA-3-tg) mice of the same background were intratracheally treated with bleomycin. The survival rate after bleomycin was significantly decreased in GATA-3-tg mice compared with wild-type mice. The degree of pulmonary fibrosis was much greater in GATA-3-tg mice than in wild-type mice 28 days after bleomycin treatment. Lung interferon-gamma concentration was significantly decreased in GATA-3-tg mice compared with wild-type mice by 7 days after either saline or bleomycin treatment. The concentration of transforming growth factor-beta, a fibrogenic cytokine, was significantly higher in GATA-3-tg mice than in wild-type mice. Exogenous administration of interferon-gamma to GATA-3-tg mice improved the degree of pulmonary fibrosis and thus increased survival. These results indicate that overexpression of GATA-3 enhances the development of pulmonary fibrosis, possibly by reducing interferon-gamma levels in the lung.

Animals↗
PubMed2006

[Endoscopic trigonoplasty II for primary vesico-ureteral reflux].

PURPOSE: We report a technique and outcome of endoscopic trigonoplasty II (ET II), anti-reflux surgery via a transvesicostomy transurethral approach and discuss its usefulness. MATERIALS AND METHODS: Fifteen female patients, aged 5 to 64, with 23 refluxing ureters (grade I : 5, II : 2, III : 14, IV : 2) underwent the ET II. The principle of this surgery is tightening the muscular backing and elongating the intramural ureter. The operation consists of three steps: 1) two 5 mm locking trocars are placed into the bladder, 2) irrigating with 3% D-sorbitol solution, the bladder wall is incised upward along each side of the ureter using a resectoscope, to make a 2 to 3 cm U-shaped bladder flap including the ureter, 3) under a pneumobladder, the incised wall is sutured to make a muscular bed with a needle-holder via the urethra and forceps via the abdominal trocar. The U-shaped flap is fixed with two distal anchor sutures and four additional mucosal sutures. Urethral catheter is indwelled and the operation is finished. In recent four cases, we closed the tracts endoscopically. RESULTS: The average operative time was 144 minutes per ureter. In one patient with unilateral reflux, we switched to open surgery because of bleeding. Of 22 refluxing ureters, the reflux disappeared in 18 ureters (82%) and improved grade III to I in 1 ureter (5%) after 3 months and disappeared in 19 ureters (86%) after 12 months postoperatively. Ureteral injury was occurred in 3 patients during the transurethral incision of the bladder. Though we repaired it by placing a double-J stent in the 2 patients, reflux recurred in 12 months postoperatively in one of them. In the other patient cystoscopy revealed a vesicoureteral fistula in the injured portion. She subsequently underwent successful open Politano-Leadbetter ureteroneocystostomy. The average duration of indwelling catheter was shortened from 4.3 to 3.0 days by closing the tracts endoscopically. CONCLUSIONS: The overall cessation rate of the ET II was inferior to those of open anti-reflux surgeries or laparoscopic extravesical ureteral reimplantation. We do not recommend ET II for vesicoureteral reflux.

Adolescent↗
PubMed2005

Transcription factor Nrf2 plays a pivotal role in protection against elastase-induced pulmonary inflammation and emphysema.

Emphysema is one of the major pathological abnormalities associated with chronic obstructive pulmonary disease. The protease/antiprotease imbalance and inflammation resulting from oxidative stress have been attributed to the pathogenesis of emphysema. Nrf2 is believed to protect against oxidative tissue damage through the transcriptional activation of a battery of antioxidant enzymes. In this study, we investigated the protective role of Nrf2 in the development of emphysema using elastase-induced emphysema as our model system. We found that elastase-provoked emphysema was markedly exacerbated in Nrf2-knockout (KO) mice compared with wild-type mice. The severity of emphysema in Nrf2-KO mice correlated intimately with the degree of lung inflammation in the initial stage of elastase treatment. The highly inducible expression of antioxidant and antiprotease genes observed in wild-type alveolar macrophages was significantly attenuated in the lungs of Nrf2-KO mice. Interestingly, transplantation of wild-type bone marrow cells into Nrf2-KO mice retarded the development of initial lung inflammation and subsequent emphysema, and this improvement correlated well with the appearance of macrophages expressing Nrf2-regulated antiprotease and antioxidant genes. Thus, Nrf2 appears to exert its protective effects through the transcriptional activation of antiprotease and antioxidant genes in alveolar macrophages.

Animals↗
PubMed2005

CCR1 acts downstream of NFAT2 in osteoclastogenesis and enhances cell migration.

UNLABELLED: We found that a chemokine receptor gene, CCR1, acts downstream of NFAT2 in RANKL-stimulated RAW264 and bone marrow cells. The upstream regulatory region of CCR1 showed RANKL-dependent and CsA-suppressible promoter activity. Downregulation of the expression and function of CCR1 suppressed cell migration. INTRODUCTION: We previously reported that the expression of NFAT2 induced by RANKL is a key process for progression to multinucleated cells in an in vitro osteoclastogenesis system. Identifying the target genes of NFAT2 would thus be informative about the differentiation process. We focused here on chemokine and chemokine receptor genes that act downstream of NFAT2 in RAW264 cells as well as osteoclast precursors prepared from bone marrow cells. MATERIALS AND METHODS: RAW264 mouse monocyte/macrophage line cells were cultured with or without cyclosporin A (CsA) in the presence of RANKL or glutathione S-transferase (GST). Osteoclast precursors were prepared from bone marrow cells. RANKL-inducible and CsA-suppressible genes were searched for by microarray analysis, and expression was confirmed by quantitative RT-PCR. Promoter activity was measured by luciferase gene reporter assay. Short interfering (si)RNA for CCR1 was introduced in RAW264 cells. Cell migration activity was examined using a Boyden chamber assay. RESULTS AND CONCLUSIONS: We identified the chemokine receptor gene CCR1 as a gene showing significant differential expression profiles in osteoclastogenesis in the presence versus the absence of CsA, an inhibitor of NFAT. This property was unique to CCR1 among the chemokine and chemokine receptor genes examined in both RAW264 and bone marrow cells. The upstream regulatory region was isolated from CCR1, and its RANKL-dependent and CsA-suppressible promoter activity was confirmed. The functional significance of CCR1 was assessed by monitoring the migration of cells in a transwell migration assay, and this activity was abolished when either CsA- or CCR1 siRNA-treated cells were used. Moreover, treatment with a Galpha inhibitor pertussis toxin (PTX) or methiolynated-regulated on activation, normal T cells expressed and secreted (Met-RANTES), an antagonist of CCR1, suppressed multinucleated cell formation in the bone marrow cell system. Together, these results suggest that the CCR1 signaling cascade is under the control of NFAT2 and seems to enhance the migration of differentiating osteoclasts.

Animals↗
PubMed2005

A unique gene expression signature discriminates familial Alzheimer's disease mutation carriers from their wild-type siblings.

Alzheimer's disease (AD) is a neurodegenerative disease with an insidious onset and progressive course that inevitably leads to death. The current diagnostic tools do not allow for diagnosis until the disease has lead to irreversible brain damage. Genetic studies of autosomal dominant early onset familial AD has identified three causative genes: amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2). We performed a global gene expression analysis on fibroblasts from 33 individuals (both healthy and demented mutation carriers as well as wild-type siblings) from three families segregating the APP(SWE), APP(ARC) and PSEN1 H163Y mutations, respectively. The mutations cause hereditary progressive cognitive disorder, including typical autosomal dominant AD. Our data show that the mutation carriers share a common gene expression profile significantly different from that of their wild-type siblings. The results indicate that the disease process starts several decades before the onset of cognitive decline, suggesting that presymptomatic diagnosis of AD and other progressive cognitive disorders may be feasible in the near future.

Alzheimer Disease↗
PubMed2005

Prediction of siRNA functionality using generalized string kernel and support vector machine.

Small interfering RNAs (siRNAs) are becoming widely used for sequence-specific gene silencing in mammalian cells, but designing an effective siRNA is still a challenging task. In this study, we developed an algorithm for predicting siRNA functionality by using generalized string kernel (GSK) combined with support vector machine (SVM). With GSK, siRNA sequences were represented as vectors in a multi-dimensional feature space according to the numbers of subsequences in each siRNA, and subsequently classified with SVM into effective or ineffective siRNAs. We applied this algorithm to published siRNAs, and could classify effective and ineffective siRNAs with 90.6%, 86.2% accuracy, respectively.

Algorithms↗
PubMed2005

Toxicity of semaphorin3A for dopaminergic neurons.

Semaphorin3A (Sema3A) is known to cause neuronal apoptosis and serves as a chemorepellent factor for axonal growth. In our previous report, we found that Sema3A was up-regulated in the 6-OHDA-injected striatum of rats, suggesting that Sema3A was likely involved in dopaminergic (DA) depletion. In this study, we investigated whether Sema3A directly worked as a neurotoxin to DA neurons both in vitro and in vivo. First, effects of various dosages of Sema3A administration on the DA neurons of the E14 murine ventral mesencephalon were examined in vitro. Sema3A at a dose over 500 ng/ml induced apoptosis to DA neurons. Next, we examined whether the continuous infusion of Sema3A exerted degeneration of DA neurons in rats. We established a Sema3A-secreting cell line (BHK-Sema3A), confirming the secreting functions by immunocytochemical and Western blot assays. Adult Sprague-Dawley rats were unilaterally implanted into the striatum with BHK-Sema3A or BHK non-Sema3A control cells, and subsequently underwent behavioral and immunohistochemical evaluations. Rats that received BHK-Sema3A did not show significant differences in the number of amphetamine- and apomorphine-induced rotations and TH-positive neurons in the substantia nigra pars compacta compared to the control group. Our results revealed that Sema3A was toxic to cultured DA neurons at very high dosages, but the continuous secretion of Sema3A at modest dosage in vivo did not produce Parkinsonian pathophysiologic symptoms. Optimizing the dosage and infusion location (i.e., nigra) and timing (more than 1 week post-transplantation) might further reveal the contribution of Sema3A to the pathogenesis of Parkinson's disease.

Amphetamine↗
PubMed2005

Role of 15-deoxy delta(12,14) prostaglandin J2 and Nrf2 pathways in protection against acute lung injury.

RATIONALE: Acute lung injury (ALI) is a disease process that is characterized by diffuse inflammation in the lung parenchyma. Recent studies demonstrated that cyclooxygenase-2 (COX-2) induced at the late phase of inflammation aids in the resolution of inflammation by generating 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2). Transcription factor Nrf2 is activated by electrophiles and exerts antiinflammatory effects by inducing the gene expression of antioxidant and detoxification enzymes. OBJECTIVES: Because 15d-PGJ2 is an endogenous electrophile, we hypothesized that it protects against ALI by activating Nrf2. METHODS: To test this hypothesis, we generated a reversible ALI model by intratracheal injection of carrageenin, an inducer of acute inflammation, whose stimulation has been known to induce COX-2. MAIN RESULTS: We found that ALI induced by carrageenin was markedly exacerbated in Nrf2-knockout mice, compared with wild-type mice. Analysis of bronchoalveolar lavage fluids also revealed that the magnitude and the duration of acute inflammation, indicated by albumin concentration and the number of neutrophils, were significantly enhanced in Nrf2-knockout mice. Treatment of wild-type mice with NS-398, a selective COX-2 inhibitor, significantly exacerbated ALI to the level of Nrf2-knockout mice. In the lungs of NS-398-treated wild-type mice, both the accumulation of 15d-PGJ2 and the induction of Nrf2 target antioxidant genes were significantly attenuated. Exogenous administration of 15d-PGJ2 reversed the exacerbating effects of NS-398 with the induction of antioxidant genes. CONCLUSIONS: These results demonstrated in vivo that 15d-PGJ2 plays a protective role against ALI by exploiting the Nrf2-mediated transcriptional pathway.

Animals↗
PubMed2005

Suppression of eosinophilic airway inflammation by treatment with alpha-galactosylceramide.

To clarify the essential role of NKT cells in allergy, we investigated the contribution of NKT cells to the pathogenesis of eosinophilic airway inflammation using alpha-galactosylceramide (alpha-GalCer), a selective ligand for NKT cells. Although continuous administration of alpha-GalCer during ovalbumin (OVA) sensitization increased OVA-specific IgE levels and worsened eosinophil inflammation, a single administration of alpha-GalCer at the time of OVA challenge completely prevented eosinophilic infiltration in wild-type mice. This inhibitory effect of alpha-GalCer was associated with a decrease in airway hyperresponsiveness, an increase in IFN-gamma, and decreases in IL-4, IL-5 and IL-13 levels in the bronchoalveolar lavage fluids. Analysis of lung lymphocytes revealed that production of IFN-gamma increased in NK cells, but not in T or NKT cells, following alpha-GalCer administration. Induction of vascular cell adhesion molecule-1 in the lungs of wild-type mice was also significantly attenuated by treatment with alpha-GalCer. These effects of alpha-GalCer were abrogated in J alpha281-/- mice, which lack NKT cells, and in wild-type mice treated with anti-IFN-gamma Ab. Hence, our data indicate that alpha-GalCer suppresses allergen-induced eosinophilic airway inflammation, possibly by inducing a Th1 bias that results in inhibition of eosinophil adhesion to the lung vessels.

Animals↗
PubMed2005

Laparoscopic pyeloplasty using endoscopic GIA stapler for ureteropelvic junction obstruction.

PURPOSE: We applied laparoscopic pyeloplasty in 10 patients with ureteropelvic junction (UPJ) obstruction. To evaluate the efficiency and safety of this procedure using an endoscopic GIA stapler, the clinical outcomes and our procedures are presented. PATIENTS AND METHODS: From August 1996 to March 2003, eight female and two male patients with a mean age of 22.3 years suffering from UPJ obstruction diagnosed by various combinations of ultrasonography, excretory urography, retrograde ureteropyelography, CT, and MRI were treated with laparoscopic dismembered Anderson-Hynes pyeloplasty with resection of a dilated redundant renal pelvis. In six cases, an endoscopic gastrointestinal automatic stapler (Endo-GIA) was used. The procedure was performed via an extraperitoneal approach in two cases and a transperitoneal approach in eight. RESULTS: Laparoscopic pyeloplasty was successful in all patients, including the six treated using an Endo- GIA stapler. The mean operating time was 291 minutes, and the mean anastomotic time was 105 minutes, with a mean estimated blood loss of 44 mL. Postoperative complications occurred in five cases: anastomotic urinary leakage in two and pyelonephritis in three. The mean time to full convalescence in the entire series was 22 days. No urolithiasis occurred in the patients treated with the Endo-GIA stapler during the follow-up period of 2 to 76 (mean 22) months. CONCLUSIONS: Laparoscopic dismembered pyeloplasty including the Endo-GIA stapler technique is an efficient and safe procedure that provides excellent results for extrinsic or complicated UPJ stenosis. The risk of stone formation has not yet been determined.

Adolescent↗
PubMed2005

Nrf2-deficient mice are highly susceptible to cigarette smoke-induced emphysema.

Inflammation, protease/anti-protease imbalance and oxidative stress play important roles in the pathogenesis of emphysema. Nrf2 counteracts oxidative tissue damage and inflammation through transcriptional activation via the anti-oxidant responsive element (ARE). To clarify the protective role of Nrf2 in the development of emphysema, the susceptibility of Nrf2-knockout mice to cigarette smoke (CS)-induced emphysema was examined. In Nrf2-knockout mice, emphysema was first observed at 8 weeks and exacerbated by 16 weeks following CS-exposure, whereas no pathological abnormalities were observed in wild-type mice. Neutrophilic lung inflammation and permeability lung damage were significantly enhanced in Nrf2-knockout mice 8 weeks after CS-exposure. Importantly, neutrophil elastase activity in bronchoalveolar lavage fluids was markedly higher in Nrf2-knockout mice preceding the pronounced neutrophil accumulation. The expression of secretory leukoprotease inhibitor, a potent inhibitor of neutrophil elastase, was inducible in wild-type, but not in Nrf2-knockout mice. This protease/anti-protease imbalance, together with the lack of inducible expression of ARE-regulated anti-oxidant/anti-inflammatory genes, may explain the predisposition of Nrf2-knockout mice to neutrophilic inflammation. Indeed, specific activators of Nrf2 induced the expression of the SLPI gene in macrophages. These results indicate that Nrf2 protects against the development of emphysema by regulating not only the oxidant/anti-oxidant balance, but also inflammation and the protease/anti-protease balance.

Animals↗
PubMed2005

Promoter activity of human tissue inhibitor of metalloproteinase 2 gene with novel single nucleotide polymorphisms.

OBJECTIVE: The single nucleotide polymorphism (SNP) -418G > C in the TIMP2 gene promoter region has been shown to be associated with in chronic obstructive pulmonary disease (COPD). The purpose of this study was to search for novel single nucleotide polymorphism (SNP) in the TIMP2 promoter region around the -418G > C locus, and to investigate whether any of these SNP, including -418G > C, had an influence on TIMP2 transcription activity. METHODOLOGY: DNA sequencing was performed on a 689 base-pair polymerase chain reaction fragment of the promoter region. The novel SNP were characterized and genotype analysis was performed for COPD and control subjects. A reporter gene assay was performed using the wild-type promoter (-418G/-177C/+34C) and the mutant-type promoter (-418C/-177T/+34A). RESULTS: Nine novel SNP were identified. The SNP -177C > T and +34C > A were in complete linkage disequilibrium with -418G > C. The other seven SNP were not associated with COPD. No significant difference was detected in the reporter gene assay between the activities of the wild-type and the mutant-type promoters. CONCLUSIONS: The SNP -418G > C, -177C > T and +34C > A, might not themselves be functional from a transcriptional point of view in the development of COPD, but may be in linkage disequilibrium with other functional polymorphisms.

Base Pairing↗
PubMed2005

Severe infundibular pulmonary stenosis and coronary artery stenosis with ventricular tachycardia 24 years after mediastinal irradiation.

A 28-year-old man developed severe infundibular pulmonary stenosis (PS), coronary artery stenosis with sustained ventricular tachycardia (VT) 24 years after mediastinal irradiation (total amount of 40 Gray) for non-Hodgkin's lymphoma. Repair of right ventricular outflow tract and coronary artery bypass graft procedure were performed. Infundibular PS was successfully relieved after operation and VT was also controlled by medication. Mediastinal irradiation often causes various cardiac complications after a latent period. Therefore, continuous careful observation is mandatory in patients with the history of mediastinal irradiation.

Adult↗