Research Areas 【 display / non-display 】

Research Areas 【 display / non-display 】

• Life sciences   Gastroenterology  

Papers 【 display / non-display 】

Papers 【 display / non-display 】

• Efficient implementation of hepatitis B surface antigen confirmatory neutralization tests.

  Hitoshi Yonezawa, Shingo Tanaka, Makito Tanaka, Ryo Kobayashi, Satoshi Takahashi

  Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   30 ( 1 ) 29 - 33  2024.01  [International journal]

  　View Summary

  INTRODUCTION: To prevent misreporting of false positives in the hepatitis B surface antigen (HBsAg) assay, it is recommended to confirm the low-positive cases with neutralization tests. However, currently not many facilities are implementing this due to the additional cost. The aim of this study was to clarify the risk factors for false positives in the high-sensitivity HBsAg quantitative tests to reduce the neutralization tests. METHODS: In this retrospective cohort study, we analyzed 47,305 patients who had their HBsAg value measured at Sapporo Medical University Hospital between November 2016 and March 2022. The patients eligible for the neutralization tests were those with HBsAg values between 0.005 and 1.000, even after reexamination by high-speed centrifugation. RESULTS: HBsAg quantitative tests were performed in 71,475 tests. Of these, 817 tests and 376 patients were subjected to neutralization tests. Of the patients who met the criteria, 329 were included in this study. Fifty-seven cases (17%) had negative results in the neutralization tests, suggesting false positives for the HBsAg assay. Multivariate analysis showed that younger age (adjusted odds ratio [aOR] 6.57), female sex (aOR 2.32), lower HBsAg values (aOR 59.6), and reagent improvement (aOR 2.06) were independent risk factors for false positives. The false-positive rate was actually high at 33.1% in the HBsAg range of 0.005-0.049 IU/mL and at 1.2% in the range above 0.050 IU/mL. CONCLUSIONS: Confirmatory neutralization tests should be performed at least in the range of 0.005-0.049 IU/mL where quantification is possible with a higher-sensitivity assay.

  DOI PubMed

• Synergistic antitumor effect of histone deacetylase class IIa inhibitor with lenvatinib in hepatocellular carcinoma.

  Ryo Ito, Koji Miyanishi, Tomohiro Kubo, Kota Hamaguchi, Takahiro Osuga, Shingo Tanaka, Hiroyuki Ohnuma, Kazuyuki Murase, Kohichi Takada, Minoru Nagayama, Yasutoshi Kimura, Toru Mizuguchi, Ichiro Takemasa, Junji Kato

  Hepatology international   17 ( 3 ) 735 - 744  2023.06  [International journal]

  　View Summary

  BACKGROUND: Histone deacetylase (HDAC) class I and IIa are highly expressed in hepatocellular carcinoma (HCC) and associated with decreased survival. However, clinically used pan and class I inhibitors have serious adverse events. In this study, we assessed the antitumor effects and tolerability of class IIa HDAC inhibitor (HDACI) with lenvatinib, which is a standard therapy for HCC. METHODS AND RESULT: Combination therapy with class IIa HDACI and lenvatinib exerted synergistic antitumor effect in human HCC cell lines. In mouse models, this therapy showed significant antitumor effects, and few adverse events occurred. In immunoblotting, the expression of fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) was high in cell lines that showed a high antitumor effect. In addition, class IIa HDACI administration decreased the expression of FGFR4. In the small interfering RNA (siRNA) analysis, knockdown of HDAC9, which is an isoform of HDAC class IIa, reduced the expression of FGFR4 and induced apoptosis. Immunohistochemistry of human clinical specimens showed a positivity rate of 32% for FGFR4 and 84% for HDAC9 in HCC, and all FGFR4-positive patients were HDAC9 positive. CONCLUSION: Class IIa HDACI and lenvatinib combination therapy induces apoptosis by downregulating FGFR4 and blocking the FGFR signaling in FGFR4-positive HCC cell lines and has demonstrated synergistic antitumor effects and safety. This combination therapy overcomes the problems of conventional therapies and will be beneficial for FGFR4-positive HCC patients.

  DOI PubMed

• Effect of albumin measurement methods on the albumin-bilirubin grade.

  Makito Tanaka, Shingo Tanaka, Ema Suzuki, Ryo Kobayashi, Satoshi Takahashi

  Annals of clinical biochemistry   60 ( 2 ) 100 - 108  2023.03  [International journal]

  　View Summary

  BACKGROUND: Albumin-bilirubin (ALBI) grade is an index of liver function based on total bilirubin (T-BIL) and albumin levels, and its usefulness has been widely reported. This study aimed to investigate the effect of different methods of measuring T-BIL and albumin levels on the ALBI grade in patients with liver disease. METHODS: In total, 170 patients from our hospital were included in this study. Correlations between T-BIL levels measured using the vanadate oxidation and enzymatic methods were analysed. Similarly, a correlation analysis of albumin levels between the bromocresol green (BCG) and modified bromocresol purple (BCP) methods was performed. Additionally, the ALBI grade was calculated for patients with liver disease, and the differences between each method of albumin measurement were compared. RESULTS: No differences were observed in the measured T-BIL values between the two methods. Contrastingly, the albumin levels of 100 random samples and 70 liver disease patients obtained using the modified BCP method were significantly lower than those measured using the BCG method. The rate of change in the modified ALBI grade between the BCG and BCP methods was 25.7%. CONCLUSIONS: Caution should be taken when comparing ALBI grades with those measured by other facilities because the method of albumin measurement can affect the ALBI grade. Standardization of albumin measurement is needed worldwide.

  DOI PubMed

• 卒前腹部超音波検査実習における「腹部超音波検診判定マニュアル」の有用性について

  田中 信悟, 高橋 聡, 加藤 淳二

  日本臨床検査医学会誌 ( (一社)日本臨床検査医学会 )  70 ( 5 ) 369 - 372  2022.05

  　View Summary

  腹部超音波検査実習の学習資料として、マニュアルの有用性について検討した。選択臨床実習で当講座を選択し、腹部超音波検査実習を行った医学部6年生12名を対象とした。マニュアルの記録断面例5断面の描出による実技試験(5点満点)については5点が11名、4点が1名、病変画像5枚についての口頭試問(5点満点)は5点が7名、4点が5名であった。アンケート調査結果について、記録断面例の描出では右肋間走査での胆嚢・肝臓の描出および膵の描出で習熟度がやや低い傾向を認めたが、他部位の描出の習熟度はおおむね良好であった。マニュアル実施基準の理解度は平均3.8点、12名中11名が学習資料としてマニュアルは適切であるとの意見であった。マニュアルを学習資料とした腹部超音波検査実習により基本的走査法のみならず、医学生として十分な基礎的知識が得られたと考えられた。

• Association between Hepatic Oxidative Stress Related Factors and Activation of Wnt/β-Catenin Signaling in NAFLD-Induced Hepatocellular Carcinoma.

  Kota Hamaguchi, Koji Miyanishi, Takahiro Osuga, Shingo Tanaka, Ryo Ito, Hiroki Sakamoto, Tomohiro Kubo, Hiroyuki Ohnuma, Kazuyuki Murase, Kohichi Takada, Minoru Nagayama, Yasutoshi Kimura, Toru Mizuguchi, Ichiro Takemasa, Junji Kato

  Cancers   14 ( 9 )  2022.04  [International journal]

  　View Summary

  We investigated the association between iron overload, oxidative stress (8-oxo-7,8-dihydroguanine: 8-oxo-dG scores), Wnt/β-catenin pathway activation (expression of glutamine synthetase: GS), and tumor hyperintensity in the Gd-EOB-DTPA-enhanced MRI hepatobiliary phase (relative enhancement ratio: RER). This was a retrospective analysis of 94 hepatocellular carcinoma (HCC) patients who underwent surgical resection. In HBV-, HCV-, and alcohol-associated HCC, serum ferritin levels in the high and low RER groups were equivalent. In contrast, ferritin levels were elevated in the 'high RER' group of patients with nonalcoholic fatty liver disease (NAFLD)-HCC. As predictors of GS positivity, high RER had a sensitivity of 57.2% and a specificity of 100%. High serum ferritin had a sensitivity of 85.7% and a specificity of 85.7%. All cases with serum ferritin ≥275.5 ng/mL and high RER were 8-oxo-dG- and iron staining-positive. Additionally, GS positivity was seen in all cases with "serum ferritin levels above the upper limits or iron staining-positive" and '8-oxo-dG high' cases. Therefore, combining serum ferritin levels with RER may increase the accuracy with which activated Wnt/β-catenin signaling is predicted in NAFLD-HCC. We suggest that 8-oxo-dG accumulates following increased oxidative stress due to hepatic tissue iron deposition; this may activate Wnt/β-catenin signaling and trigger carcinogenesis.

  DOI PubMed

display all >>

Misc 【 display / non-display 】

Misc 【 display / non-display 】

• 【超音波ルーチン検査の実際-With SMI、そしてWith ATIの時代-】(第二部)With ATI Attenuation Imagingから始まる脂肪肝診療 当院検査部での取り組みについて

  田中 信悟, 大場 騰, 阿部 記代士, 田本 悠佳, 安井 謙司, 大久保 亜友美, 小林 千紘, 齋藤 和, 淺沼 康一, 宮西 浩嗣, 高橋 聡, 加藤 淳二

  映像情報Medical ( 産業開発機構(株) )  54 ( 5 ) 45 - 49  2022.05

• 【鉄と肝がん:肝胆相照らす】肝疾患における肝内鉄蓄積 非アルコール性脂肪肝炎 鉄吸収亢進の観点から

  田中 信悟, 宮西 浩嗣, 加藤 淳二

  肝胆膵 ( (株)アークメディア )  84 ( 4 ) 459 - 464  2022.04

• 【Helicobacter pylori除菌による胃がん予防の国際的潮流】 ラテンアメリカにおけるHelicobacter pylori除菌による胃がん予防

  田中 信悟, 山岡 吉生

  Helicobacter Research ( (株)先端医学社 )  21 ( 4 ) 363 - 369  2017.08

  　View Summary

  ラテンアメリカ各地域の成人Helicobacter pylori感染率は概ね50%を超え、70%を超える地域も数多く存在する。小児では各地域で感染率に大きな差を認め、衛生状況の比較的良い地域での感染率は低下傾向である。ラテンアメリカにおいてH.pyloriの診断・除菌を中心とした胃がんの一次予防が導入されている国はなく、早期胃がん発見目的の二次予防についても大規模なものはチリでおこなわれているのみである。今後、とくに若年者のH.pylori感染率が高く、胃がん発症率が高い国において一次予防が重要と考えられる。それらの国に対して、世界で唯一保険診療により除菌治療がおこなわれているわが国の経験・知識が貢献できるものと思われる。(著者抄録)

• 【日常臨床のジレンマ-NASHかASHか】 脂肪性肝疾患における中等量飲酒の影響

  土居 忠, 田中 信悟, 秋山 剛英, 大井 雅夫, 高橋 稔, 本間 久登, 森井 一裕, 古川 勝久

  消化器内科 ( (有)科学評論社 )  57 ( 6 ) 681 - 684  2013.12

• 非アルコール性脂肪肝炎からの発癌における酸化ストレスの関与についての検討

  田中 信悟, 宮西 浩嗣, 河野 豊, 保木 寿文, 久保 智洋, 高田 弘一, 林 毅, 佐藤 勉, 佐藤 康史, 小船 雅義, 瀧本 理修, 加藤 淳二

  肝臓 ( (一社)日本肝臓学会 )  54 ( Suppl.2 ) A580 - A580  2013.09

display all >>

Research Projects 【 display / non-display 】

Research Projects 【 display / non-display 】

• 酸化的DNA傷害修復酵素欠損マウス由来肝腫瘍オルガノイドを用いた新規治療法の探索

  基盤研究(C)

  Project Year :

  2021.04

  -

  2024.03

   

  田中 信悟, 加藤 淳二, 宮西 浩嗣

  　View Summary

  肝細胞癌は依然予後不良の疾患であり，分子標的薬導入後の平均生存期間は1年程度である．肝細胞癌の背景肝疾患は多岐にわたり，遺伝子変異も多様かつ低頻度に生じることが報告されている．このことが分子標的薬開発の進まない原因とされ，前臨床段階からの背景肝疾患別アプローチが必要と考えられている．また，分子標的薬の開発において，腫瘍の状態を忠実に反映した新規in vitroスクリーニング試験の開発が強く求められている．申請者らはこれまでに酸化的DNA傷害修復酵素MUTYH欠損マウスに高脂質・高糖質・鉄過剰食を給餌して肝発癌モデルマウス(HCV，NASHモデル)を作成した．本研究の目的は同マウス肝腫瘍由来オルガノイドを作成し，新規肝細胞癌治療薬を探索することである． 研究計画としては，1. MUTYH欠損マウス由来肝腫瘍(HCV，NASHモデル)とヒト肝細胞癌との類似性の評価 (令和3年度)，2. MUTYH欠損マウス由来肝腫瘍からのオルガノイド作成 (令和3,4年度)，3. 肝腫瘍オルガノイドを用いた抗腫瘍薬スクリーニング (令和4,5年度)と設定し，まず令和3年度は上記1,2に取り組んだ． 上記1についはNASHモデルの肝腫瘍についてデータを取得し，現在比較対象となるヒト肝細胞癌のsomatic mutationデータ（International Cancer Genome Consortium，The Cancer Genome Atlas，Cancer Gene Census)との相同性について解析中である．上記2については，培養法の確立に取り組んでいる．

• Novel strategies for the treatment of solid tumors with CAR and CIML NK cells

  Grant-in-Aid for Scientific Research (B)

  Project Year :

  2021.04

  -

  2024.03

   

  宮西 浩嗣, 久保 智洋, 大須賀 崇裕, 田中 信悟, 加藤 淳二, 濱口 孝太

  　View Summary

  Chimeric antigen receptor（CAR）を用いた遺伝子改変Ｔ細胞療法（CAR-T療法）は、Ｂ細胞性腫瘍に対して劇的な治療効果をもたらした。更にallogenic source を用いたCAR-NK 療法がB細胞性腫瘍に対してCAR-T療法と同等の効果があることが報告され、同治療ではCAR-T療法に比べ、cytokine release syndromeや重篤な神経毒性の出現が少なく、安全性が高いことが示された。しかしながら固形腫瘍、特に膵癌に対するCAR-NK療法の効果に関しては、造血器腫瘍に対するCD19 CAR療法の劇的な治療効果と比較すると抗腫瘍効果は限定的であり、その免疫阻害の克服方法が問われている。本研究においては、CARコンストラクトにIL-12/15/18を組み込んだ”armored CAR-NK”(IL-12/15/18を自己分泌する)を作製し、膵癌細胞株に対する抗腫瘍効果を検討することを目的とした。まず前段階としてIL-12/15/18でNK細胞を刺激して作製したCytokine Induced Memory Like (CIML) NK細胞が、実際に膵癌に対して抗腫瘍効果を発揮するかどうかを検討するため、複数の膵臓癌細胞株とCIML NK細胞を共培養し、7AADおよびAnnexin Vを用いてアポトーシスを解析したところ、コントロールNK細胞(IL-2での刺激のみ)と比較し、有意にアポトーシスを誘導することを示した。以上より当該年度の研究において、通常のCAT-NKと比較し、本研究で作成を予定しているarmored CAR-NKはより膵癌細胞に対してより高い効果を発揮できる可能性を示す貴重なデータを得られたと考える。

• Elucidation of NASH hepatocarcinogenesis mechanism and therapeutic application using oxidative DNA damage repair enzyme-deficient mice

  Grant-in-Aid for Early-Career Scientists

  Project Year :

  2019.04

  -

  2022.03

   

  Tanaka Shingo

  　View Summary

  The applicants established a new NASH model mouse created by loading high-calorie and high-oxidative stress on oxidative DNA injury repair enzyme (MUTYH)-deficient mice. The purpose of this study was to evaluate this mice and to develop a novel antioxidant therapy. Increased levels of 4-HNE and 8-OHdG, which are indicators of oxidative stress, were observed in the liver tissue of mice fed a high-fat, cholesterol and iron-rich diet(HFHC+Fe). When MUTYH-null mice were fed with HFHC+Fe, 25% of the mice showed liver tumors. Comparison of gene expression revealed that Wnt/β catenin signaling, which is relatively frequent in human hepatocellular carcinoma, is involved.

• Development of novel treatment for liver cancer with class-selective HDAC inhibitors

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2018.04

  -

  2021.03

   

  Miyanishi Koji

  　View Summary

  Histone deacetylase (HDAC) is expressed in various cancers and is involved in cancer treatment resistance. HDAC class IIa is found in hepatocellular carcinoma cells. In this study, we found that the combined use of HDAC class IIa inhibitors with lenvatinib induces a synergistic antitumor effect. Lenvatinib is thought to exert an antitumor effect by inhibition of fibroblast growth factor receptor 4 (FGFR4) . It is considered that the induction of apoptosis by the combined use of both drugs depends on the expression of FGFR4. Furthermore, the decreased expression of FGFR4 was considered to induce a synergistic effect.

• Elucidation of induction mechanism of iron oxidative stress in NASH and application to treatment

  Grant-in-Aid for Young Scientists (B)

  Project Year :

  2017.04

  -

  2019.03

   

  TANAKA Shingo, KATO junji, MIYANISHI koji, SAKAMOTO hiroki

  　View Summary

  Caco-2/TC7 cells were cultured on a porous filter in order to form monolayers having the morphology and function of small intestinal epithelial cells as in vitro experiments. It was possible to measure DMT1 mRNA expression level and IRP activity. In vivo experiment, a steatohepatitis model mouse was prepared. It was reared in Surwit diet, iron content was added 450 mg/kg diet in iron excess group. After liver tissue was collected and fixed specimens were prepared, liver injury, fibrosis, iron deposition, degree of oxidative stress using 8-OHdG antibody, and carcinogenesis could be analyzed.

display all >>