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論文

Prognostic significance of amino-acid transporter expression (LAT1, ASCT2, and xCT) in surgically resected tongue cancer

豊田 実*; 解良 恭一*; 大島 康宏; 石岡 典子; 紫野 正人*; 坂倉 浩一*; 高安 幸弘*; 高橋 克昌*; 富永 英之*; 織内 昇*; et al.

British Journal of Cancer, 110(10), p.2506 - 2513, 2014/05

 被引用回数:89 パーセンタイル:95.79(Oncology)

Amino-acid transporters are necessary for the tumor cell growth and survival, and play a crucial role in the development of cancer. But, it remains unclear about the prognostic significance of L-type amino acid transporter 1 (LAT1), System ASC amino acid transporter 2 (ASCT2) and xCT expression in patients with tongue cancer. We conducted the clinicopathological study to investigate the protein expression of these amino acid transporters in tongue cancer. Eighty-five patients with surgically resected tongue cancer were evaluated. Tumor sections were stained by immunohistochemistry for LAT1, ASCT2, xCT, CD98, Ki-67, CD34 and p53. The expression of LAT1 and ASCT2 was significantly associated with disease staging, lymph node metastasis, lymphatic permeation, vascular invasion, CD98 expression and cell proliferation (Ki-67). xCT expression indicated a significant association with advanced stage and tumor factor, correlated with CD98. By univariate analysis, both LAT1 and ASCT2 had a significant relationship with prognosis. Multivariate analysis confirmed that LAT1 were independent prognostic factors for predicting poor prognosis. These results suggest that LAT1 and ASCT2 can serve as a significant prognostic factor for predicting worse outcome after surgical treatment and may play an important role in the development and pathogenesis for tongue cancer.

論文

Biological significance of fluorine-18-$$alpha$$-methyltyrosine (FAMT) uptake on PET in patients with oesophageal cancer

鈴木 茂正*; 解良 恭一*; 大島 康宏; 石岡 典子; 宗田 真*; 横堀 武彦*; 宮崎 達也*; 織内 昇*; 富永 英之*; 金井 好克*; et al.

British Journal of Cancer, 110(8), p.1985 - 1991, 2014/04

 被引用回数:20 パーセンタイル:61.85(Oncology)

Fluorine-18-$$alpha$$-methyltyrosine (FAMT) as an amino acid tracer for positron emission tomography (PET) is useful for detecting human neoplasms. FAMT is accumulated in tumor cells solely via L-type amino acid transporter 1 (LAT1). This study was conducted to investigate the biological significance of FAMT uptake in patients with esophageal cancer. From April 2008 to December 2011, 42 patients with esophageal cancer underwent both FAMT PET and FDG PET before surgical treatment. The immunohistochemical analysis of LAT1, CD98, Ki-67, CD34, p53, p-Akt and p-mTOR was performed on the primary lesions. ${it In vitro}$ experiments were performed to examine the mechanism of FAMT uptake using LAT1 inhibitor, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH). High uptake of FAMT was significantly associated with advanced stage, lymph node metastasis and the expression of LAT1, CD98, Ki-67 and CD34. LAT1 expression yielded a statistically significant correlation with CD98 expression, cell proliferation, angiogenesis and glucose metabolism. ${it In vitro}$ experiments revealed that FAMT was specifically transported by LAT1. The uptake of FAMT within tumor cells is determined by the LAT1 expression and correlated with cell proliferation and angiogenesis in esophageal cancer. The present experiments also confirmed the presence of LAT1 as an underlying mechanism of FAMT accumulation.

論文

Clinical significance of L-type amino acid transporter 1 expression as a prognostic marker and potential of new targeting therapy in biliary tract cancer

解良 恭一*; 須納瀬 豊*; 大島 康宏; 石岡 典子; 荒川 和久*; 小川 哲史*; 砂長 則明*; 清水 公裕*; 富永 英之*; 織内 昇*; et al.

BMC Cancer, 13, p.482_1 - 482_12, 2013/10

 被引用回数:51 パーセンタイル:85.76(Oncology)

The expression of L-type amino acid transporter 1 (LAT1) has been described to play essential roles in tumor growth and survival. However, it remains unclear about the clinicopathological significance of LAT1 expression in biliary tract cancer. This study was conducted to determine clinical significance of LAT1 expression and investigate whether LAT1 could be a new therapeutic target for biliary tract cancer. A total of 139 consecutive patients with resected pathologic stage I-IV biliary tract adenocarcinoma were retrospectively reviewed. Tumor sections were stained by immunohistochemistry for LAT1, CD98, Ki-67, microvessel density determined by CD34 and p53. Further, anti-tumor activity of LAT inhibitor, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) was investigated using cholangiocarcinoma cell line. The expression of LAT1 was recognized in 64% of total patients, and closely correlated with CD98 expression, lymphatic metastases, cell proliferation and angiogenesis, and was a significant indicator for predicting poor outcome after surgery. Experiments showed that BCH significantly suppressed the tumor growth and BCH yielded an additive therapeutic efficacy to gemcitabine and 5-FU. A cooperative high expression of LAT1 with CD98 is a promising pathological marker to predict the outcome in biliary tract adenocarcinoma. Inhibition of LAT1 may be an effective targeted therapy for this distressing disease.

論文

Biological evaluation of 3-[$$^{18}$$F]fluoro-$$alpha$$-methyl-D-tyrosine (D-[$$^{18}$$F]FAMT) as a novel amino acid tracer for positron emission tomography

大島 康宏; 花岡 宏史*; 富永 英之*; 金井 好克*; 解良 恭一*; 山口 藍子*; 永森 收志*; 織内 昇*; 対馬 義人*; 遠藤 啓吾*; et al.

Annals of Nuclear Medicine, 27(4), p.314 - 324, 2013/05

 被引用回数:13 パーセンタイル:51.48(Radiology, Nuclear Medicine & Medical Imaging)

Since D-amino acid is not distributed much in the non-target organs and is rapidly excreted in the urine, radiotracer using D-amino acid would allow clear PET image of the tumor early after administration. In this study, we prepared 3-[$$^{18}$$F]fluoro-$$alpha$$-methyl-D-tyrosine (D-[$$^{18}$$F]FAMT) and evaluated its usefulness. In biodistribution studies, D-[$$^{18}$$F]FAMT showed rapid clearance from the blood, marked accumulation and retention in the tumor and low accumulation in non-target organs. The amount of D-[$$^{18}$$F]FAMT in the tumor was also lowered, tumor-to-blood ratio and tumor-to-muscle ratio of D-[$$^{18}$$F]FAMT were similar to those of correspondign L-isomer, 3-[$$^{18}$$F]fluoro-$$alpha$$-methyl-L-tyrosine (L-[$$^{18}$$F]FAMT), at every timepoint. Consequently, PET imaging with D-[$$^{18}$$F]FAMT could not show clear image of the tumor early after the administration. However, D-[$$^{18}$$F]FAMT enabled higher tumor-to-background contrast than L-[$$^{18}$$F]FAMT. In conclusions, D-[$$^{18}$$F]FAMT showed rapid blood clearance, low accumulation in non-target organs, and tumor-selective image compared with L-[$$^{18}$$F]FAMT. Thus, D-[$$^{18}$$F]FAMT could potentially serve as a novel PET tracer for imaging malignant tumors.

口頭

3-[$$^{18}$$F]fluoro-$$alpha$$-methyl-D-tyrosine(D-[$$^{18}$$F]FAMT)のPET用新規アミノ酸トレーサーとしての生物学的評価

大島 康宏; 花岡 宏史*; 富永 英之*; 金井 好克*; 解良 恭一*; 山口 藍子*; 永森 收志*; 織内 昇*; 対馬 義人*; 遠藤 啓吾*; et al.

no journal, , 

3-[$$^{18}$$F]Fluoro-$$alpha$$-methyl-L-tyrosine(L-[$$^{18}$$F]FAMT)は臨床応用される有用なPositron Emission Tomography(PET)用アミノ酸トレーサーであるが、正常組織である腎臓及び膵臓に対しても高度に集積・滞留する。一方で、非天然アミノ酸であるD体アミノ酸は、L体に比べ正常組織への分布が非常に低く、速やかな血液クリアランス及び癌組織集積性を示すことから、D体アミノ酸を利用することで明瞭かつ癌組織選択的なPETイメージングを実現できる可能性がある。そこで、本研究では3-[$$^{18}$$F]fluoro-$$alpha$$-methyl-D-tyrosine(D-[$$^{18}$$F]FAMT)を合成し、PET用アミノ酸トレーサーとしての有用性について検討した。体内分布実験の結果、D-[$$^{18}$$F]FAMTは非常に早い血液クリアランスを示し、投与直後に腎臓,膵臓への集積が認められたが、L-[$$^{18}$$F]FAMTのような滞留は認められず、速やかに消失した。また、D-[$$^{18}$$F]FAMTの癌組織集積量はL-[$$^{18}$$F]FAMTに比べて低かったが、正常組織分布も非常に低く、放射能の腫瘍血液比,腫瘍筋肉比はL-[$$^{18}$$F]FAMTと同等な高値を示した。さらにPETイメージングの結果、D-[$$^{18}$$F]FAMTによってL-[$$^{18}$$F]FAMTに比べて明瞭かつ癌組織選択的なPETイメージングが可能であることが示された。以上の結果より、D-[$$^{18}$$F]FAMTがPET用新規アミノ酸トレーサーとして有用であることが示唆された。

口頭

Biological evaluation of 3-[$$^{18}$$F]fluoro-$$alpha$$-methyl-D-tyrosine (D-[$$^{18}$$F]FAMT) as a novel amino acid tracer for positron emission tomography

大島 康宏; 花岡 宏史*; 富永 英之*; 金井 好克*; 解良 恭一*; 山口 藍子*; 永森 收志*; 織内 昇*; 対馬 義人*; 遠藤 啓吾*; et al.

no journal, , 

3-[$$^{18}$$F]Fluoro-$$alpha$$-methyl-L-tyrosine (L-[$$^{18}$$F]FAMT) is a useful amino acid tracer, and it is selectively accumulated in the tumor without an incorporation in the protein synthesis. However, L-[$$^{18}$$F]FAMT is highly retained in the kidney, which causes the reduction of sensitivity for tumor detection by positron emission tomography (PET). L-amino acids have corresponding D-isomers which have some favorable properties for development of PET tracers. Since mammals rarely use D-amino acids for their biological activity, D-amino acids would not be taken up by the normal tissues. In addition, D-amino acids are highly excreted in the urine compared with L-isomers, and rapidly cleared from the circulation. Thus, D-isomer of FAMT would lower the high retention of L-isomer in the kidney and allow clear imaging of the tumor by PET. In this study, we synthesized 3-[$$^{18}$$F]fluoro-$$alpha$$-methyl-D-tyrosine (D-[$$^{18}$$F]FAMT) and evaluated its potential. In biodistribution studies, D-[$$^{18}$$F]FAMT showed rapid clearance from blood, marked accumulation and retention in the tumor and low retention in non-target organs, especially kidney. Furthermore, PET imaging using D-[$$^{18}$$F]FAMT enabled clear visualization of implanted tumor, compared with L-[$$^{18}$$F]FAMT. In conclusion, D-[$$^{18}$$F]FAMT could potentially serve as a useful tracer for imaging malignant tumors.

口頭

Efficacy of in-air microanalysis of particles in interstitial pneumonia lung tissue

古賀 康彦*; 解良 恭一*; 山田 正信*; 土橋 邦生*; 松崎 晋一*; 久田 剛志*; 江夏 昌志; 山田 尚人; 佐藤 隆博; 横山 彰人; et al.

no journal, , 

The aim of this study was to assess the utility of in-air micro-PIXE (particle induced X-ray emission) analysis for lung biopsy specimens of patients with occupational dust exposure. Some patients with evidence of interstitial pneumonia (IP) on computed tomography were enrolled in this study. Lung specimens were obtained by transbronchial lung biopsy (TBLB) at bronchofiberscopy or video-assisted thoracic surgery (VATS). These samples were measured with the in-air micro-PIXE analyzer at TIARA after freeze-drying. As a result, it was revealed that the elemental distributions in tiny particles in the lung tissues varied widely among those patient specimens. For example, aluminum was detected in a lung specimen of a patient working at aluminum plant. Therefore, elemental analysis of lung specimens by in-air micro PIXE is useful for the biopsy of dust-exposed patients.

口頭

Clinical significance of l-type amino acid transporter 1 expression as a prognostic marker and potential of new targeting therapy in tongue cancer

解良 恭一*; 豊田 実*; 大島 康宏; 織内 昇*; 金井 好克*; 小山 徹也*; 山田 正信*; 浅尾 高行*; 近松 一朗*

no journal, , 

This study was conducted to determine biological significance of L-type amino acid transporter 1 (LAT1) expression and investigate whether LAT1 could be a prognostic biomarker for tongue cancer. Eighty-five patients with surgically resected tongue cancer were evaluated. Tumor sections were stained by immunohistochemistry for LAT1, ASCT2, xCT, CD98, CD147, Ki-67, microvessel density determined by CD34, and p53. Biological significance of LAT1 expression was investigated by ${it in vitro}$ experiments with LAT inhibitor, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) using tongue cell line. LAT1, ASCT2, xCT, CD98 and CD147 were highly expressed in 61%, 59%, 21%, 45% and 33%, respectively. The expression of LAT1 was significantly associated with disease staging, lymph node metastasis, lymphatic permeation, cell proliferation (Ki-67), and the expression level of CD98, ASCT2 and CD147 as amino acid transporter complexes. Multivariate analysis confirmed that LAT1 was an independent prognostic factor for predicting poor prognosis. ${it In vitro}$ preliminary experiment indicated that BCH significantly suppressed growth of the tumor and yielded an additive therapeutic efficacy to cisplatin. These rusults suggests that LAT1 can serve as a promising pathological marker to predict the outcome in patients with tongue cancer. Inhibition of LAT1 may be an effective targeted therapy for this distressing disease.

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