105 results on '"Ohga N"'
Search Results
2. Evaluation of the level of progression of extracapsular spread for cervical lymph node metastasis in oral squamous cell carcinoma
- Author
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Yamada, S., Yanamoto, S., Otani, S., Hasegawa, T., Miyakoshi, M., Minamikawa, T., Ohga, N., Kamata, T., Komori, T., Kitagawa, Y., Kurita, H., and Umeda, M.
- Published
- 2016
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3. OR255 - CLINICAL STUDY OF A NOVEL DOUBLE-FLAP CLOSURE TECHNIQUE FOR PALATAL FISTULA USING THE HINGE AND PALATAL ISLAND FLAPS
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Tanabe, T., Sakata, K., Asaka, T., Ohga, N., Sato, J., Yoshimura, H., Sano, K., and Kitagawa, Y.
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- 2024
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4. FMISO-PET reflects not only hypoxia but also cell proliferation in oral squamous cell carcinoma
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Sato, J., Kitagawa, Y., Watanabe, S., Asaka, T., Ohga, N., Miyakoshi, M., Hata, H., Okamoto, S., Shiga, T., Shindoh, M., and Tamaki, N.
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- 2015
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5. Lysyl oxidase secreted by tumour endothelial cells promotes angiogenesis and metastasis.
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Osawa, T, Ohga, N, Akiyama, K, Hida, Y, Kitayama, K, Kawamoto, T, Yamamoto, K, Maishi, N, Kondoh, M, Onodera, Y, Fujie, M, Shinohara, N, Nonomura, K, Shindoh, M, and Hida, K
- Abstract
Background: Molecules that are highly expressed in tumour endothelial cells (TECs) may be candidates for specifically targeting TECs. Using DNA microarray analysis, we found that the lysyl oxidase (LOX) gene was upregulated in TECs compared with its expression in normal endothelial cells (NECs). LOX is an enzyme that enhances invasion and metastasis of tumour cells. However, there are no reports on the function of LOX in isolated TECs.Methods: TECs and NECs were isolated to investigate LOX function in TECs. LOX inhibition of in vivo tumour growth was also assessed using β-aminopropionitrile (BAPN).Results: LOX expression was higher in TECs than in NECs. LOX knockdown inhibited cell migration and tube formation by TECs, which was associated with decreased phosphorylation of focal adhesion kinase (Tyr 397). Immunostaining showed high LOX expression in human tumour vessels in vivo. Tumour angiogenesis and micrometastasis were inhibited by BAPN in an in vivo tumour model.Conclusion: LOX may be a TEC marker and a possible therapeutic target for novel antiangiogenic therapy. [ABSTRACT FROM AUTHOR]- Published
- 2013
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6. Intra-articular fracture of the mandibular condyle: a case report.
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Yura S, Ohga N, Ooi K, and Izumiyama Y
- Abstract
The authors describe a case of intra-articular fracture of the left mandibular condyle, successfully treated by the pumping technique in the upper and lower joint cavities, and show arthroscopic findings in these cavities. The patient was a 15-year-old boy whose maximum mouth opening was 30 mm. Computed tomography revealed a left intra-articular sagittal fracture of the condylar head. Aspiration of the hematoma in the upper and lower joint spaces was performed with ten pumping actions. In the upper and lower joint spaces, arthroscopic examination revealed the disappearance of the hematoma. The patient continued opening, protrusive, and lateral excursive exercises. One month after the surgery, the maximal interincisal distance was improved to 45 mm with straight opening. In the case presented, mouth-opening exercises, along with the pumping technique for treatment of an intraarticular fracture of the mandibular condyle, allowed satisfactory and stable results in the improvement of limited mouth movement. [ABSTRACT FROM AUTHOR]
- Published
- 2012
7. Biglycan is a specific marker and an autocrine angiogenic factor of tumour endothelial cells.
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Yamamoto, K, Ohga, N, Hida, Y, Maishi, N, Kawamoto, T, Kitayama, K, Akiyama, K, Osawa, T, Kondoh, M, Matsuda, K, Onodera, Y, Fujie, M, Kaga, K, Hirano, S, Shinohara, N, Shindoh, M, and Hida, K
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PROTEOGLYCANS , *AUTOCRINE mechanisms , *VASCULAR endothelial growth factors , *CELL tumors , *GENE expression profiling , *LEUCINE , *CANCER patients , *CELL migration inhibition - Abstract
Background:We isolated tumour endothelial cells (TECs), demonstrated their abnormalities, compared gene expression profiles of TECs and normal endothelial cells (NECs) by microarray analysis and identified several genes upregulated in TECs. We focused on the gene encoding biglycan, a small leucine-rich repeat proteoglycan. No report is available on biglycan expression or function in TECs.Methods:The NEC and TEC were isolated. We investigated the biglycan expression and function in TECs. Western blotting analysis of biglycan was performed on sera from cancer patients.Results:Biglycan expression levels were higher in TECs than in NECs. Biglycan knockdown inhibited cell migration and caused morphological changes in TECs. Furthermore, immunostaining revealed strong biglycan expression in vivo in human tumour vessels, as in mouse TECs. Biglycan was detected in the sera of cancer patients but was hardly detected in those of healthy volunteers.Conclusion:These findings suggested that biglycan is a novel TEC marker and a target for anti-angiogenic therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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8. HuR keeps an angiogenic switch on by stabilising mRNA of VEGF and COX-2 in tumour endothelium.
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Kurosu, T., Ohga, N., Hida, Y., Maishi, N., Akiyama, K., Kakuguchi, W., Kuroshima, T., Kondo, M., Akino, T., Totsuka, Y., Shindoh, M., Higashino, F., and Hida, K.
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ENDOTHELIAL growth factors , *MESSENGER RNA , *ENDOTHELIUM , *PHOSPHORYLATION , *NEOVASCULARIZATION - Abstract
Background: Tumour stromal cells differ from its normal counterpart. We have shown that tumour endothelial cells (TECs) isolated from tumour tissues are also abnormal. Furthermore, we found that mRNAs of vascular endothelial growth factor-A (VEGF-A) and cyclooxygenase-2 (COX-2) were upregulated in TECs. Vascular endothelial growth factor-A and COX-2 are angiogenic factors and their mRNAs contain an AU-rich element (ARE). AU-rich element-containing mRNAs are reportedly stabilised by Hu antigen R (HuR), which is exported to the cytoplasm.Methods: Normal endothelial cell (NEC) and two types of TECs were isolated. We evaluated the correlation of HuR and accumulation of VEGF-A and COX-2 mRNAs in TECs and effects of HuR on biological phenotypes of TECs.Results: The HuR protein was accumulated in the cytoplasm of TECs, but not in NECs. Vascular endothelial growth factor-A and COX-2 mRNA levels decreased due to HuR knockdown and it was shown that these ARE-mRNA were bound to HuR in TECs. Furthermore, HuR knockdown inhibited cell survival, random motility, tube formation, and Akt phosphorylation in TECs.Conclusion: Hu antigen R is associated with the upregulation of VEGF-A and COX-2 mRNA in TECs, and has an important role in keeping an angiogenic switch on, through activating angiogenic phenotype in tumour endothelium. [ABSTRACT FROM AUTHOR]- Published
- 2011
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9. Salivary miRNAs as a novel therapeutic marker in a patient with advanced oral squamous cell carcinoma: A case report.
- Author
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Kimura T, Sakata KI, Ohga N, Sato J, Itagaki T, Munekata T, Yanagawa-Matsuda A, Maeda T, Hojo M, Hatanaka KC, Hatanaka Y, and Iizasa H
- Abstract
The global prevalence of oral squamous cell carcinoma (OSCC) has been increasing. OSCC at the advanced stage tends to resist conventional treatment and causes local recurrence and distant metastasis, resulting in poor prognosis. Therefore, detecting this cancer at an early stage and performing early intervention are important. Promising biomarkers to detect OSCC have yet to be established; however, microRNAs (miRNAs/miRs) serve a crucial role in OSCC tumorigenesis and may be potential biomarkers. In the present case report, the availability of salivary miRNAs as a therapeutic and prognostic marker for patients with OSCC was assessed. The patient was a 33-year-old woman who was diagnosed with advanced OSCC of the tongue, and their miRNA profile isolated from a saliva sample at each clinical course was evaluated. Microarray analysis of the salivary samples revealed changes in the levels of four miRNAs (hsa-miR-6798-5p, miR-6803-5p, miR-6805-5p and miR-6845-5p) in accordance with the clinical course. Neoadjuvant chemotherapy and surgical procedure decreased the levels, whereas the levels increased when the patient was diagnosed with lung metastasis. Furthermore, tongue and lung metastatic lesion specimens exhibited expression of the vascular endothelial growth factor receptor-2, which is regulated by the four miRNAs. Accordingly, the present report proposed that salivary miRNAs could be a therapeutic and prognostic biomarker for OSCC., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Kimura et al.)
- Published
- 2024
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10. Expression analysis of zinc-metabolizing enzymes in the saliva as a new method of evaluating zinc content in the body: two case reports and a review of the literature.
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Sakata KI, Hashimoto A, Kambe T, Sato J, Ohga N, Yamazaki Y, Koyachi M, Tatsuki I, Okada M, Taro O, Hikasa H, and Kitagawa Y
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- Female, Humans, Aged, Aged, 80 and over, Saliva metabolism, Taste Disorders diagnosis, Zinc Acetate, Zinc, Alkaline Phosphatase
- Abstract
Background: The activity level of alkaline phosphatase, a zinc-requiring enzyme in the serum, is used to indicate zinc nutritional status; however, it does not correlate with serum zinc levels or subjective symptoms of taste disorder in many cases. Hence, this study focused on the total activity of alkaline phosphatase, a zinc-requiring enzyme. The total alkaline phosphatasa activity level in the saliva was measured before and after zinc supplementation, and the results were compared with serum zinc levels., Case Presentation: This study included patients with hypozincemia, specifically a patient with zinc-deficient taste disorder (patient 1: a 69-year-old Japanese woman) and a patient with glossodynia with zinc deficiency (patient 2: an 82-year-old Japanese woman). Saliva samples were collected, and blood tests were performed before and after zinc supplementation. Subjective symptoms and serum zinc levels were simultaneously evaluated. Zinc supplementation was performed using zinc acetate hydrate or Polaprezinc., Conclusions: Total alkaline phosphatase activity levels were found to be associated with serum zinc levels and subjective symptoms. A further study with a higher number of patients is necessary to confirm whether total alkaline phosphatase activity levels more accurately reflect the amounts of zinc in the body than serum zinc levels., (© 2024. The Author(s).)
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- 2024
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11. Genotypes and virulence-related activities of Candida albicans derived from oral cavity of patients in Hokkaido.
- Author
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Ouchi C, Hasebe A, Sakata KI, Sato J, Yamazaki Y, Ohga N, and Kitagawa Y
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- Humans, Virulence genetics, Genotype, Peptide Hydrolases, Candida albicans genetics, Candidiasis, Oral microbiology
- Abstract
Objective: This study aimed to elucidate the difference in virulence of Candida albicans derived from oral candidiasis and non-oral candidiasis patients, and its genotype differences in Hokkaido to obtain a clue of a platform to develop new approaches for diagnosis and treatment., Design: C. albicans strains were collected from patients who visited the Hokkaido University Hospital Dental Center. Each strain was examined to i) identify the Candida albicans genotype by PCR, ii) measure the strain's extracellular secretory enzyme activity, iii) determine the strain's ability to induce the production of interleukin-8, and iv) determine the strain's ability to induce cell death., Results: Certain virulence-related protease activities and cytotoxicity were higher in strains derived from patients with oral candidiasis compared with strains derived from patients without oral candidiasis. This is the first report on genotypes and the virulence-related activities, such as some protease secretion, IL-8 induction and cytotoxicity of C. albicans in Hokkaido., Conclusions: The virulence-related activities of the fungal strain may influence the pathogenesis of oral candidiasis, such as production of secreted aspartyl protease and cytotoxicity. In addition, C. albicans genotype C may be important for pathogenicity in Hokkaido, because the ratio of genotype C was increased in strains derived from oral candidiasis patients., Competing Interests: Declaration of Competing Interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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12. Potential relationship between the dosage of prednisolone and delayed healing at tooth extraction: A retrospective study.
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Hato H, Sakata KI, Watanabe H, Sugitani A, Sato J, Asaka T, Ohga N, and Kitagawa Y
- Abstract
Background/purpose: Delayed healing of the extraction socket is not uncommon when tooth extraction is performed on patients taking prednisolone. This study aimed to identify specific dosage of prednisolone and factors associated with delayed healing of the extraction socket in patients taking prednisolone., Materials and Methods: This single-center retrospective study included 80 patients who underwent tooth extraction under local anesthesia and were taking prednisolone orally. Patients were divided into the nondelayed healing group ( n = 50) and delayed healing group ( n = 30), and their background and dosage of prednisolone were compared., Results: The dosage of prednisolone was significantly higher in the delayed healing group than in the nondelayed healing group. A receiver operating characteristics curve analysis resulted in moderate accuracy when the cutoff value was set at 8.0, with 67% sensitivity, 76% specificity, and 0.765 area under the curve. The multivariate logistic regression analysis revealed that prednisolone dosage >8.0 mg/day (odds ratio [OR], 10.8; 95% confidence interval [CI], 2.79-41.6) and osteosclerotic changes beyond the alveolar bone around the tooth to be extracted (OR, 10.3; 95% CI, 2.81-37.8) in X-ray imaging had significant effects on delayed healing., Conclusion: The results of this study suggested that delayed healing following tooth extractions in patients taking prednisolone was related to a dosage of 8.0 mg/day or higher and osteosclerotic changes., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2022 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)
- Published
- 2023
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13. Thermodynamic Bound on the Asymmetry of Cross-Correlations.
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Ohga N, Ito S, and Kolchinsky A
- Abstract
The principle of microscopic reversibility says that, in equilibrium, two-time cross-correlations are symmetric under the exchange of observables. Thus, the asymmetry of cross-correlations is a fundamental, measurable, and often-used statistical signature of deviation from equilibrium. Here we find a simple and universal inequality that bounds the magnitude of asymmetry by the cycle affinity, i.e., the strength of thermodynamic driving. Our result applies to a large class of systems and all state observables, and it suggests a fundamental thermodynamic cost for various nonequilibrium functions quantified by the asymmetry. It also provides a powerful tool to infer affinity from measured cross-correlations, in a different and complementary way to the thermodynamic uncertainty relations. As an application, we prove a thermodynamic bound on the coherence of noisy oscillations, which was previously conjectured by Barato and Seifert [Phys. Rev. E 95, 062409 (2017)PRESCM2470-004510.1103/PhysRevE.95.062409]. We also derive a thermodynamic bound on directed information flow in a biochemical signal transduction model.
- Published
- 2023
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14. Information-geometric structure for chemical thermodynamics: An explicit construction of dual affine coordinates.
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Ohga N and Ito S
- Abstract
We construct an information-geometric structure for chemical thermodynamics, applicable to a wide range of chemical reaction systems including nonideal and open systems. For this purpose, we explicitly construct dual affine coordinate systems, which completely designate an information-geometric structure, using the extent of reactions and the affinities of reactions as coordinates on a linearly constrained space of amounts of substances. The resulting structure induces a metric and a divergence (a function of two distributions of amounts), both expressed with chemical potentials. These quantities have been partially known for ideal-dilute solutions, but their extensions for nonideal solutions and the complete underlying structure are novel. The constructed geometry is a generalization of dual affine coordinates for stochastic thermodynamics. For example, the metric and the divergence are generalizations of the Fisher information and the Kullback-Leibler divergence. As an application, we identify the chemical-thermodynamic analog of the Hatano-Sasa excess entropy production using our divergence.
- Published
- 2022
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15. Ethyl loflazepate as a treatment for patients with idiopathic and psychogenic taste disorder.
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Sakata KI, Hato H, Sato J, Iori T, Ohga N, Watanabe H, Yamazaki Y, and Kitagawa Y
- Abstract
Background: Ethyl loflazepate (EL) is a benzodiazepine derivative that has been reported to activate the gustatory cortex. Our department routinely uses EL as a first-line treatment for idiopathic and psychogenic taste disorders, although little has been reported in the literature with respect to patient outcomes, so we conducted a retrospective study examining its safety and efficacy., Methods: Between 2008 and 2020, 49 patients (14 males and 35 females; mean age, 62.1 years) were diagnosed with taste disorders and received EL as their only treatment for > 14 days. Severity of taste disorder was evaluated using the paper disc method by Sakai et al., and treatment efficacy was evaluated using the Visual Analog Scale, wherein patients gave subjective ratings for their symptoms (reductions by > 50% after administration of EL for 4 weeks were defined as improvements)., Results: Results showed that the improvement rates for patients with idiopathic and psychogenic taste disorders were 55 and 70%, respectively. Additionally, the majority (78%) improved within 2 weeks, and side effects were mild (seven cases with drowsiness and one case with dizziness)., Conclusions: We conclude that EL is an appropriate first-line medication for patients with idiopathic and psychogenic taste disorders., (© 2022. The Author(s).)
- Published
- 2022
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16. Novel antiangiogenic therapy targeting biglycan using tumor endothelial cell-specific liposomal siRNA delivery system.
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Maishi N, Sakurai Y, Hatakeyama H, Umeyama Y, Nakamura T, Endo R, Alam MT, Li C, Annan DA, Kikuchi H, Morimoto H, Morimoto M, Akiyama K, Ohga N, Hida Y, Harashima H, and Hida K
- Subjects
- Angiogenesis Inhibitors, Animals, Biglycan genetics, Endothelial Cells, Humans, Liposomes, Mice, RNA, Small Interfering genetics, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell therapy, Kidney Neoplasms genetics
- Abstract
Tumor blood vessels play important roles in tumor progression and metastasis. Targeting tumor endothelial cells (TECs) is one of the strategies for cancer therapy. We previously reported that biglycan, a small leucine-rich proteoglycan, is highly expressed in TECs. TECs utilize biglycan in an autocrine manner for migration and angiogenesis. Furthermore, TEC-derived biglycan stimulates tumor cell migration in a paracrine manner leading to tumor cell intravasation and metastasis. In this study, we explored the therapeutic effect of biglycan inhibition in the TECs of renal cell carcinoma using an in vivo siRNA delivery system known as a multifunctional envelope-type nanodevice (MEND), which contains a unique pH-sensitive cationic lipid. To specifically deliver MEND into TECs, we incorporated cyclo(Arg-Gly-Asp-D-Phe-Lys) (cRGD) into MEND because α
V β3 integrin, a receptor for cRGD, is selective and highly expressed in TECs. We developed RGD-MEND-encapsulating siRNA against biglycan. First, we confirmed that MEND was delivered into OS-RC-2 tumor-derived TECs and induced in vitro RNAi-mediated gene silencing. MEND was then injected intravenously into OS-RC-2 tumor-bearing mice. Flow cytometry analysis demonstrated that MEND was specifically delivered into TECs. Quantitative RT-PCR indicated that biglycan was knocked down by biglycan siRNA-containing MEND. Finally, we analyzed the therapeutic effect of biglycan silencing by MEND in TECs. Tumor growth was inhibited by biglycan siRNA-containing MEND. Tumor microenvironmental factors such as fibrosis were also normalized using biglycan inhibition in TECs. Biglycan in TECs can be a novel target for cancer treatment., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)- Published
- 2022
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17. Metastatic basal cell carcinoma of buccal mucosa: a report of a rare case.
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Kimura T, Sakata KI, Sato J, Ouchi C, Ohga N, Yanagawa-Matsuda A, Hida K, and Kitagawa Y
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- Humans, Mouth Mucosa pathology, Mouth Mucosa surgery, Neoplasm Recurrence, Local surgery, Phenotype, Carcinoma, Basal Cell surgery, Skin Neoplasms pathology
- Abstract
Background: Basal cell carcinoma (BCC) is the most common cancer worldwide. Most of BCCs can be detected in the early stages and are generally well controlled with local resection. Despite the high incidence of BCC, metastasis is rarely observed. Metastatic BCCs generally have an aggressive phenotype and are refractory to conventional treatment., Case Presentation: We describe a rare case of BCC in which a series of local relapses culminated in metastasis into the oral cavity 10 years after the first diagnosis of cutaneous BCC. We performed surgical resection and postoperative radiotherapy in this patient; 11 months after the final course of radiotherapy, the BCC remains stable, and the patient continues to be monitored regularly., Conclusions: Because metastatic BCC is refractory to current treatment and difficult to control, his treatment history and the pathohistological features of BCC had to be considered in posttreatment planning., (© 2022. The Author(s).)
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- 2022
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18. Efficacy of rikkosan for primary burning mouth syndrome: a retrospective study.
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Hato H, Sakata KI, Sato J, Asaka T, Ohga N, Yamazaki Y, and Kitagawa Y
- Abstract
Background: Burning mouth syndrome (BMS) is a chronic condition characterized by pain in the oral cavity. Kampo medicine is a traditional Japanese medical system that has its roots partly in ancient Chinese medicine. The purpose of this study is to evaluate the efficacy of rikkosan-a traditional Japanese herbal medicine (Kampo)-in the treatment of primary BMS., Main Body: A single-center retrospective study was conducted in 32 patients who were diagnosed with primary BMS and treated with rikkosan alone through gargling (2.5 g rikkosan dissolved in 50 mL hot water) three times daily. Patients were asked to evaluate their pain using a numerical rating scale (NRS) at first visit and after 1 month. One patient had stomatitis as a side effect after gargling with rikkosan, however, no side effects were observed in other patients. Overall NRS scores decreased significantly between the first visit (7.6 ± 2.7) and the 1-month visit (5.6 ± 2.8)., Conclusions: Rikkosan may be an effective treatment for primary BMS., (© 2021. The Author(s).)
- Published
- 2021
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19. Monitoring indices of bone inflammatory activity of the jaw using SPECT bone scintigraphy: a study of ARONJ patients.
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Hata H, Kitao T, Sato J, Asaka T, Ohga N, Imamachi K, Hirata K, Shiga T, Yamazaki Y, and Kitagawa Y
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- Aged, Aged, 80 and over, Bisphosphonate-Associated Osteonecrosis of the Jaw immunology, Bone Density Conservation Agents adverse effects, Diphosphonates adverse effects, Female, Humans, Jaw diagnostic imaging, Jaw drug effects, Jaw immunology, Male, Middle Aged, Osteomyelitis immunology, Pilot Projects, Prognosis, Retrospective Studies, Software, Bisphosphonate-Associated Osteonecrosis of the Jaw complications, Osteomyelitis diagnosis, Tomography, Emission-Computed, Single-Photon
- Abstract
Development of quantitative analysis software has enabled application of several standardised uptake values (SUV) for bone analysis in single photon emission computed tomography (SPECT). The present retrospective study aimed to develop a reliable method of monitoring bone inflammatory activity in antiresorptive agent-related osteonecrosis of the jaw (ARONJ) using SPECT quantitative analysis software. Fifteen ARONJ patients underwent SPECT before and after anti-inflammatory therapy. We calculated the mean maximum SUV (SUVmax) of the bilateral cranial bones using quantitative analysis software and used this as the control [C]. We attempted to adjust the SUVmax of the lesion [L] as follows: adjusted SUVmax (aSUVmax) = [L] - [C]. The optimum threshold to calculate the metabolic bone volume (MBV) (cm
3 ) was [C] + 3. The threshold values obtained for each case were input to calculate MBV at each osteomyelitis site. Retrospectively, we compared aSUVmax and MBV of each patient's ARONJ before and after anti-inflammatory therapy. The patients' high aSUVmax or large MBV of the ARONJ reduced rapidly, reflecting individual clinical findings after treatment. Application of SPECT quantitative analysis software to monitor bone inflammatory activity in ARONJ could improve the prognosis-deciding abilities of clinicians and enable them to treat ARONJ effectively.- Published
- 2020
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20. Imaging modalities for drug-related osteonecrosis of the jaw (3), Positron emission tomography imaging for the diagnosis of medication-related osteonecrosis of the jaw.
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Kitagawa Y, Ohga N, Asaka T, Sato J, Hata H, Helman J, Tsuboi K, Amizuka N, Kuge Y, and Shiga T
- Abstract
Medication-related osteonecrosis of jaws (MRONJ) is one of the most complicated inflammatory conditions in oral and maxillofacial region. It is very difficult to correctly evaluate the degree and extent of necrosis and infection. This refractory osteonecrosis often needs extended surgery, leading to impaired quality-of-life. We have performed hyperbaric oxygen therapy (HBO) combined with conservative surgery for advanced cases. We have appraised the value of FDG-PET and 3-phase bone scintigraphy in the diagnosis and management of this condition. MRONJ showed significantly higher SUV
max on FDG-PET than the others. Although the 3 phase pool bone images did not change significantly, perfusion and static bone image as well as PET showed remarkable response to HBO for MRONJ. SUVmax after HBO was significantly lower than those of before HBO. These preliminary results indicate that FDG-PET is useful for monitoring the effect of HBO for MRONJ.- Published
- 2019
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21. The identification of autoantigens in mucous membrane pemphigoid using immortalized oral mucosal keratinocytes.
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Kamaguchi M, Iwata H, Miyauchi T, Ujiie H, Ujiie I, Nomura T, Ohga N, Shimizu H, and Kitagawa Y
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- Adult, Aged, Aged, 80 and over, Autoantigens isolation & purification, Biomarkers analysis, Female, Humans, Immunoblotting methods, Male, Middle Aged, Autoantigens analysis, Keratinocytes immunology, Mouth Mucosa cytology, Pemphigoid, Benign Mucous Membrane diagnosis, Pemphigoid, Benign Mucous Membrane immunology
- Abstract
Background: Mucous membrane pemphigoid (MMP) is a rare chronic autoimmune subepithelial blistering disorder, targeting multiple basement membrane zone (BMZ) proteins including collagen XVII (COL17). Circulating autoantibodies of MMP are often undetected due to their lower titers. The oral mucosa is a valuable substrate for the detection of autoantibodies in MMP patients. However, obtaining normal human oral mucosa is more difficult than obtaining normal human skin. We established immortalized normal human oral mucosal keratinocytes (OMKs) and performed immunoblotting using immortalized OMK lysate for detecting autoantigens in MMP., Methods: Immortalized OMKs were generated from primary OMKs using E6/E7 proteins of HPV. We compared the protein expression levels of major BMZ proteins between primary OMKs and immortalized OMKs. We performed immunoblotting to detect autoantigens using cell lysates from immortalized OMKs in 30 MMP patients., Results: There were no significant differences between primary OMKs and immortalized OMKs in terms of protein expression levels of the BMZ proteins, including COL17, laminin 332, integrin α6/β4, collagen VII, and collagen IV. Cell lysates of immortalized OMKs effectively identified MMP autoantigens in 60% (18/30) of MMP sera. We found an interesting case of MMP whose autoantibodies preferentially reacted to the 120-kD protein that is an ectodomain of COL17., Conclusion: We demonstrated that a cell lysate of immortalized OMKs is a reliable substrate for the detection of MMP autoantigens. This newly developed immunoblotting analysis method promises to contribute to the diagnosis of MMP., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2019
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22. Mucosal substrates successfully identify the autoantigen in a case of mucous membrane pemphigoid.
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Kamaguchi M, Iwata H, Ujiie H, Ohga N, Kitagawa Y, and Shimizu H
- Subjects
- Autoantigens immunology, Humans, Pemphigoid, Benign Mucous Membrane etiology, Kalinin, Collagen Type XVII, Autoantigens metabolism, Cell Adhesion Molecules immunology, Non-Fibrillar Collagens immunology, Pemphigoid, Benign Mucous Membrane diagnosis, Pemphigoid, Benign Mucous Membrane metabolism
- Published
- 2018
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23. Schleimhautsubstrate identifizieren erfolgreich das Autoantigen bei einem Schleimhautpemphigoid.
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Kamaguchi M, Iwata H, Ujiie H, Ohga N, Kitagawa Y, and Shimizu H
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- 2018
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24. Successful conservative treatment of jaw osteonecrosis caused by denosumab in patients with multiple bone metastasis.
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Ohga N, Sato J, Asaka T, Morimoto M, Yamazaki Y, and Kitagawa Y
- Subjects
- Aged, Breast Neoplasms pathology, Female, Humans, Male, Middle Aged, Bisphosphonate-Associated Osteonecrosis of the Jaw drug therapy, Bone Density Conservation Agents adverse effects, Bone Neoplasms secondary, Breast Neoplasms drug therapy, Conservative Treatment, Denosumab adverse effects
- Abstract
We report a case of osteonecrosis of the jaw (ONJ) associated with denosumab therapy in a 62-year-old female patient being treated for bone metastases from breast cancer. Upon initial presentation at the Department of Oral Medicine, Hokkaido University Hospital, the patient's mandibular molar teeth were extracted because of severe periodontal disease. Two months later, epithelialization of the sockets was observed and treatment with anti-resorptive drugs was started for bone metastases. One year after tooth extraction, bone exposure in the right lower first molar region was observed, and stage 2 medication-related ONJ (MRONJ) was diagnosed. Up to this time, the patient had received zoledronic acid twice and denosumab 22 times. Denosumab was discontinued by the oncologist, and oral antibiotics with rinsing of the exposed bone area were prescribed. By 36 weeks after discontinuation of denosumab, a sequestrum in the posterior part of the mandible was naturally shed, and the site was healed. Bisphosphonate is deposited in bones, whereas denosumab functions extracellularly and circulates in the blood. The effect of denosumab on bone remodeling is reversed shortly after the drug has been discontinued.
- Published
- 2018
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25. Tumor endothelial cells with high aldehyde dehydrogenase activity show drug resistance.
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Hida K, Maishi N, Akiyama K, Ohmura-Kakutani H, Torii C, Ohga N, Osawa T, Kikuchi H, Morimoto H, Morimoto M, Shindoh M, Shinohara N, and Hida Y
- Subjects
- Animals, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell pathology, Cell Line, Tumor, Cell Lineage genetics, Drug Resistance, Neoplasm drug effects, Fluorouracil administration & dosage, Humans, Mice, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells pathology, RNA, Messenger genetics, Xenograft Model Antitumor Assays, Aldehyde Dehydrogenase genetics, Carcinoma, Renal Cell drug therapy, Drug Resistance, Neoplasm genetics, Endothelial Cells drug effects
- Abstract
Tumor blood vessels play an important role in tumor progression and metastasis. We previously reported that tumor endothelial cells (TEC) exhibit several altered phenotypes compared with normal endothelial cells (NEC). For example, TEC have chromosomal abnormalities and are resistant to several anticancer drugs. Furthermore, TEC contain stem cell-like populations with high aldehyde dehydrogenase (ALDH) activity (ALDH
high TEC). ALDHhigh TEC have proangiogenic properties compared with ALDHlow TEC. However, the association between ALDHhigh TEC and drug resistance remains unclear. In the present study, we found that ALDH mRNA expression and activity were higher in both human and mouse TEC than in NEC. Human NEC:human microvascular endothelial cells (HMVEC) were treated with tumor-conditioned medium (tumor CM). The ALDHhigh population increased along with upregulation of stem-related genes such as multidrug resistance 1, CD90, ALP, and Oct-4. Tumor CM also induced sphere-forming ability in HMVEC. Platelet-derived growth factor (PDGF)-A in tumor CM was shown to induce ALDH expression in HMVEC. Finally, ALDHhigh TEC were resistant to fluorouracil (5-FU) in vitro and in vivo. ALDHhigh TEC showed a higher grade of aneuploidy compared with that in ALDHlow TEC. These results suggested that tumor-secreting factor increases ALDHhigh TEC populations that are resistant to 5-FU. Therefore, ALDHhigh TEC in tumor blood vessels might be an important target to overcome or prevent drug resistance., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)- Published
- 2017
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26. 18 F-Fluoromisonidazole positron emission tomography (FMISO-PET) may reflect hypoxia and cell proliferation activity in oral squamous cell carcinoma.
- Author
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Sato J, Kitagawa Y, Watanabe S, Asaka T, Ohga N, Hirata K, Okamoto S, Shiga T, Shindoh M, Kuge Y, and Tamaki N
- Subjects
- Adult, Aged, 80 and over, Female, Fluorodeoxyglucose F18, Humans, Male, Middle Aged, Radiopharmaceuticals, Carcinoma, Squamous Cell diagnostic imaging, Carcinoma, Squamous Cell metabolism, Cell Proliferation, Misonidazole analogs & derivatives, Mouth Neoplasms diagnostic imaging, Mouth Neoplasms metabolism, Positron-Emission Tomography, Radiation-Sensitizing Agents, Tumor Hypoxia
- Abstract
Objective: Hypoxia is a common feature and prognostic factor in cancer.
18 F-fluoromisonidazole (FMISO) positron emission tomography (PET) can detect tumor hypoxia noninvasively. The aim of this study was to assess the correlations between FMISO-PET and18 F-fluorodexyglucose (FDG)-PET parameters with cell proliferation and hypoxia in patients with oral squamous cell carcinoma (OSCC)., Study Design: Twenty-three preoperative patients with OSCC were included. The tumor/muscle ratio (TMR) of FMISO-PET, the maximum standardized uptake values (SUVmax ) of FDG-PET, metabolic tumor volume, and total lesion glycolysis were measured. Ki-67 and hypoxia-inducible factor-1α (HIF-1α) expression was immunohistochemically evaluated., Results: FMISO TMR (P = .003) and FDG SUVmax (P = .04) were significantly higher in patients with high expression of Ki-67 compared with those with low expression of Ki-67. FMISO TMR (P = .006) and FDG SUVmax (P = .01) were also significantly higher in patients with HIF-1α expression than in those without HIF-1α expression. Metabolic tumor volume was not significantly related to either Ki-67 or HIF-1α expression. Multivariate analysis showed that FMISO TMR was independently predictive of Ki-67 (P = .002; odds ratio 31.1) and HIF-1α (P = .049; odds ratio 10.5) expression., Conclusions: FMISO-PET showed significant relationships with Ki-67 and HIF-1α expression, which are key features of cell proliferation and hypoxia in OSCC., (Copyright © 2017 Elsevier Inc. All rights reserved.)- Published
- 2017
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27. Platelet-rich fibrin may reduce the risk of delayed recovery in tooth-extracted patients undergoing oral bisphosphonate therapy: a trial study.
- Author
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Asaka T, Ohga N, Yamazaki Y, Sato J, Satoh C, and Kitagawa Y
- Subjects
- Administration, Oral, Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Treatment Outcome, Bone Density Conservation Agents administration & dosage, Diphosphonates administration & dosage, Osteoporosis drug therapy, Platelet-Rich Fibrin physiology, Tooth Extraction, Wound Healing physiology
- Abstract
Objectives: The aim of the present study was to evaluate the effectiveness of platelet-rich fibrin (PRF) as a wound-healing accelerator in patients undergoing oral bisphosphonate therapy and requiring tooth extractions., Materials and Methods: A total of 102 patients were divided into a PRF group and control group. The patients received oral bisphosphonate therapy for osteoporosis for an average of 32 months. Blood was collected and PRF was introduced into the socket of the PRF group only. Monitoring of mucosal healing was conducted for 3 months in both groups, and radiographic evaluation in the sockets was performed in the PRF group. Delayed recovery was defined as exposed bone and vulnerable granulation tissue without epithelization after 4 weeks and resolving by 8 weeks., Results: There were no intraoperative complications, and none of the patients exhibited onset of medication-related osteonecrosis of the jaw (MRONJ). Delayed recovery was observed in 9 out of 73 control patients (12%), whereas 29 PRF patients exhibited complete epithelialization of the socket within 1 month. The prevalence of delayed recovery was significantly higher in the control group than the PRF group (P < 0.05). Multivariate logistic regression analysis revealed that risk factors and use of PRF were independent significant factors to relate to delayed recovery (P = 0.02)., Conclusions: Early epithelization was confirmed in all PRF patients. Thus, PRF may reduce the risk of delayed recovery in patients undergoing oral bisphosphonate therapy., Clinical Relevance: PRF may be useful in preventing MRONJ in patients receiving oral bisphosphonate (BP).
- Published
- 2017
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28. miR-145 promoted anoikis resistance in tumor endothelial cells.
- Author
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Hida K, Kawamoto T, Maishi N, Morimoto M, Akiyama K, Ohga N, Shindoh M, Shinohara N, and Hida Y
- Subjects
- Cell Adhesion, Endothelial Cells metabolism, Humans, MicroRNAs genetics, Neoplasms pathology, Oligonucleotide Array Sequence Analysis, RNA, Messenger genetics, RNA, Messenger metabolism, Anoikis, MicroRNAs metabolism, Neoplasms metabolism
- Abstract
Tumor progression is dependent on tumor angiogenesis. We previously reported that the phenotype of tumor endothelial cells (TECs) is distinct from normal endothelial cells (NECs). Herein, we conducted a pathway analysis using a public TEC microarray database and identified several putative TEC-specific miRNAs. We found that miR-145 expression was upregulated in TECs and that miR-145 enhanced cell adhesion and anoikis resistance and upregulated Bcl-2 and Bcl-xl via ERK1/2 in human microvascular endothelial cells. These findings suggested that miR-145 is involved in the acquisition of the TEC phenotype, partially. Therefore, miR-145 and its target genes may be molecular targets for anti-angiogenic therapy., (© The Authors 2017. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)
- Published
- 2017
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29. ROS enhance angiogenic properties via regulation of NRF2 in tumor endothelial cells.
- Author
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Hojo T, Maishi N, Towfik AM, Akiyama K, Ohga N, Shindoh M, Hida Y, Minowa K, Fujisawa T, and Hida K
- Subjects
- Biglycan metabolism, Cell Line, Tumor, Cell Movement genetics, Gene Expression Regulation, Neoplastic, Humans, NF-E2-Related Factor 2 metabolism, Neoplasms genetics, Neoplasms metabolism, Neoplasms pathology, Oxidative Stress, Smad2 Protein metabolism, Smad3 Protein metabolism, Endothelial Cells metabolism, NF-E2-Related Factor 2 genetics, Neovascularization, Pathologic genetics, Neovascularization, Pathologic metabolism, Reactive Oxygen Species metabolism
- Abstract
Reactive oxygen species (ROS) are unstable molecules that activate oxidative stress. Because of the insufficient blood flow in tumors, the tumor microenvironment is often exposed to hypoxic condition and nutrient deprivation, which induces ROS accumulation. We isolated tumor endothelial cells (TECs) and found that they have various abnormalities, although the underlying mechanisms are not fully understood. Here we showed that ROS were accumulated in tumor blood vessels and ROS enhanced TEC migration with upregulation of several angiogenesis related gene expressions. It was also demonstrated that these genes were upregulated by regulation of Nuclear factor erythroid 2-related factor 2 (NRF2). Among these genes, we focused on Biglycan, a small leucine-rich proteoglycan. Inhibition of Toll-like receptors 2 and 4, known BIGLYCAN (BGN) receptors, cancelled the TEC motility stimulated by ROS. ROS inhibited NRF2 expression in TECs but not in NECs, and NRF2 inhibited phosphorylation of SMAD2/3, which activates transcription of BGN. These results indicated that ROS-induced BGN caused the pro-angiogenic phenotype in TECs via NRF2 dysregulation.
- Published
- 2017
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30. Vasohibin-1 as a Novel Prognostic Factor for Head and Neck Squamous Cell Carcinoma.
- Author
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Torii C, Hida Y, Shindoh M, Akiyama K, Ohga N, Maishi N, Ohiro Y, Ono M, Totsuka Y, Kitagawa Y, Tei K, Sato Y, and Hida K
- Subjects
- Aged, Antigens, CD34 metabolism, Biomarkers, Tumor metabolism, Disease-Free Survival, Female, Gene Expression Profiling, Humans, Lymphatic Metastasis, Male, Middle Aged, Neoplasm Recurrence, Local, Neovascularization, Pathologic, Prognosis, Treatment Outcome, Carcinoma, Squamous Cell diagnosis, Carcinoma, Squamous Cell metabolism, Cell Cycle Proteins metabolism, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms diagnosis, Head and Neck Neoplasms metabolism
- Abstract
Aim: We evaluated the prognostic value of vasohibin-1 (VASH1) expression in head and neck squamous cell carcinoma., Materials and Methods: Immunohistochemistry for VASH1 and cluster of differentiation 34 (CD34) was performed on 61 head and neck squamous cell carcinoma specimens. The association between VASH1 expression in the tumour and clinical outcomes was analyzed statistically., Results: VASH1 staining in normal tissue adjacent to cancerous tissue was negative, whereas it was positive in tumour blood vessels and AE1/AE3 and Ki67-positive tumour cells. Therefore, we examined the association between VASH1 expression in the tumour and clinical outcomes. Patients with high VASH1 expression in tumour had significantly shorter disease-free survival and more frequently had lymph node recurrence than those with low VASH1 expression., Conclusion: These results suggest that VASH1 expression is associated with tumour progression and may be useful as a prognostic marker of head and neck squamous cell carcinoma., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
- Published
- 2017
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31. Unusual maxillary osteoblastic and osteolytic lesions presenting as an initial manifestation of childhood acute myeloid leukemia: A case report.
- Author
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Shimizu R, Ohga N, Miyakoshi M, Asaka T, Sato J, and Kitagawa Y
- Subjects
- Child, Diagnosis, Differential, Fluorodeoxyglucose F18, Humans, In Situ Hybridization, Fluorescence, Male, Positron Emission Tomography Computed Tomography, Radiopharmaceuticals, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy, Maxillary Neoplasms diagnosis, Maxillary Neoplasms drug therapy
- Abstract
Changes in facial bones may represent a manifestation of systemic disease. Dentists play an important role in the early detection of these manifestations of complex systemic diseases. A case of unusual maxillary mixed (osteoblastic and osteolytic) lesions as an initial manifestation of childhood acute myeloid leukemia (AML) is presented. A 12-year-old male patient was referred to the Department of Oral Medicine complaining of severe swelling in the right buccal region. 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) showed enhanced FDG uptake in the right maxillary sinus. In addition, PET maximum intensity projection image showed diffused FDG uptake in the entire bone marrow. Bone marrow aspiration was performed on the lumbar vertebra, and fluorescence in situ hybridization (FISH) demonstrated AML. The patient was diagnosed with AML (M5a) and treated with chemotherapy by the pediatric department. Six months later, the patient achieved complete remission. After chemotherapy, the disappearance of the osteoblastic and osteolytic lesion and 18F-FDG accumulation were confirmed by PET/CT. Dentists should be familiar with oral manifestations of leukemia because early detection of oral lesions would increase the life span of the patients and reduce the severity of complications.
- Published
- 2017
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32. Tumor endothelial cells express high pentraxin 3 levels.
- Author
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Hida K, Maishi N, Kawamoto T, Akiyama K, Ohga N, Hida Y, Yamada K, Hojo T, Kikuchi H, Sato M, Torii C, Shinohara N, and Shindoh M
- Subjects
- Animals, Blood Vessels physiopathology, C-Reactive Protein metabolism, Cell Proliferation genetics, Humans, Mice, Serum Amyloid P-Component metabolism, C-Reactive Protein genetics, Endothelial Cells pathology, Gene Expression Regulation, Neoplastic, Neoplasms physiopathology, Serum Amyloid P-Component genetics
- Abstract
It has been described that tumor progression has many similarities to inflammation and wound healing in terms of the signaling processes involved. Among biological responses, angiogenesis, which is necessary for tumor progression and metastasis, is a common hallmark; therefore, tumor blood vessels have been considered as important therapeutic targets in anticancer therapy. We focused on pentraxin 3 (PTX3), which is a marker of cancer-related inflammation, but we found no reports on its expression and function in tumor blood vessels. Here we showed that PTX3 is expressed in mouse and human tumor blood vessels based on immunohistochemical analysis. We found that PTX3 is upregulated in primary mouse and human tumor endothelial cells compared to normal endothelial cells. We also showed that PTX3 plays an important role in the proliferation of the tumor endothelial cells. These results suggest that PTX3 is an important target for antiangiogenic therapy., (© 2016 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)
- Published
- 2016
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33. Elimination of oral candidiasis may increase stimulated whole salivary flow rate.
- Author
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Ohga N, Yamazaki Y, Sato J, Asaka T, Morimoto M, Hata H, Satoh C, and Kitagawa Y
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Pain Measurement, Treatment Outcome, Antifungal Agents therapeutic use, Candidiasis, Oral drug therapy, Saliva microbiology, Salivation drug effects, Xerostomia prevention & control
- Abstract
Objectives: Candida infections are frequently encountered fungal infections in the oral mucosa. This study aimed to evaluate the effect of eliminating Candida spp. on stimulated whole salivary flow rate (SWS) in patients with oral candidiasis., Subjects and Methods: This study involved 66 patients with oral candidiasis. Fifty-two consecutive patients, successfully treated by antifungal therapy, were available to examine the effect of elimination of oral Candida spp. on SWS (success group); the 14 patients who tested positive for Candida after therapy were retrospectively included (control group). SWS were used to measure saliva production. Moreover, tongue pain and xerostomia were evaluated using visual analog score (VAS)., Results: By eliminating oral Candida spp., SWS significantly increased in the success group after antifungal therapy [SWS: mean value 0.89±0.51ml/min (median 0.82ml/min: 0.15-2.14) to mean value 1.16±0.58ml/min (median 1.05ml/min: 0.2-2.93), P<0.001]. Furthermore, VAS scores for subjective tongue pain and xerostomia were significantly decreased compared with those before therapy in the success group [xerostomia: mean value 52.5±28.8 (median 53: 9-100) to 24.2±1.6 (median 17: 0-70), tongue pain: mean value 52.6±27.2 (median 56: 1-93) to 15.3±18.0 (median 9: 0-62). P<0.001]. There was no significant difference in SWS, subjective tongue pain, or xerostomia in the control group after antifungal therapy. [SWS: mean value 1.08±0.83ml/min (median 0.69ml/min: 0.2-2.7) to 0.98±0.59ml/min (median 0.8ml/min: 0.45-2.5), P=0.65], [xerostomia: mean value 62.8±5.3 (median 62: 28-70) to 64.0±8.8 (median 64: 56-73), P=0.58, tongue pain: mean value 64.3±18.6 (median 67: 31-87) to 58.4±20.0 (median 8: 20-78), respectively; P=0.24] CONCLUSION: Our study demonstrated that SWS may increase by eliminating oral Candida spp. in patients with oral candidiasis., (Copyright © 2016. Published by Elsevier Ltd.)
- Published
- 2016
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34. Tumour endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan.
- Author
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Maishi N, Ohba Y, Akiyama K, Ohga N, Hamada J, Nagao-Kitamoto H, Alam MT, Yamamoto K, Kawamoto T, Inoue N, Taketomi A, Shindoh M, Hida Y, and Hida K
- Subjects
- Animals, Biglycan metabolism, Cell Line, Tumor, Endothelial Cells cytology, Endothelial Cells metabolism, Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms genetics, Lung Neoplasms metabolism, Lung Neoplasms pathology, MAP Kinase Signaling System, Melanoma genetics, Melanoma metabolism, Mice, NF-kappa B metabolism, NIH 3T3 Cells, Neoplasm Metastasis, Neoplasm Transplantation, RAW 264.7 Cells, Up-Regulation, Biglycan genetics, DNA Methylation, Endothelial Cells pathology, Endothelial Cells transplantation, Lung Neoplasms secondary, Melanoma pathology
- Abstract
Tumour blood vessels are gateways for distant metastasis. Recent studies have revealed that tumour endothelial cells (TECs) demonstrate distinct phenotypes from their normal counterparts. We have demonstrated that features of TECs are different depending on tumour malignancy, suggesting that TECs communicate with surrounding tumour cells. However, the contribution of TECs to metastasis has not been elucidated. Here, we show that TECs actively promote tumour metastasis through a bidirectional interaction between tumour cells and TECs. Co-implantation of TECs isolated from highly metastatic tumours accelerated lung metastases of low metastatic tumours. Biglycan, a small leucine-rich repeat proteoglycan secreted from TECs, activated tumour cell migration via nuclear factor-κB and extracellular signal-regulated kinase 1/2. Biglycan expression was upregulated by DNA demethylation in TECs. Collectively, our results demonstrate that TECs are altered in their microenvironment and, in turn, instigate tumour cells to metastasize, which is a novel mechanism for tumour metastasis.
- Published
- 2016
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35. CXCL12-CXCR7 axis is important for tumor endothelial cell angiogenic property.
- Author
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Yamada K, Maishi N, Akiyama K, Towfik Alam M, Ohga N, Kawamoto T, Shindoh M, Takahashi N, Kamiyama T, Hida Y, Taketomi A, and Hida K
- Subjects
- Animals, Autocrine Communication, Cell Hypoxia, Cell Line, Tumor, Chemokine CXCL12 genetics, Endothelial Cells physiology, Endothelium, Vascular metabolism, Endothelium, Vascular pathology, Female, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms blood supply, Lung Neoplasms secondary, MAP Kinase Signaling System, Mice, Nude, Neoplasm Transplantation, Receptors, CXCR genetics, Up-Regulation, Vascular Endothelial Growth Factor A physiology, Chemokine CXCL12 metabolism, Lung Neoplasms metabolism, Neovascularization, Pathologic metabolism, Receptors, CXCR metabolism
- Abstract
We reported that tumor endothelial cells (TECs) differ from normal endothelial cells (NECs) in many aspects, such as gene expression profiles. Although CXCR7 is reportedly highly expressed in blood vessels of several tumors, its function in TECs is still unknown. To investigate this role, we isolated TECs from mouse tumor A375SM xenografts, and compared them with NECs from normal mouse dermis. After confirming CXCR7 upregulation in TECs, we analyzed its function using CXCR7 siRNA and CXCR7 inhibitor; CCX771. CXCR7 siRNA and CCX771 inhibited migration, tube formation and resistance to serum starvation in TECs but not in NECs. ERK1/2 phosphorylation was inhibited by CXCR7 knockdown in TECs. These results suggest that CXCR7 promotes angiogenesis in TECs via ERK1/2 phosphorylation. Using ELISA, we also detected CXCL12, a ligand of CXCR7, in conditioned medium from TECs, but not from NECs. CXCL12 neutralizing antibody significantly inhibited TEC random motility. VEGF stimulation upregulated CXCR7 expression in NECs, implying that VEGF mediates CXCR7 expression in endothelial cells. A CXCR7 inhibitor, CCX771 also inhibited tumor growth, lung metastasis and tumor angiogenesis in vivo. Taken together, the CXCL12-CXCR7 autocrine loop affects TEC proangiogenic properties, and could be the basis for an antiangiogenic therapy that specifically targets tumor blood vessels rather than normal vessels., (© 2015 UICC.)
- Published
- 2015
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36. Differences in sequential posttreatment salivary IL-6 levels between patients with and patients without locoregional recurrences of oral squamous cell carcinoma: Part III of a cohort study.
- Author
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Sato J, Ohuchi M, Wada M, Ohga N, Asaka T, Yoshikawa K, Miyakoshi M, Hata H, Satoh A, and Kitagawa Y
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Squamous Cell surgery, Female, Humans, Male, Middle Aged, Mouth Neoplasms surgery, Neoplasm Recurrence, Local, Prospective Studies, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell pathology, Interleukin-6 metabolism, Mouth Neoplasms metabolism, Mouth Neoplasms pathology, Saliva chemistry
- Abstract
Objective: Sequential postoperative salivary interleukin-6 (IL-6) concentrations were examined in patients with oral squamous cell carcinoma (OSCC) who had early or late locoregional recurrences or those who did not., Study Design: Twenty-seven consecutive patients with OSCC were originally included in the study. All patients underwent radical surgery. Four saliva samples were collected before (periods I and II) and after (periods III and IV) surgery, and IL-6 concentrations were measured., Results: Although postoperative (period III: at the time of discharge) salivary IL-6 level was significantly higher in patients with early locoregional recurrence (P = .02) than in those without, no such relationships were observed for preoperative IL-6 concentrations (periods I and II). Postoperative (period IV: 24 months after surgery) IL-6 level was significantly higher in patients with late locoregional recurrence (P = .03) than in those without, but no such relationships were observed for IL-6 concentrations in periods I, II, and III., Conclusions: Sequential postoperative salivary IL-6 concentration may be a useful marker for diagnosis of early and late locoregional recurrence in OSCC., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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37. Healing of osteonecrosis of the jaw (ONJ) after discontinuation of denosumab in a patient with bone metastases of colorectal cancer: a case report and hypothesis.
- Author
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Ohga N, Yamazaki Y, Tsuboi K, and Kitagawa Y
- Subjects
- Contrast Media, Female, Humans, Middle Aged, Radiography, Panoramic, Tomography, X-Ray Computed, Bisphosphonate-Associated Osteonecrosis of the Jaw diagnostic imaging, Bone Density Conservation Agents adverse effects, Colorectal Neoplasms pathology, Denosumab adverse effects, Spinal Neoplasms drug therapy, Spinal Neoplasms secondary
- Abstract
Osteonecrosis of the jaw (ONJ) is associated with the use of bisphosphonates (BPs), denosumab, and antiangiogenic drugs; however, the pathophysiology of medication-related ONJ (MRONJ) remains unknown. Recent advances in therapies for diseases that affect bone remodeling have led to the development of agents that inhibit the receptor activator of nuclear factor-kappa B ligand (RANKL). One such inhibitor is denosumab, a highly specific, fully human immunoglobulin G2 monoclonal antibody against RANKL. We report a case of ONJ that developed following dental extraction in a patient treated for metastatic colorectal cancer with denosumab. At the first medical examination at our hospital, her clinical presentation was indistinguishable from stage 2 MRONJ, classified according to the 2014 American Academy of Oral Medicine position paper. Discontinuation of denosumab was directed by her oncologist, and we prescribed oral antibiotics and irrigated the exposed area of bone. Seven months after denosumab cessation, the sequestrum of the anterior part of the mandible was naturally shed and the site was healed. Denosumab and BPs have significantly different mechanisms of action. The effects of denosumab on bone turnover are more rapid and reversible than those of BPs. Discontinuation of denosumab may be effective in the management of denosumab-related ONJ, depending on the primary tumor control.
- Published
- 2015
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38. Inhibition of multidrug transporter in tumor endothelial cells enhances antiangiogenic effects of low-dose metronomic paclitaxel.
- Author
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Akiyama K, Maishi N, Ohga N, Hida Y, Ohba Y, Alam MT, Kawamoto T, Ohmura H, Yamada K, Torii C, Shindoh M, and Hida K
- Subjects
- ATP Binding Cassette Transporter, Subfamily B antagonists & inhibitors, ATP Binding Cassette Transporter, Subfamily B metabolism, Animals, Cell Line, Tumor, Endothelial Cells pathology, Humans, Lung Neoplasms metabolism, Lung Neoplasms pathology, Lung Neoplasms secondary, Mice, Mice, Nude, Neoplasm Metastasis, Neovascularization, Pathologic metabolism, Neovascularization, Pathologic pathology, Xenograft Model Antitumor Assays, Administration, Metronomic, Anti-Arrhythmia Agents pharmacology, Antineoplastic Agents, Phytogenic pharmacology, Drug Resistance, Neoplasm drug effects, Endothelial Cells metabolism, Lung Neoplasms drug therapy, Neovascularization, Pathologic drug therapy, Paclitaxel pharmacology, Verapamil pharmacology
- Abstract
Tumor angiogenesis plays an important role in tumor progression and metastasis. Tumor endothelial cells (TECs) are a therapeutic target of antiangiogenic chemotherapy that was recently developed and is currently being investigated in the clinic with promising results. Low-dose chemotherapy, which is the long-term administration of relatively low doses of chemotherapeutic agents, has been proposed for targeting tumor angiogenesis in various types of cancers. Although the efficacy of low-dose chemotherapy has been confirmed in several clinical models, some studies show insufficient therapeutic effect for malignant cancers. As a possible mechanism of the treatment failure, it has been considered that tumor cells may acquire resistance to this therapy. However, drug resistance by TECs may also be due to another mechanism for resistance of tumor cells to low-dose chemotherapy. We reported elsewhere that TECs were resistant to the anticancer drug paclitaxel, which is a mitotic inhibitor, concomitant with P-glycoprotein up-regulation. Verapamil, a P-glycoprotein inhibitor, abrogated TEC resistance in vitro. Herein, we demonstrated that verapamil coadministration enhanced the effects of low-dose paclitaxel concomitant with inhibiting tumor angiogenesis in a preclinical in vivo mouse melanoma xenograft model. Furthermore, verapamil coadministration reduced lung metastasis. These results suggest that inhibiting P-glycoprotein in TECs may be a novel strategy for low-dose chemotherapy targeting TECs., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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39. Identification of tumor endothelial cells with high aldehyde dehydrogenase activity and a highly angiogenic phenotype.
- Author
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Ohmura-Kakutani H, Akiyama K, Maishi N, Ohga N, Hida Y, Kawamoto T, Iida J, Shindoh M, Tsuchiya K, Shinohara N, and Hida K
- Subjects
- Aldehyde Dehydrogenase analysis, Aldehyde Dehydrogenase genetics, Animals, Cell Line, Endothelial Cells enzymology, Endothelial Cells metabolism, Gene Expression Regulation, Neoplastic, Humans, Melanoma genetics, Mice, Nude, Neovascularization, Pathologic genetics, Tumor Cells, Cultured, Vascular Endothelial Growth Factor A analysis, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor Receptor-2 analysis, Vascular Endothelial Growth Factor Receptor-2 genetics, Aldehyde Dehydrogenase metabolism, Endothelial Cells pathology, Melanoma enzymology, Melanoma pathology, Neovascularization, Pathologic enzymology, Neovascularization, Pathologic pathology
- Abstract
Tumor blood vessels play an important role in tumor progression and metastasis. It has been reported that tumor endothelial cells (TECs) exhibit highly angiogenic phenotypes compared with those of normal endothelial cells (NECs). TECs show higher proliferative and migratory abilities than those NECs, together with upregulation of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2). Furthermore, compared with NECs, stem cell markers such as Sca-1, CD90, and multidrug resistance 1 are upregulated in TECs, suggesting that stem-like cells exist in tumor blood vessels. In this study, to reveal the biological role of stem-like TECs, we analyzed expression of the stem cell marker aldehyde dehydrogenase (ALDH) in TECs and characterized ALDHhigh TECs. TECs and NECs were isolated from melanoma-xenografted nude mice and normal dermis, respectively. ALDH mRNA expression and activity were higher in TECs than those in NECs. Next, ALDHhigh/low TECs were isolated by fluorescence-activated cell sorting to compare their characteristics. Compared with ALDHlow TECs, ALDHhigh TECs formed more tubes on Matrigel-coated plates and sustained the tubular networks longer. Furthermore, VEGFR2 expression was higher in ALDHhigh TECs than that in ALDHlow TECs. In addition, ALDH was expressed in the tumor blood vessels of in vivo mouse models of melanoma and oral carcinoma, but not in normal blood vessels. These findings indicate that ALDHhigh TECs exhibit an angiogenic phenotype. Stem-like TECs may have an essential role in tumor angiogenesis.
- Published
- 2014
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40. Suprabasin as a novel tumor endothelial cell marker.
- Author
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Alam MT, Nagao-Kitamoto H, Ohga N, Akiyama K, Maishi N, Kawamoto T, Shinohara N, Taketomi A, Shindoh M, Hida Y, and Hida K
- Subjects
- Animals, Antigens, Differentiation genetics, Biomarkers, Tumor metabolism, Cell Line, Tumor, Endothelial Cells metabolism, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Mice, Mice, Nude, Neoplasm Metastasis pathology, Neoplasm Proteins genetics, Neoplasms metabolism, Neovascularization, Pathologic metabolism, Signal Transduction, Antigens, Differentiation metabolism, Endothelial Cells pathology, Neoplasm Proteins metabolism, Neoplasms pathology
- Abstract
Recent studies have reported that stromal cells contribute to tumor progression. We previously demonstrated that tumor endothelial cells (TEC) characteristics were different from those of normal endothelial cells (NEC). Furthermore, we performed gene profile analysis in TEC and NEC, revealing that suprabasin (SBSN) was upregulated in TEC compared with NEC. However, its role in TEC is still unknown. Here we showed that SBSN expression was higher in isolated human and mouse TEC than in NEC. SBSN knockdown inhibited the migration and tube formation ability of TEC. We also showed that the AKT pathway was a downstream factor of SBSN. These findings suggest that SBSN is involved in the angiogenic potential of TEC and may be a novel TEC marker., (© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)
- Published
- 2014
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41. Ligand density at the surface of a nanoparticle and different uptake mechanism: two important factors for successful siRNA delivery to liver endothelial cells.
- Author
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Akhter A, Hayashi Y, Sakurai Y, Ohga N, Hida K, and Harashima H
- Subjects
- Cell Line, Gene Transfer Techniques, Humans, Ligands, Liposomes administration & dosage, Liposomes metabolism, Peptides administration & dosage, Peptides metabolism, Endothelial Cells metabolism, Liver metabolism, Nanoparticles administration & dosage, Nanoparticles metabolism, RNA, Small Interfering administration & dosage, RNA, Small Interfering metabolism
- Abstract
The specific delivery of a gene to liver sinusoidal endothelial cells (LSEC) could become a useful strategy for treating various liver diseases associated with such cells. We previously reported that the accumulation of KLGR peptide modified liposomes through liver sinusoidal blood vessels was enhanced after an intravenous administration. Here, we report on an attempt to develop an LSEC targeted nanocarrier system to deliver siRNA for the successful knockdown of LSEC specific gene expression. The system involved the development of a multifunctional envelop-type nano device (MEND) modified with the KLGR peptide for siRNA delivery targeting LSEC. Our developed carrier successfully lowered specific gene expression in LSEC. An in vivo study showed that at a lower density of ligand at the surface of the MEND resulted in the highest knockdown of gene expression in LSEC. This is the first report of the successful delivery of siRNA to LSECs. Further experiments suggest that not only a higher endosomal escape efficiency into the cytosol but also the uptake mechanism as a function of ligand density are two important factors to be considered for targeting LSEC., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
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42. Identification and expression of troponin T, a new marker on the surface of cultured tumor endothelial cells by aptamer ligand.
- Author
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Ara MN, Hyodo M, Ohga N, Akiyama K, Hida K, Hida Y, Shinohara N, and Harashima H
- Subjects
- Animals, Aptamers, Nucleotide chemistry, Aptamers, Peptide, Humans, Mice, SELEX Aptamer Technique, Staining and Labeling, Tumor Cells, Cultured, Biomarkers, Tumor metabolism, Endothelial Cells metabolism, Troponin T metabolism
- Abstract
The identification of a specific biomarker involves the development of new clinical diagnostic tools, and an in-depth understanding of the disease at the molecular level. When new blood vessels form in tumor cells, endothelial cell production is induced, a process that plays a key role in disease progression and metastasis to distinct organs for solid tumor types. The present study reports on the identification of a new biomarker on primary cultured mouse tumor endothelial cells (mTECs) using our recently developed high-affinity DNA aptamer AraHH001 (Kd = 43 nmol/L) assisted proteomics approach. We applied a strategy involving aptamer-facilitated biomarker discovery. Biotin-tagged AraHH001 was incubated with lysates of mTECs and the aptamer-proteins were then conjugated with streptavidin magnetic beads. Finally, the bound proteins were separated by sodiumdodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) with silver staining. We identified troponin T via matrix assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry, the molecular target of aptamer AraHH001, and its presence was confirmed by measuring mRNA, protein levels, western blot, immunostaining, a gel shift assay of AraHH001 with troponin T. We first report here on the discovery of troponin T on mTECs, a promising and interesting diagnostic tool in the development of antiangiogenic therapy techniques the involves the targeting of the tumor vasculature., (© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
- Published
- 2014
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43. An aptamer ligand based liposomal nanocarrier system that targets tumor endothelial cells.
- Author
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Ara MN, Matsuda T, Hyodo M, Sakurai Y, Hatakeyama H, Ohga N, Hida K, and Harashima H
- Subjects
- Animals, Cell Line, Tumor, Cells, Cultured, Drug Carriers chemistry, Endothelial Cells metabolism, Humans, Ligands, Liposomes chemistry, Mice, Microscopy, Confocal, Phosphatidylethanolamines chemistry, Polyethylene Glycols chemistry, Aptamers, Nucleotide chemistry, Drug Delivery Systems methods, Endothelial Cells drug effects, Nanostructures chemistry
- Abstract
The objective of this study was to construct our recently developed aptamer-modified targeted liposome nano-carrier (Apt-PEG-LPs) system to target primary cultured mouse tumor endothelial cells (mTEC), both in vitro and in vivo. We first synthesized an aptamer-polyethylene glycol 2000-distearoyl phosphoethanolamine (Apt-PEG2000-DSPE). The conjugation of the Apt-PEG2000-DSPE was confirmed by MALDI-TOF mass spectroscopy. A lipid hydration method was used to prepare Apt-PEG-LPs, in which the outer surface of the PEG-spacer was decorated with the aptamer. Apt-PEG-LPs were significantly taken up by mTECs. Cellular uptake capacity was observed both quantitatively and qualitatively using spectrofluorometry, and confocal laser scanning microscopy (CLSM), respectively. In examining the extent of localization of aptamer-modified liposomes that entered the cells, approximately 39% of the Apt-PEG-LPs were not co-localized with lysotracker, indicating that they had escaped from endosomes. The uptake route involved a receptor mediated pathway, followed by clathrin mediated endocytosis. This Apt-PEG-LP was also applied for in vivo research whether this system could target tumor endothelial cells. Apt-PEG-LP and PEG5000-DSPE modified Apt-PEG-LP (Apt/PEG5000-LP) were investigated by human renal cell carcinoma (OS-RC-2 cells) inoculating mice using CLSM. Apt-PEG-LP and Apt/PEG5000-LP showed higher accumulation on tumor vasculature compared to PEG-LP and the co-localization efficacy of Apt-PEG-LP and Apt/PEG5000-LP on TEC were quantified 16% and 25% respectively, which was also better than PEG-LP (3%). The findings suggest that this system is considerable promise for targeting tumor endothelial cells to deliver drugs or genes in vitro and in vivo., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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44. Identification of novel targets for antiangiogenic therapy by comparing the gene expressions of tumor and normal endothelial cells.
- Author
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Otsubo T, Hida Y, Ohga N, Sato H, Kai T, Matsuki Y, Takasu H, Akiyama K, Maishi N, Kawamoto T, Shinohara N, Nonomura K, and Hida K
- Subjects
- Animals, Carcinoma, Renal Cell blood supply, Cell Line, Tumor, Cell Movement, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Endothelial Cells drug effects, Endothelial Cells metabolism, Endothelial Cells pathology, Endothelium, Vascular metabolism, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Guanine Nucleotide Exchange Factors, Humans, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mice, Nude, Middle Aged, Neoplasm Transplantation, Nuclear Proteins genetics, Nuclear Proteins metabolism, Oligonucleotide Array Sequence Analysis, RNA Interference, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Up-Regulation, Angiogenesis Inhibitors therapeutic use, Biomarkers, Tumor genetics, Endothelium, Vascular pathology, Neovascularization, Pathologic drug therapy, Neovascularization, Pathologic genetics
- Abstract
Targeting tumor angiogenesis is an established strategy for cancer therapy. Because angiogenesis is not limited to pathological conditions such as cancer, molecular markers that can distinguish between physiological and pathological angiogenesis are required to develop more effective and safer approaches for cancer treatment. To identify such molecules, we determined the gene expression profiles of murine tumor endothelial cells (mTEC) and murine normal endothelial cells using DNA microarray analysis followed by quantitative reverse transcription-polymerase chain reaction analysis. We identified 131 genes that were differentially upregulated in mTEC. Functional analysis using siRNA-mediated gene silencing revealed five novel tumor endothelial cell markers that were involved in the proliferation or migration of mTEC. The expression of DEF6 and TMEM176B was upregulated in tumor vessels of human renal cell carcinoma specimens, suggesting that they are potential targets for antiangiogenic intervention for renal cell carcinoma. Comparative gene expression analysis revealed molecular differences between tumor endothelial cells and normal endothelial cells and identified novel tumor endothelial cell markers that may be exploited to target tumor angiogenesis for cancer treatment., (© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)
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- 2014
- Full Text
- View/download PDF
45. RNAi-mediated gene knockdown and anti-angiogenic therapy of RCCs using a cyclic RGD-modified liposomal-siRNA system.
- Author
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Sakurai Y, Hatakeyama H, Sato Y, Hyodo M, Akita H, Ohga N, Hida K, and Harashima H
- Subjects
- Animals, Drug Delivery Systems, HEK293 Cells, Human Umbilical Vein Endothelial Cells, Humans, Lipids chemistry, Liposomes metabolism, Male, Mice, Mice, Inbred BALB C, Neoplasms blood supply, Neoplasms genetics, Neoplasms pathology, Neovascularization, Pathologic genetics, Neovascularization, Pathologic pathology, Peptides, Cyclic metabolism, Piperidines chemistry, Piperidines metabolism, RNA, Small Interfering genetics, RNA, Small Interfering therapeutic use, Liposomes chemistry, Neoplasms therapy, Neovascularization, Pathologic therapy, Peptides, Cyclic chemistry, RNA Interference, RNA, Small Interfering administration & dosage, Vascular Endothelial Growth Factor Receptor-2 genetics
- Abstract
Angiogenesis is one of crucial processes associated with tumor growth and development, and consequently a prime target for cancer therapy. Although tumor endothelial cells (TECs) play a key role in pathological angiogenesis, investigating phenotypical changes in neovessels when a gene expression in TEC is suppressed is a difficult task. Small interfering RNA (siRNA) represents a potential agent due to its ability to silence a gene of interest. We previously developed a system for in vivo siRNA delivery to cancer cells that involves a liposomal-delivery system, a MEND that contains a unique pH-sensitive cationic lipid, YSK05 (YSK-MEND). In the present study, we report on the development of a system that permits the delivery of siRNA to TECs by combining the YSK-MEND and a ligand that is specific to TECs. Cyclo(Arg-Gly-Asp-D-Phe-Lys) (cRGD) is a well-known ligand to αVβ3 integrin, which is selectively expressed at high levels in TECs. We incorporated cRGD into the YSK-MEND (RGD-MEND) to achieve an efficient gene silencing in TECs. Quantitative RT-PCR and the 5' rapid amplification of cDNA ends PCR indicated that the intravenous injection of RGD-MEND at a dose of 4.0mg/kg induced a significant RNAi-mediated gene reduction in TEC but not in endothelial cells of other organs. Finally, we evaluated the therapeutic potency of the RGD-MEND encapsulating siRNA against vascular endothelial growth factor receptor 2. A substantial delay in tumor growth was observed after three sequential RGD-MEND injections on alternate days. In conclusion, the RGD-MEND represents a new approach for the characterization of TECs and for us in anti-angiogenic therapy., (© 2013.)
- Published
- 2014
- Full Text
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46. Construction of an aptamer modified liposomal system targeted to tumor endothelial cells.
- Author
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Ara MN, Matsuda T, Hyodo M, Sakurai Y, Ohga N, Hida K, and Harashima H
- Subjects
- Animals, Aptamers, Nucleotide chemistry, Cell Line, Tumor, Cells, Cultured, Humans, Liposomes, Lysosomes metabolism, Maleimides chemistry, Mice, Mice, Nude, NIH 3T3 Cells, Nanoparticles, Phosphatidylethanolamines chemistry, Polyethylene Glycols chemistry, Proteomics, Skin cytology, Aptamers, Nucleotide administration & dosage, Endothelial Cells metabolism, HSP70 Heat-Shock Proteins metabolism, Neoplasms metabolism
- Abstract
We describe herein the development of a high affinity and specific DNA aptamer as a new ligand for use in liposomal nanoparticles to target cultured mouse tumor endothelial cells (mTECs). Active targeted nanotechnology based drug delivery systems are currently of great interest, due to their potential for reducing side effects and facilitating the delivery of cytotoxic drugs or genes in a site specific manner. In this study, we report on a promising aptamer candidate AraHH036 that shows selective binding towards mTECs. The aptamer does not bind to normal cells, normal endothelial cells or tumor cells. Therefore, we synthesized an aptamer-polyethylene glycol (PEG) lipid conjugate and prepared aptamer based liposomes (ALPs) by the standard lipid hydration method. First, we quantified the higher capacity of ALPs to internalize into mTECs by incubating ALPs containing 1 mol%, 5 mol% and 10 mol% aptamer of total lipids and compared the results to those for unmodified PEGylated liposomes (PLPs). A confocal laser scanning microscope (CLSM) uptake study indicated that the ALPs were taken up more efficiently than PLPs. The measured Kd value of the ALPs was 142 nM. An intracellular trafficking study confirmed that most of the rhodamine labeled ALPs were taken up and co-localized with the green lysotracker, thus confirming that they were located in lysosomes. Finally, using an aptamer based proteomics approach, the molecular target protein of the aptamer was identified as heat shock protein 70 (HSP70). The results suggest that these ALPs offer promise as a new carrier molecule for delivering anti-angiogenesis drugs to tumor vasculature.
- Published
- 2014
- Full Text
- View/download PDF
47. Hypoxia-induced reactive oxygen species cause chromosomal abnormalities in endothelial cells in the tumor microenvironment.
- Author
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Kondoh M, Ohga N, Akiyama K, Hida Y, Maishi N, Towfik AM, Inoue N, Shindoh M, and Hida K
- Subjects
- Animals, Cell Cycle genetics, Humans, Hypoxia metabolism, Hypoxia-Inducible Factor 1 metabolism, Karyotype, Mice, Tumor Cells, Cultured, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor Receptor-2 metabolism, Chromosome Aberrations, Chromosomes, Human, Pair 17 genetics, Endothelial Cells metabolism, Hypoxia physiopathology, Reactive Oxygen Species metabolism, Tumor Microenvironment genetics
- Abstract
There is much evidence that hypoxia in the tumor microenvironment enhances tumor progression. In an earlier study, we reported abnormal phenotypes of tumor-associated endothelial cells such as those resistant to chemotherapy and chromosomal instability. Here we investigated the role of hypoxia in the acquisition of chromosomal abnormalities in endothelial cells. Tumor-associated endothelial cells isolated from human tumor xenografts showed chromosomal abnormalities, >30% of which were aneuploidy. Aneuploidy of the tumor-associated endothelial cells was also shown by simultaneous in-situ hybridization for chromosome 17 and by immunohistochemistry with anti-CD31 antibody for endothelial staining. The aneuploid cells were surrounded by a pimonidazole-positive area, indicating hypoxia. Human microvascular endothelial cells expressed hypoxia-inducible factor 1 and vascular endothelial growth factor A in response to either hypoxia or hypoxia-reoxygenation, and in these conditions, they acquired aneuploidy in 7 days. Induction of aneuploidy was inhibited by either inhibition of vascular endothelial growth factor signaling with vascular endothelial growth factor receptor 2 inhibitor or by inhibition of reactive oxygen species by N-acetyl-L-cysteine. These results indicate that hypoxia induces chromosomal abnormalities in endothelial cells through the induction of reactive oxygen species and excess signaling of vascular endothelial growth factor in the tumor microenvironment.
- Published
- 2013
- Full Text
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48. A liposomal delivery system that targets liver endothelial cells based on a new peptide motif present in the ApoB-100 sequence.
- Author
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Akhter A, Hayashi Y, Sakurai Y, Ohga N, Hida K, and Harashima H
- Subjects
- Animals, Cell Line, Tumor, Female, Liposomes, Liver metabolism, Lung metabolism, Male, Maleimides chemistry, Mice, Mice, Inbred ICR, Oligopeptides chemistry, Oligopeptides pharmacokinetics, Phosphatidylethanolamines chemistry, Polyethylene Glycols chemistry, Spleen metabolism, Apolipoprotein B-100 chemistry, Endothelial Cells metabolism, Liver cytology, Oligopeptides administration & dosage
- Abstract
Liver dysfunction is associated with a variety of liver diseases, including viral or alcoholic hepatitis, fibrosis, cirrhosis, and portal hypertension. A targeted drug delivery system would be very useful in the treatment of these diseases. We herein describe the development of a system comprised of a new peptide-lipid conjugate for the efficient delivery of molecules to LEC. The RLTRKRGLK sequence (3359-3367), which mediates the association of LDL with arterial CSPG and an LDL receptor, was utilized as a ligand for achieving this goal. The peptide modified PEG-LPs (RLTR-PEG-LPs) were efficiently taken up by primary liver endothelial cells (liver ECs) and other types of cells. In vivo biodistribution and confocal microscopy analysis showed that RLTR-PEG-LPs became widely accumulated in LECs within a short time. Distribution of RLTR-PEG-LPs was greatly reduced with a pretreatment of unlabeled RLTR-PEG-LPs, not cationic LPs, indicating that the sequence is important for LECs. The findings indicate that a reverse sequence of RLTR (KLGR) modified PEG-LPs (KLGR-PEG-LP) did the same pattern compared with RLTR-PEG-LPs, suggesting that the RKR or RXXR sequence might be essential for LECs targeting. Collectively RLTR-PEG-LPs and KLGR-PEG-LPs have the potential for delivering drugs to LECs., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
49. Heterogeneity of tumor endothelial cells.
- Author
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Hida K, Ohga N, Akiyama K, Maishi N, and Hida Y
- Subjects
- Angiogenesis Inhibitors pharmacology, Animals, Cell Shape, Drug Resistance, Neoplasm, Endothelial Cells drug effects, Endothelial Cells physiology, Endothelium, Vascular drug effects, Endothelium, Vascular physiopathology, Humans, Neoplasms blood supply, Neoplasms drug therapy, Neovascularization, Pathologic, Phenotype, Endothelium, Vascular pathology, Neoplasms pathology
- Abstract
Tumor blood vessels play important roles in tumor progression and metastasis. Thus, targeting tumor blood vessels is an important strategy for cancer therapy. Tumor endothelial cells (TECs) are the main targets of anti-angiogenic therapy. Although tumor blood vessels generally sprout from pre-existing vessels and have been thought to be genetically normal, they display a markedly abnormal phenotype, including morphological changes. The degree of angiogenesis is determined by the balance between the positive and negative regulating molecules that are released by tumor and host cells in the microenvironment. Reportedly, tumor blood vessels are heterogeneous with TECs differing from normal endothelial cells (in contrast to the conventional view). We recently compared characteristics of different TECs isolated from highly and low metastatic tumors. We found TECs from highly metastatic tumors had more proangiogenic phenotypes than those from low metastatic tumors. Elucidating the variety of TEC phenotypes and identifying TEC molecular signatures should lead to more complete understanding of the mechanisms of tumor progression, discovery of new therapeutic targets, and development of biomarkers. This review considers current studies on TEC heterogeneity and discusses the therapeutic implications of these findings., (© 2013 Japanese Cancer Association.)
- Published
- 2013
- Full Text
- View/download PDF
50. Application of POLARIC™ fluorophores in an in vivo tumor model.
- Author
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Maishi N, Kawamoto T, Ohga N, Yamada K, Akiyama K, Yamamoto K, Osawa T, Hida Y, and Hida K
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation, Female, Humans, Lung Neoplasms diagnosis, Lung Neoplasms secondary, Melanoma diagnosis, Mice, Mice, Inbred BALB C, Mice, Nude, Xenograft Model Antitumor Assays, Fluorescent Dyes, Lung Neoplasms metabolism, Melanoma metabolism, Staining and Labeling methods, Whole Body Imaging methods
- Abstract
Fluorescent and luminescent tools are commonly used to study the dynamics of cancer progression and metastases in real-time. Fluorophores have become essential tools to study biological events. However, few can sustain fluorescence long enough during long-term studies. In the present study, we focused on a series of new amphiphilic fluorophores known as POLARIC™, which emit strong fluorescence in lipid bilayers and can be readily modified using the Suzuki-Miyaura cross-coupling reaction. Appropriate chemical modifications of substituent groups can improve target-site specificity, reduce cytotoxicity and prolong emission. Therefore, in contrast to conventional fluorescent probes, these fluorophores show promise for long-term monitoring of biological processes. In the present study, we conducted long-term observations of tumor growth and metastasis using a POLARIC derivative as a novel fluorescent probe. For this purpose, we studied the metastatic melanoma cell line A375-SM, which proliferates at a high rate. We compared the characteristics of the POLARIC probe with the commercially available fluorescent dye PKH26 and fluorescent protein mRFP1. A375-SM cells were labeled with these fluorescent probes and orthotopically implanted into nude mice. The fluorescence emitted by POLARIC was detected more than five weeks after implantation without causing detectable harmful effects on tumor growth. By contrast, fluorescence of cells labeled with PKH26 could not be detected at this same time. Furthermore, POLARIC-, but not PKH26-labeled cells, were also detected in lung metastases. These results indicate that labeling cells with POLARIC fluorophores can significantly extend the time course of in vivo studies on tumor cell growth.
- Published
- 2013
- Full Text
- View/download PDF
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