Publications by authors named "Yutaka Okamoto"

20 Publications

  • Page 1 of 1

Fabrication of Gd-DOTA-functionalized carboxylated nanodiamonds for selective MR imaging (MRI) of the lymphatic system.

Nanotechnology 2021 Mar 3. Epub 2021 Mar 3.

Department of Mechanical Engineering, Keio University Faculty of Science and Technology Graduate School of Science and Technology, 3-14-1 Hiyoshi Kohoku-ku, Yokohama, 223-8542, JAPAN.

Magnetic resonance imaging (MRI) contrast agents with the particle diameter of around 3-10 nm hold the potential to be selectively uptaken by lymphatic vessels and be filtered in the kidney for final excretion. However, there are no existing MRI contrast agents based on gadolinium (Gd) complexes within the size of this range, and thus the selective imaging of the lymphatic system has not yet been achieved. In our previous report, we succeeded in fabricating nano-scale MRI contrast agents by complexing ordinary contrast agents (Gd-diethylenetriaminepentaacetic acid (DTPA)) with carboxylated nanodiamond (CND) particles to conquer this problem. However, DTPA has recently been reported to release Gd ions in the course of time, leading to the potential danger of severe side effects in the human body. In this study, we utilized cyclic-chained DOTA as an alternative chelating material for DTPA to fabricate CND-based MRI contrast agents for the selective lymphatic imaging. The newly fabricated contrast agents possessed the diameter ranging from 3 nm to 10 nm in distilled water and serum, indicating that these particles can be selectively uptaken by lymphatic vessels and effectively filtered in the kidney. Furthermore, the DOTA-applied CND contrast agents exhibited stronger MRI visibility in water and serum compared to DTPA-applied CND contrast agents. These results indicate that DOTA-applied CND contrast agents are promising materials for the selective MR imaging of lymphatic systems.
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http://dx.doi.org/10.1088/1361-6528/abeb9cDOI Listing
March 2021

Screening for Gaucher Disease Using Dried Blood Spot Tests: A Japanese Multicenter, Cross-sectional Survey.

Intern Med 2021 1;60(5):699-707. Epub 2021 Mar 1.

Division of Pediatrics, Graduate School of Medical Science, Kumamoto University, Japan.

Objective For patients with Gaucher disease (GD), a rare, inherited lysosomal storage disease, obtaining a definitive diagnosis is currently time-consuming and costly. A simplified screening method to measure the glucocerebrosidase (GBA) activity using dried blood spots (DBS) on filter paper has recently been developed. Using this newly developed screening method, we evaluated real-world GD screening in patients suspected of having GD. Methods This multicenter, cross-sectional, observational study with a diagnostic intervention component evaluated real-world screening in patients suspected of having GD based on their clinical symptoms and a platelet count <120,000/μL. The endpoint was the number of patients with low GBA activity determined using DBS. Results In 994 patients who underwent initial DBS screening, 77 had low GBA activity. The assay was not repeated in 1 patient who was diagnosed as having a high possibility of GD due to clinical symptoms, and a further 21 patients completed the study without undergoing the second assay. Of the remaining 55 patients who had 2 DBS assays performed, 11 had a low GBA activity in both assays. Overall, DBS screening identified 12 (1.2%) patients with a low GBA activity, a proportion consistent with prior screening studies. Conclusion These results suggest that the simplified DBS method was less burdensome to patients, was easily utilized by many physicians, and could be a useful first-tier screening assay for GD prior to initiating burdensome genetic testing.
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http://dx.doi.org/10.2169/internalmedicine.5064-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990619PMC
April 2021

Interferon-β sensitizes human malignant melanoma cells to temozolomide-induced apoptosis and autophagy.

Int J Oncol 2019 May 7;54(5):1864-1874. Epub 2019 Mar 7.

Division of Neurosurgery, Department of Neurological Surgery, Nihon University School of Medicine, Tokyo 173-8610, Japan.

Malignant melanoma is a highly aggressive skin cancer that is highly resistant to chemotherapy. Adjuvant therapy is administered to patients with melanoma that possess no microscopic metastases or have a high risk of developing microscopic metastases. Methylating agents, including dacarbazine (DTIC) and temozolomide (TMZ), pegylated interferon (IFN)‑α2b and interleukin‑2 have been approved for adjuvant immuno‑chemotherapy; however, unsatisfactory results have been reported following the administration of methylating agents. IFN‑β has been considered to be a signaling molecule with an important therapeutic potential in cancer. The aim of the present study was to elucidate whether antitumor effects could be augmented by the combination of TMZ and IFN‑β in malignant melanoma. We evaluated the efficacy of TMZ and IFN‑β by comparing O6‑methylguanine‑DNA transferase (MGMT)‑proficient and ‑deficient cells, as MGMT has been reported to be associated with the resistance to methylating agents. Cell viability was determined by counting living cells with a Coulter counter, and apoptosis was analyzed by dual staining with Annexin V Alexa Fluor® 488 and propidium iodide. The expression of proteins involved in the cell cycle, apoptosis and autophagy was evaluated by western blot analysis. The combined treatment with TMZ and IFN‑β suppressed cell proliferation and induced cell cycle arrest. We also demonstrated that a combination of TMZ and IFN‑β enhanced apoptosis and autophagy more efficiently compared with TMZ treatment alone. These findings suggest that antitumor activity may be potentiated by IFN‑β in combination with TMZ.
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http://dx.doi.org/10.3892/ijo.2019.4743DOI Listing
May 2019

Clade Ib basic helix-loop-helix transcription factor, bHLH101, acts as a regulatory component in photo-oxidative stress responses.

Plant Sci 2018 Sep 19;274:101-108. Epub 2018 May 19.

Department of Advanced Bioscience, Faculty of Agriculture, Kindai University, Nakamachi, Nara, 631-8505, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Kawaguchi, 332-0012, Japan. Electronic address:

The accumulation of reactive oxygen species (ROS) leads to oxidative damage; however, ROS also acts as signaling molecules. We previously demonstrated that the inducible silencing of thylakoid membrane-bound ascorbate peroxidase Arabidopsis plants (IS-tAPX) accumulated HO in their chloroplasts, resulting in the clarification of ROS-responsive genes. In IS-tAPX plants, the transcript levels of the basic helix-loop-helix (bHLH) transcription factor bHLH101, which belongs to clade Ib bHLH, were down-regulated. In order to investigate the participation of bHLH101 in chloroplastic HO-mediated signaling, we isolated dominant negative expression mutants of bHLH101 (DN-bHLH101). DN-bHLH101 plants showed a significant phenotype that was sensitive to a methylviologen treatment, even under iron-sufficient conditions. Furthermore, the knock out mutant of bHLH101 showed a photo-oxidative sensitive phenotype, indicating that other clade Ib bHLHs do not compensate for the function of bHLH101. Thus, bHLH101 appears to act as a regulatory component in photo-oxidative stress responses. We also found that ferric chelate reductase activity was stronger in IS-tAPX plants than in control plants, suggesting that there is a close relationship between iron metabolism and oxidative stress responses.
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http://dx.doi.org/10.1016/j.plantsci.2018.05.012DOI Listing
September 2018

Efficacy of ribavirin against malignant glioma cell lines: Follow-up study.

Oncol Rep 2018 Feb 11;39(2):537-544. Epub 2017 Dec 11.

Department of Neurological Surgery, Nihon University School of Medicine, Tokyo 173-8610, Japan.

Ribavirin, a nucleic acid analog, has been employed as an antiviral agent against RNA and DNA viruses and has become the standard agent used for chronic hepatitis C in combination with interferon-α2a. Furthermore, the potential antitumor efficacy of ribavirin has attracted increasing interest. Recently, we demonstrated a dose-dependent antitumor effect of ribavirin for seven types of malignant glioma cell lines. However, the mechanism underlying the antitumor effect of ribavirin has not yet been fully elucidated. Therefore, the main aim of the present study was to provide further relevant data using two types of malignant glioma cell lines (U-87MG and U-138MG) with different expression of MGMT. Dotted accumulations of γH2AX were found in the nuclei and increased levels of ATM and phosphorylated ATM protein expression were also observed following ribavirin treatment (10 µM of ribavirin, clinical relevant concentration) in both the malignant glioma cells, indicating double-strand breaks as one possible mechanism underlying the antitumor effect of ribavirin. In addition, based on assessements using FACS, ribavirin treatment tended to increase the G0/G1 phase, with a time‑lapse, indicating the induction of G0/G1-phase arrest. Furthermore, an increased phosphorylated p53 and p21 protein expression was confirmed in both glioma cells. Additionally, analysis by FACS indicated that apoptosis was induced following ribavirin treatment and caspase cascade, downstream of the p53 pathway, which indicated the activation of both exogenous and endogenous apoptosis in both malignant glioma cell lines. These findings may provide an experimental basis for the clinical treatment of glioblastomas with ribavirin.
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http://dx.doi.org/10.3892/or.2017.6149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783620PMC
February 2018

Repeated Small Bowel Obstruction Caused by Chestnut Ingestion without the Formation of Phytobezoars.

Intern Med 2016 15;55(12):1565-8. Epub 2016 Jun 15.

Department of Gastroenterology, Hirosaki University Graduate School of Medicine, Japan.

A small number of cases of small bowel obstruction caused by foods without the formation of phytobezoars have been reported. Repeated small bowel obstruction due to the ingestion of the same food is extremely rare. We present the case of 63-year-old woman who developed small bowel obstruction twice due to the ingestion of chestnuts without the formation of phytobezoars. This is the first reported case of repeated small bowel obstruction caused by chestnut ingestion. Careful interviews are necessary to determine the meal history of elderly patients and psychiatric patients.
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http://dx.doi.org/10.2169/internalmedicine.55.6811DOI Listing
March 2017

Diagnostic and therapeutic single-operator cholangiopancreatoscopy in biliopancreatic diseases: Prospective multicenter study in Japan.

World J Gastroenterol 2016 Feb;22(5):1891-901

Toshio Kurihara, Takao Itoi, Department of Gastroenterology and Hepatology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.

Aim: To assess the utility and safety of single-operator cholangiopancreatoscopy (SOCPS) using the SpyGlass system in widespread clinical application for biliary and pancreatic diseases.

Methods: This study was a prospective case series conducted in 20 referral centers in Japan. There were 148 patients who underwent SOCPS; 124 for biliary diseases and 24 for pancreatic diseases. The attempted interventions were SOCPS examination, SOCPS-directed tissue sampling, and therapy for stone removal, among others. The main outcomes were related to the procedure success rate in terms of visualizing the target lesions, SOCPS-directed adequate tissue sampling, and complete stone removal.

Results: A total of 148 patients were enrolled for the diagnosis of indeterminate biliary and pancreatic lesions or treatment of biliary and pancreatic disease. The overall procedure success rate of visualizing the target lesions was 91.2% (135/148). The overall procedural success rates of visualizing the target lesions of diagnostic SOCPS in the bile duct and pancreatic duct were 95.5% (84/89) and 88.2% (15/17), respectively.

Diagnosis: the overall adequate tissue for histologic examination was secured in 81.4% of the 86 patients who underwent biopsy under SOCPS (bile duct, 60/75, 80.0%; pancreatic duct, 10/11, 90.9%). The accuracy of histologic diagnosis using SOCPS-directed biopsies in indeterminate bile duct lesions was 70.7% (53/75). In the pancreatic duct, the accuracy of SOCPS visual impression of intraductal papillary mucinous neoplasm was 87.5% (14/16). Stone therapy: complete biliary and pancreatic stone clearance combined with SOCPS-directed stone therapy using electrohydraulic lithotripsy or laser lithotripsy was achieved in 74.2% (23/31) and 42.9% (3/7) of the patients, respectively. Others: SOCPS using the SpyGlass system was used in cannulation of the cystic duct in two patients and for passing across the obstructed self-expandable metallic stent for a malignant biliary stricture in two patients. All procedures were successful in both SOCPS-guided therapies. The incidence of procedure-related adverse events was 5.4% (8/148).

Conclusion: SOCPS with direct visualization and biopsy for diagnosis and SOCPS-directed therapy for biliary and pancreatic diseases can be safely performed with a high success rate. The clinical trial was registered at UMIN CTR (http://www.umin.ac.jp). The registration identification number is UMIN000015155.
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http://dx.doi.org/10.3748/wjg.v22.i5.1891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724621PMC
February 2016

Antitumorigenic effect of interferon-β by inhibition of undifferentiated glioblastoma cells.

Int J Oncol 2015 Nov 14;47(5):1647-54. Epub 2015 Sep 14.

Department of Neurological Surgery, Nihon University School of Medicine, Tokyo, Japan.

Glioma stem-like cells (GSCs) are undifferentiated cells that are considered to be an origin of glioblastomas. Furthermore, they may contribute to treatment resistance and recurrence in glioblastomas. GSCs differentiate into differentiated glioma cells (non-glioma stem-like cells: non‑GSCs), and interconversion might occur between GSCs and non-GSCs. We investigated whether interferon-beta (IFN-β) could exert any efficacy towards GSCs or such interconversion processes. The neural stem cell marker CD133 and pluripotency marker Nanog in GSCs were analyzed to evaluate their differentiation levels. GSCs were considered to undergo differentiation into non-GSCs upon serum exposure, since the expression of CD133 and Nanog in the GSCs was negatively affected. Furthermore, the cells regained their undifferentiated features upon removal of the serum. However, we verified that IFN-β reduced cell proliferation and tumor sphere formation in GSCs, and induced suppression of the restoration of such undifferentiated features. In addition, we also confirmed that IFN-β suppressed the acquisition process of undifferentiated features in human malignant glioma cell lines. Our data thus suggest that IFN-β could be an effective agent not only through its cell growth inhibitory effect on GSCs but also as a means of targeting the interconversion between GSCs and non-GSCs, indicating the possibility of IFN-β being used to prevent treatment resistance and recurrence in glioblastomas, via the inhibition of undifferentiated features.
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http://dx.doi.org/10.3892/ijo.2015.3165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599190PMC
November 2015

Characterization of glioma stem-like cells from human glioblastomas.

Int J Oncol 2015 Jul 7;47(1):91-6. Epub 2015 May 7.

Department of Neurological Surgery, Nihon University School of Medicine, Tokyo, Japan.

Glioma stem-like cells (GSCs) could have potential for tumorigenesis, treatment resistance, and tumor recurrence (GSC hypothesis). However, the mechanisms underlying such potential has remained elusive and few ultrastructural features of the cells have been reported in detail. We therefore undertook observations of the antigenic characteristics and ultrastructural features of GSCs isolated from human glioblastomas. Tumor spheres formed by variable numbers of cells, exhibiting a variable appearance in both their size and shape, were frequently seen in GSCs expressing the stem cell surface markers CD133 and CD15. Increased cell nucleus atypia, mitochondria, rough endoplasmic reticulum, coated vesicles, and microvilli, were noted in the GSCs. Furthermore, cells at division phases and different phases of the apoptotic process were occasionally observed. These findings could imply that GSCs have certain relations with human neural stem cells (NSCs) but are primitively different from undifferentiated NSCs. The data may provide support for the GSC hypothesis, and also facilitate the establishment of future glioblastoma treatments targeting GSCs.
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http://dx.doi.org/10.3892/ijo.2015.2992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485645PMC
July 2015

Efficacy of ribavirin against malignant glioma cell lines.

Oncol Lett 2014 Dec 26;8(6):2469-2474. Epub 2014 Sep 26.

Department of Neurological Surgery, Nihon University School of Medicine, Tokyo 173-8610, Japan.

Ribavirin (1-β-D-ribofuranosy-1,2,4-triazole-3-carboxamide) has been widely administered as an antiviral agent against RNA and DNA viruses. Ribavirin, in combination with interferon, has predominantly been applied in the treatment of the hepatitis C virus infection and its potential antitumor efficacy has recently become a point of interest. The aim of the present study was to evaluate the effect of ribavirin on the growth of malignant glioma cells, to identify novel predictive genes in malignant glioma cells (by analyzing gene expression profiles) and to assess the influence of ribavirin on the cell cycle of malignant glioma cells. The present study evaluated the antitumor efficacy of ribavirin against various malignant glioma cell lines (A-172, AM-38, T98G, U-87MG, U-138MG, U-251MG and YH-13). After culturing the cells in ribavirin-containing culture medium (final concentration, 0-1,000 μM) for 72 h, the viable proliferated cells were harvested and counted. The half maximal inhibitory concentration of ribavirin, with regard to the growth of the malignant glioma cell lines, was determined from the concentration of ribavirin required for 50% growth inhibition in comparison to the untreated control cells. Furthermore, the current study identified the genes in which the gene expression levels correlated with the ribavirin sensitivity of the malignant glioma cells lines, using a high-density oligonucleotide array. Finally, cell cycle analysis was performed on the U-87MG cell line. It was identified that ribavirin inhibited the growth of all of the malignant glioma cell lines in a dose-dependent manner, although the ribavirin sensitivity varied between each cell line. Of the extracted genes, demonstrated the strongest positive correlation between gene expression level and ribavirin sensitivity. Cell cycle analysis of the U-87MG cell line demonstrated that ribavirin treatment induces G0/G1 arrest and thus may be an effective agent for inhibiting malignant glioma cell growth. Therefore, the results of the current study indicate that ribavirin may have potential as a therapeutic agent in the treatment of malignant gliomas.
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http://dx.doi.org/10.3892/ol.2014.2569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214453PMC
December 2014

[Drug sensitivity of causative agents in ocular infection of external adnexa and anterior segments--multicenter study of causative agents and drug sensitivity of ocular infection by the Japanese Association for Ocular Infection part II].

Nippon Ganka Gakkai Zasshi 2011 Sep;115(9):814-24

Hatano Eye Clinic, Japan.

Purpose: To report the drug sensitivity of causative agents produced by ocular infection of external adnexa and anterior segments investigated by the nationwide survey conducted by Japanese Association for Ocular Infection between September, 2007 and August, 2008.

Subjects And Methods: Among all strains isolated, causative and presumed causative agents were selected according to the criteria described, and drug sensitivity tests were conducted by minimum inhibitory concentrations (MIC) with 10 kinds of antimicrobial agents including 5 fluoroquinolones.

Results: Among 281 causative isolates, cefmenoxime (CMX) showed the highest sensitivity, followed by fluoroquinolones. Staphylococci and Streptococci were more sensitive to fluoroquinolones when compared to the others. Haemophilus influenzae was very sensitive to all fluoroquinolones. Corynebacterium spp. and Propionibacterium acnes were most sensitive to CMX and erythromycin respectively.

Conclusion: CMX and fluoroquinolones showed generally good sensitivity among causative pathogens of ocular infection.
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September 2011

[Determination of causative agents in ocular infection of external adnexa and anterior segments--multicenter study of causative agents and drug sensitivity of ocular infection by the Japanese Association for Ocular Infection part I].

Nippon Ganka Gakkai Zasshi 2011 Sep;115(9):801-13

Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, Japan.

Purpose: To determine the causative agents of ocular infection of external adnexa and anterior segments due to selected criteria.

Subjects And Methods: Between September 22, 2007 and August 25, 2008, 890 bacterial strains were collected from 476 patients in 18 facilities nationwide participating in the Drug Sensitivity for Ocular Infection Study Group. Usual aerobic and anaerobic cultures, enrichment cultures, smears, and measurements of bacterial quantity were performed and the determination of causative agents was made from the results of smears and culture, the presence of polymorphonuclear cells and bacterial quantity. The selection was divided into two categories, causative agents and presumed causative agents. Staphylococcus aureus, Moraxella bacilli, Haemophilus influenzae, Streptococcus pneumoniae, Pseudomonas aeruginosa, and Neisseria gonorrhoeae were distinctively considered as specified bacteria.

Results: Among 890 strains, 18.8% were determined to be causative agents, and 15.1% were determined to be presumed causative agents. Among the bacteria detected in normal flora, 2.0% of Staphylococcus epidermidis, 2.6% of Propionibacterium acnes, and 38.3% of Corynebacterium spp. were determined to be causative agents.

Conclusion: To determine the causative agents, the results of smears and bacterial quantity should be considered together with culture results. Bacteria constituting normal flora have the potential of becoming causative agents.
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September 2011

Gene expression profiles predicting the response to IFN-β and a combination of temozolomide and IFN-β in malignant gliomas.

Int J Oncol 2011 Sep 6;39(3):529-42. Epub 2011 Jun 6.

Department of Neurological Surgery, Nihon University School of Medicine, 30-1 Oyaguchi-Kamimachi, Itabashi-ku, Tokyo 173-8610, Japan.

Temozolomide (TMZ) is an alkylating agent that has yielded significant benefits and is a current standard agent in the treatment of malignant gliomas. However, its survival benefit remains unsatisfactory. Recently, a synergistic antitumor effect between TMZ and interferon-β (IFN-β) was reported in malignant glioma cells. The Japan Clinical Oncology Group (JCOG) brain tumor study group has recently began a randomized phase II study to evaluate the clinical effectiveness of combination therapy with TMZ and IFN-β in glioblastomas. However, it is not sufficient just to evaluate the mechanisms and establish an experimental basis for rational clinical therapy with IFN-β and TMZ. The precise mechanisms governing the direct effects of IFN-β and a combination of IFN-β and TMZ in gliomas are not yet fully understood. To gain insight into the mechanisms of sensitivity/resistance involving IFN-β and combination therapy with IFN-β and TMZ, and further to identify new marker(s) that could be used clinically to predict the response to such therapy and new target gene(s) for therapies related to malignant glioma patho-genesis, we evaluated the gene expression profiles of human malignant glioma cell lines employing a high-density oligo-nucleotide DNA array, GeneChip. We present a list of the most highly upregulated and downregulated genes which may be involved in conferring a response to IFN-β and synergistic effect between IFN-β and TMZ in malignant gliomas. Although the present study has several limitations, our reported candidate genes could represent not only potential molecular markers but also chemotherapy targets for improving the treatment outcome by devising strategies that are able to circumvent primary drug resistance in malignant gliomas.
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http://dx.doi.org/10.3892/ijo.2011.1068DOI Listing
September 2011

Evaluation of microvessels in colorectal tumors by narrow band imaging magnification: including comparison with magnifying chromoendoscopy.

Dig Dis Sci 2011 Feb 11;56(2):532-8. Epub 2010 Jun 11.

Department of Gastroenterology, Dokkyo Medical University, Mibu, Tochigi, Japan.

Background/aims: Narrow band imaging (NBI) magnification analysis has entered use in clinical settings to diagnose colorectal tumors. Pit pattern analysis with magnifying endoscopy is already widely used to assess colorectal lesions and invasion depth. Our study compared diagnoses by vascular pattern analysis and pit pattern analysis with NBI magnification.

Methods: We examined 296 colorectal lesions-15 hyperplastic polyps (HP), 213 low-grade adenomas (L-Ad), 26 high-grade adenomas (H-Ad), 31 with intramucosal to scanty submucosal invasion (M-Sm-s), and 11 with massive submucosal invasion (Sm-m)-applying the system of Kudo et al. to analyze pit patterns, and the system of Tanaka et al. to analyze and classify vascular patterns by NBI into three categories: type A (hyperplasia pattern), type B (adenomatous pattern), and type C (carcinomatous pattern). Type C cases were subdivided into subtypes C1, C2, and C3. We used this system to examine histology type and invasion depth.

Results: Diagnostic sensitivity, specificity, and accuracy were 100% for both type II pit pattern HP and type A HP. Diagnostic sensitivity, specificity, and accuracy were 85.4, 94.5, and 93.2% for Vi and Vn pit pattern cancer and 95.2, 91.7, and 92.2% for type C cancer (no significant differences in sensitivity, specificity, or accuracy). Diagnostic sensitivity, specificity, and accuracy were comparable for Vi high-grade irregularity and Vn pit pattern Sm-m (90.9, 96.8, and 96.7%) and type C2/C3 Sm-m (90.1, 98.2, and 98.0%), with no significant differences in sensitivity, specificity, or accuracy.

Conclusions: Vascular pattern analysis by NBI magnification proved comparable to pit pattern analysis.
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http://dx.doi.org/10.1007/s10620-010-1293-3DOI Listing
February 2011

Gene expression profiling predicts response to temozolomide in malignant gliomas.

Int J Oncol 2010 Jun;36(6):1367-77

Department of Neurological Surgery, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan.

Malignant gliomas are highly lethal neoplasms that cannot be cured with currently available therapies. Temozolomide (TMZ) is a recently introduced alkylating agent that has yielded significant benefits and become a key agent in the treatment of high-grade gliomas. However, its survival benefit remains unsatisfactory. Understanding the molecular basis of TMZ sensitivity/resistance is necessary for improving the treatment outcome by devising strategies that are able to circumvent primary drug resistance. We therefore combined the in vitro TMZ response with microarray gene expression data to identify genes that could potentially be used to predict the response of malignant gliomas to TMZ therapy. We first obtained the individual IC50 values for TMZ in seven malignant glioma cell lines (A-172, AM-38, T98G, U-87MG, U-138MG, U-251MG and YH-13) and then identified the genes whose expression correlated most highly with TMZ sensitivity employing a cDNA microarray. We present here a list of the most highly up-regulated and down-regulated genes which may be involved in conferring TMZ sensitivity/resistance in malignant gliomas, although most of the genes have not been implicated as a causal factor in the TMZ response except MGMT. We also demonstrated and confirmed the MGMT methylation status, quantitative MGMT mRNA levels, and MGMT protein expression levels in TMZ resistant glioma cells in vitro. Our results are thus consistent with previous studies and suggest that a dominant mechanism conferring sensitivity/resistance to TMZ exists in malignant glioma cells. Although the present study dose have several limitations, our reported candidate genes could represent not only potential molecular markers for TMZ sensitivity/resistance but also chemotherapy targets. Furthermore, the present study could provide a foundation for alternative therapeutic strategies including novel combination treatments that incorporate additional reagents directed at overcoming resistance to TMZ.
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http://dx.doi.org/10.3892/ijo_00000621DOI Listing
June 2010

Effect of IFN-beta on human glioma cell lines with temozolomide resistance.

Int J Oncol 2009 Jul;35(1):139-48

Department of Neurological Surgery, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan.

Human interferon-beta (IFN-beta) is known to exhibit pleiotropic biological activities including antitumor effects. On the other hand, temozolomide (TMZ), an oral bioavailable alkylating agent with excellent tolerability, has demonstrated efficacy and has become a key therapeutic agent in patients with malignant gliomas; however, its survival benefit remains unsatisfactory. More recent studies have indicated that there might be favorable therapeutic interactions between IFN-beta and TMZ, although the therapeutic advantages of such a combination have not yet been fully explored. The main aim of the present study was to determine whether an antitumor effect could be potentiated by a combination of IFN-beta and TMZ. The antitumor effect of and cell sensitivity to IFN-beta and TMZ and the synergistic potential of IFN-beta and TMZ in combination were evaluated in six malignant glioma cell lines. Correlations among the MGMT methylation status, quantitative level of MGMT mRNA, MGMT protein expression and the antitumor effect of these agents were also evaluated, since one of the most prominent resistance mechanisms to TMZ involves the DNA repair protein MGMT. The cell growth inhibitory effects of IFN-beta and TMZ on all tumor cell lines were observed in a dose-dependent manner, and the human malignant glioma-derived cell lines differed in their sensitivity to TMZ. The MGMT status, including promoter hypermethylation, quantitative mRNA expression and protein expression, was strongly correlated with TMZ sensitivity. A synergistic cell growth inhibitory effect and down-regulated MGMT mRNA levels were significantly observed when a clinically achievable CNS dose of IFN-beta was combined with TMZ, as compared to treatment with IFN-beta or TMZ alone in TMZ-resistant T98G cells. Furthermore, significant amounts of endogenous IFN-beta protein were detected in TMZ-treated T98G cells by ELISA. These results suggest that the clinical therapeutic efficacy of TMZ might be improved by a combination with IFN-beta in malignant gliomas unmethylated at the MGMT gene. The data provide an experimental basis for future strategies in TMZ chemotherapy, although further studies are needed to determine the detailed role of combined IFN-beta and TMZ chemotherapy in increasing tumor sensitivity.
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http://dx.doi.org/10.3892/ijo_00000322DOI Listing
July 2009

A randomized prospective trial comparing unsedated endoscopy via transnasal and transoral routes using 5.5-mm video endoscopy.

Dig Dis Sci 2009 Oct 11;54(10):2155-60. Epub 2008 Dec 11.

Department of Gastroenterology, Dokkyo Medical University, Mibu, Tochigi 321-0293, Japan.

We performed a randomized prospective trial to compare unsedated endoscopy via transnasal and transoral routes using a small-caliber endoscope. Two hundred patients referred for diagnostic esophagogastroduodenoscopy (EGD) were randomly allocated to two groups: those undergoing transnasal (TN) and transoral (TO) endoscopy. We examined the insertion rate, examination duration, nasal pain, pharyngeal pain, number of occurrences of pharyngeal reflex, severity of discomfort throughout the examination, and rate of adverse events. Patients were asked to rate the severity of their pain or discomfort on a 10-cm visual analog scale (VAS). We identified statistically significant differences between the TN and TO groups in rate of insertion (95% versus 100%, respectively, P < 0.05) and examination duration (9.7 +/- 3.0 min versus 8.4 +/- 2.7 min, respectively, P < 0.005). Severity of discomfort throughout the examination was comparable in the TN and TO groups (3.0 +/- 1.8 versus 2.9 +/- 2.3, NS). Nasal bleeding occurred as an adverse event in 4.1% of patients in the TN group. Patients in the TO group were more likely than those in the TN group to prefer the present method in the subsequent endoscopic examination (99.0% versus 82.1%, P < 0.00005). These results indicated that transoral insertion is superior to transnasal insertion in endoscopy procedures performed with small-caliber endoscope.
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http://dx.doi.org/10.1007/s10620-008-0614-2DOI Listing
October 2009

Distinctive bacteria-binding property of cloth materials.

Am J Infect Control 2004 Feb;32(1):27-30

Department of Health Promotion Science, Graduate School of Medicine, Osaka University, 1-7 Yamada-oka, Suita, Osaka 565-0871, Japan.

Background: Nosocomial infections may be caused by pathogens that are transmitted from the hands or clothes of hospital personnel. Handwashing has been evaluated as effective against the spread of pathogens, but transmission through clothes has been little investigated. Evaluation of bacterial adherence to clothes is difficult because of the nonuniform amount of water absorbance by cloth. Therefore, we measured binding of bacteria to cloth fibers made of cotton, nylon, polyester, acrylic, or sheep's wool and tried to characterize bacterial binding to cloth.

Methods: We chose to study the opportunistic pathogens Staphylococcus aureus and Pseudomonas aeruginosa. Cloth fibers were incubated with bacterial suspensions in silicone-coated tubes. We evaluated the reduction of numbers of bacteria in solutions incubated with the fibers and calculated binding ratios of bacteria to the fibers.

Results: Polyester or acrylic fibers bound S aureus and P aeruginosa at high ratios (>80%), but cotton fibers bound them at low ratios (<10%). Nylon fibers bound S aureus at low ratios, but P aeruginosa at intermediate ratios.

Conclusion: The results suggested that polyester, acrylic, or wool clothes could be good carriers of S aureus and P aeruginosa and thus should be covered with cotton clothes to minimize the spread of the pathogens.
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http://dx.doi.org/10.1016/j.ajic.2003.05.003DOI Listing
February 2004

Pedestrian head impact conditions depending on the vehicle front shape and its construction--full model simulation.

Traffic Inj Prev 2003 Mar;4(1):74-82

Honda R&D Co, Ltd, Tochigi R&D Center, Tochigi, Japan.

For the evaluation of pedestrian protection, the European Enhanced Vehicle-Safety Committee Working Group 17 report is now commonly used. In the evaluation of head injuries, the report takes into account only the hood area of the vehicle. But recent pedestrian accident data has shown the injury source for head injury changing to the windshield and A-pillar from the hood. The head contact points are considered to fall on a parallel to the front shape of the vehicle along the lateral direction, but the rigidity of the outer side construction is different from the center area. The purpose of this study is to consider the reason for the change in injury source for recent vehicle models. The head contact points and contact conditions, speed and angle, are thought to be influenced not only by the vehicle's geometry, but also its construction (rigidity). In this study, vehicle-pedestrian impact simulations were calculated with a finite element model for several hitting positions, including the outer side areas. Full dummy sled tests were conducted to confirm the simulation results. These results show that, for impacts at the outer sides of the vehicle, the head contact points are more rearward than at the vehicle center. In addition, the speed and angle of the head contact were found to be influenced by the pedestrian height.
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http://dx.doi.org/10.1080/15389580309856DOI Listing
March 2003