The possibility of HSP70 as a therapeutic target in combination with HDACi

• Project/Area Number: 24591626
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Dermatology
• Research Institution: Kagoshima University (2014); Okayama University (2012-2013)
• Principal Investigator: FUJII Kazuyasu 鹿児島大学, 医学部・歯学部附属病院, 講師 (70452571)
• Co-Investigator(Kenkyū-buntansha): KONDO Tadashi 独立行政法人国立がん研究センター, 希少がん研究分野, 分野長 (30284061)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: HDAC阻害剤 / HSP72 / HSP70 / HSPA1A / 感受性

Outline of Final Research Achievements

Using proteomic analysis of lymphoid cell lines, we identified HSP72, an inducible isoform of HSP70 family, was increased in histone deacetylase inhibitor (HDACi)-resistant cell line group. However, the functional role of HSP72 on HDACi-resistance had been largely unknown. In this study, we first established HSP72 stably transfected Jurkat cells, and we identified that HDACi-induced apoptosis and caspase activities were decreased and that base line expression level of bcl-2 and XIAP were increased in HSP72 overexpressed cells. On the other hand, HSP72 knock down Hut78 cell line was more sensitive for HDACi compared to MOCK cell line. Finally, we identified quercetin, an inhibitor of HSP70, enhanced HDACi-induced suppression of cell proliferation and HDACi-induced apoptosis in Hut78 cells. In conclusion, HSP72 is a possible target for combination therapy of HDACi.

Research Products

• [Journal Article] Clues to diagnosis for unusual mucosal pemphigus demonstrating undetectable anti-desmoglein 3 serum antibodies by routine tests. (2015)
  • Author(s): Kamiya K, Aoyama Y, Yamaguchi M, Ukida A, Mizuno-Ikeda K, Fujii K, Hamada T, Tokura Y, Iwatsuki K.
  • Journal Title: J Dermatol. Volume: - Issue: 6 Pages: 572-579
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• [Journal Article] Rare case of Langerhans cell sarcoma with cutaneous manifestation arising on the inguinal region. (2014)
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  • Journal Title: J Dermatol. Volume: 41 Issue: 12 Pages: 1127-1128
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• [Journal Article] Erdheim-Chester症候群の1例 (2014)
  • Author(s): 光井聖子、藤井一恭、大塚文男、岩月啓氏
  • Journal Title: 皮膚科の臨床 Volume: 56 Pages: 1524-1525
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• [Journal Article] Global PROTOMAP Profiling to Search for Biomarkers of Early-Recurrent Hepatocellular Carcinoma (2014)
  • Author(s): Taoka, Masato; Morofuji, Noriaki; Yamauchi, Yoshio; Ojima, Hidenori; Kubota, Daisuke; Terukina, Goro; Nobe, Yuko; Nakayama, Hiroshi; Takahashi, Nobuhiro; Kosuge, Tomoo; Isobe, Toshiaki; Kondo, Tadashi
  • Journal Title: J. Proteome Res. Volume: 13 Issue: 11 Pages: 4847-4858
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• [Journal Article] Clinical relevance and therapeutic significance of microRNA-133a expression profiles and functions in malignant osteosarcoma-initiating cells. (2014)
  • Author(s): Fujiwara T, Katsuda T, Hagiwara K, Kosaka N, Yoshioka Y, Takahashi RU, Takeshita F, Kubota D, Kondo T, Ichikawa H, Yoshida A, Kobayashi E, Kawai A, Ozaki T, Ochiya T.
  • Journal Title: Stem Cells. Volume: 32 Issue: 4 Pages: 959-973
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  • Peer Reviewed / Open Access
• [Journal Article] Proteomics identified overexpression of SET oncogene product and possible therapeutic utility of protein phosphatase 2A in alveolar soft part sarcoma. (2014)
  • Author(s): Kubota D, Yoshida A, Kawai A, Kondo T.
  • Journal Title: J Proteome Res. Volume: 13 Issue: 5 Pages: 2250-2261
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• [Journal Article] α- Parvin, a pseudopodial constituent, promotes cell motility and is associated with lymph node metastasis of lobular breast carcinoma. (2014)
  • Author(s): Ito M, Hagiyama M, Mimae T, Inoue T, Kato T, Yoneshige A, Nakanishi J, Kondo T, Okada M, Ito A.
  • Journal Title: Breast Cancer Res Treat Volume: 144 Issue: 1 Pages: 59-69
  • DOI: 10.1007/s10549-014-2859-0
  • Peer Reviewed / Open Access
• [Journal Article] Casting doubt on the traditional approach of cancer biomarker discovery through proteomics (2014)
  • Author(s): Kondo T
  • Journal Title: Expert Rev Proteomics Volume: 11(1) Issue: 1 Pages: 9-12
  • DOI: 10.1586/14789450.2014.871496
  • NAID: 130005454644
  • Peer Reviewed / Open Access
• [Journal Article] A higher correlation of the antibody activities against the calcium-dependent epitopes of desmoglein 3 quantified by ethylenediaminetetraacetic acid-treated enzyme-linked immunosorbent assay with clinical disease activities of pemphigus vulgaris. (2013)
  • Author(s): Kamiya K, Aoyama Y, Shirafuji Y, Hamada T, Morizane S, Fujii K, Iwatsuki K.
  • Journal Title: J Dermatol Sci. Volume: 70 Issue: 3 Pages: 190-195
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• [Journal Article] Proteomics identified nuclear N-myc downstream-regulated gene 1 as a prognostic tissue biomarker candidate in renal cell carcinoma. (2013)
  • Author(s): Hosoya N, Sakumoto M, Nakamura Y, Narisawa T, Bilim V, Motoyama T, Tomita Y, Kondo T.
  • Journal Title: Biochim Biophys Acta. Volume: 1834 Issue: 12 Pages: 2630-2639
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  • Peer Reviewed
• [Journal Article] Gene expression network analysis of ETV1 reveals KCTD10 as a novel prognostic biomarker in gastrointestinal stromal tumor. (2013)
  • Author(s): Kubota D, Yoshida A, Tsuda H, Suehara Y, Okubo T, Saito T, Orita H, Sato K, Taguchi T, Yao T, Kaneko K, Katai H, Kawai A, Kondo T.
  • Journal Title: PLoS One. Volume: 8 Issue: 8 Pages: e73896-e73896
  • DOI: 10.1371/journal.pone.0073896
  • Peer Reviewed
• [Journal Article] Proteomics study of open biopsy samples identifies peroxiredoxin 2 as a predictive biomarker of response to induction chemotherapy in osteosarcoma (2013)
  • Author(s): Kubota D, Kawai A, Kondo T
  • Journal Title: J Proteomics Volume: 91 Pages: 393-404
  • DOI: 10.1016/j.jprot.2013.07.022
  • Peer Reviewed
• [Journal Article] Laser microdissection and two-dimensional difference gel electrophoresis reveal the role of a novel macrophage-capping protein in lymph node metastasis in gastric cancer. (2013)
  • Author(s): Ichikawa H, Kanda T, Kosugi S, Kawachi Y, Sasaki H, Wakai T, Kondo T.
  • Journal Title: J Proteome Res. Volume: 12 Issue: 8 Pages: 3780-3791
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• [Journal Article] Proteomic approach toward molecular backgrounds of drug resistance of osteosarcoma cells in spheroid culture system. (2013)
  • Author(s): Arai K, Sakamoto R, Kubota D, Kondo T.
  • Journal Title: Proteomics. Volume: 13 Issue: 15 Pages: 2351-2360
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  • Peer Reviewed
• [Journal Article] The prognostic value of pfetin: a validation study in gastrointestinal stromal tumors using a commercially available antibody. (2013)
  • Author(s): Kubota D, Mukaihara K, Yoshida A, Suehara Y, Saito T, Okubo T, Gotoh M, Orita H, Tsuda H, Kaneko K, Kawai A, Kondo T, Sato K, Yao T.
  • Journal Title: Jpn J Clin Oncol. Volume: 43 Issue: 6 Pages: 669-675
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• [Journal Article] Interactomic approach for evaluating nucleophosmin-binding proteins as biomarkers for Ewing's sarcoma. (2013)
  • Author(s): Haga A
  • Journal Title: Electrophoresis Volume: 34 Issue: 11 Pages: 1670-1678
  • DOI: 10.1002/elps.201200661
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• [Journal Article] Quantitative proteomic analysis identified paraoxonase 1 as a novel serum biomarker for microvascular invasion in hepatocellular carcinoma. (2013)
  • Author(s): Huang C, Wang Y, Liu S, Ding G, Liu W, Zhou J, Kuang M, Ji Y, Kondo T, Fan J.
  • Journal Title: J Proteome Res. Volume: 12 Issue: 4 Pages: 1838-1846
  • DOI: 10.1021/pr3011815
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• [Journal Article] Use of potassium channel tetramerization domain-containing 12 as a biomarker for diagnosis and prognosis of gastrointestinal stromal tumor. (2013)
  • Author(s): Hasegawa T, Asanuma H, Ogino J, Hirohashi Y, Shinomura Y, Iwaki H, Kikuchi H, Kondo T.
  • Journal Title: Hum Pathol. Volume: 44 Issue: 7 Pages: 1271-1277
  • DOI: 10.1016/j.humpath.2012.10.013
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• [Journal Article] Erdheim-Chester病が強く疑われた下垂体機能低下症の一例 (2013)
  • Author(s): 三好智子, 大塚文男, 稲垣兼一, 田中康司, 越智可奈子, 藤井一恭, 藤井伸治, 当真貴志雄, 中村絵里, 塚本尚子, 武田昌也, 三村由香里, 小倉俊郎, 景山甚郷, 槇野博史
  • Journal Title: 日本内分泌学会雑誌 Volume: 89 Pages: 21-23
• [Journal Article] 【皮膚リンパ腫-いかに診断・治療するか】 皮膚リンパ腫に対する分子標的薬 HDAC阻害剤の作用機序と使い方 (2013)
  • Author(s): 藤井一恭
  • Journal Title: 医学のあゆみ Volume: 245 Pages: 589-592
• [Journal Article] Close Up実験法(Series 244) 蛍光二次元電気泳動法のポイント (2013)
  • Author(s): 近藤格
  • Journal Title: 実験医学 Volume: 31 Pages: 2985-2990
• [Journal Article] 【臨床検査における電気泳動解析法の活用】 プロテオーム解析における電気泳動法の活用 (2013)
  • Author(s): 近藤格
  • Journal Title: 医療と検査機器・試薬 Volume: 36 Pages: 297-300
• [Journal Article] Proteomic study identified HSP 70kDa protein 1A as a possible therapeutic target, in combination with histone deacetylase inhibitors, for lymphoid neoplasms (2012)
  • Author(s): Fujii K, Suzuki N, Ikeda K, Hamada T,Yamamoto T, Kondo T, Iwatsuki K
  • Journal Title: JProteomics Volume: 75巻 Issue: 4 Pages: 1401-1410
  • DOI: 10.1016/j.jprot.2011.11.010
  • Peer Reviewed
• [Journal Article] Eccrine poromatosis associated with polychemotherapy (2012)
  • Author(s): Fujii K, et al
  • Journal Title: Acta DermatoVenereologica Volume: 92 Issue: 6 Pages: 687-690
  • DOI: 10.2340/00015555-1279
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• [Journal Article] Hydroa vacciniforme is associated with increased numbers of Epstein-Barrvirus-infected γδT-cells (2012)
  • Author(s): Hirai Y, et al
  • Journal Title: Journal of Investigative Dermatology Volume: 132 Issue: 5 Pages: 1401-1408
  • DOI: 10.1038/jid.2011.461
  • Peer Reviewed
• [Journal Article] Valproic acid inhibits proliferation of EB virus-infectednatural killer cells (2012)
  • Author(s): Fujii K, Suzuki N, Yamamoto T, Duzuki D,Iwatsuki K
  • Journal Title: Hematology Volume: 17巻 Issue: 3 Pages: 163-169
  • DOI: 10.1179/102453312x13376952196494
  • Peer Reviewed
• [Journal Article] Decreased selenium-binding protein 1 enhances glutathione peroxidase 1 activity and downregulates HIF-1α to promote hepatocellular carcinoma invasiveness (2012)
  • Author(s): Huang C, Ding G, Gu C, Zhou J, Kuang M, Ji Y, He Y, Kondo T, Fan J
  • Journal Title: Clin Cancer Res Volume: 18 Issue: 11 Pages: 3042-53
  • DOI: 10.1158/1078-0432.ccr-12-0183
  • Peer Reviewed
• [Journal Article] Validation study on Pfetin and ATP-dependent RNA helicase DDX39 as prognostic biomarkers in gastrointestinal stromal tumour (2012)
  • Author(s): Kubota D, Kawai A, Kondo T
  • Journal Title: Jpn J Clin Oncol Volume: 42 Issue: 8 Pages: 730-741
  • DOI: 10.1093/jjco/hys092
  • Peer Reviewed
• [Journal Article] Proteomic-based identification of the APC-binding protein EB1 as a candidate of novel tissue biomarker and therapeutic target for colorectal cancer (2012)
  • Author(s): Sugihara Y, Taniguchi H, Kushima R, Tsuda H, Kubota D, Ichikawa H, Sakamoto K, Nakamura Y, Tomonaga T, Fujita S, Kondo T
  • Journal Title: J Proteomics Volume: 75 Issue: 17 Pages: 5342-55
  • DOI: 10.1016/j.jprot.2012.06.013
  • Peer Reviewed
• [Journal Article] Novel application for pseudopodia proteomics using excimer laser ablation and two-dimensional difference gel electrophoresis. (2012)
  • Author(s): Ito A, Murakami Y, Kondo T et al.
  • Journal Title: Lab Invest Volume: 92 Issue: 9 Pages: 1374-1385
  • DOI: 10.1038/labinvest.2012.98
  • Peer Reviewed
• [Journal Article] Application of Proteomics to Soft Tissue Sarcomas (2012)
  • Author(s): Kondo T, Kawai A
  • Journal Title: International Journal of Proteomics Volume: 42 (8) Pages: 730-741
  • DOI: 10.1155/2012/876401
  • Peer Reviewed
• [Journal Article] Cathepsin D as a potential prognostic marker for lung adenocarcinoma. (2012)
  • Author(s): Mimae T, Tsuta K, Maeshima AM, Okada M, Asamura H, Kondo T, Tsuda H.
  • Journal Title: Pathol Res Pract. Volume: 208 Issue: 9 Pages: 534-5540
  • DOI: 10.1016/j.prp.2012.05.020
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• [Journal Article] Clinical proteomics. (2012)
  • Author(s): Vegvari A, Kondo T, Marshall JG.
  • Journal Title: Int J Proteomics. Volume: 2012 Pages: 641491-641491
  • DOI: 10.1155/2012/641491
• [Journal Article] Discovery of biomarkers for osteosarcoma by proteomics approaches. (2012)
  • Author(s): Suehara Y
  • Journal Title: Hindawi Publishing Corporation Volume: 2012 Pages: 425636-425636
  • DOI: 10.1155/2012/425636
  • Peer Reviewed
• [Presentation] 生検後に縮小したEBER陰性Diffuse large B cell lymphoma (DLBCL) (2015)
  • Author(s): 藤井一恭、馬場淳徳、勝江浩未、地村 望、東 裕子、米良修二、金蔵拓郎
  • Organizer: 日本皮膚科学会第372回福岡地方会今福信一皮膚科主任教授就任記念
  • Place of Presentation: 福岡（ホテルニューオータニ博多）
  • Year and Date: 2015-03-14 – 2015-03-15
• [Presentation] The role of versican on the pathogenesis of Sèzary syndrome (2014)
  • Author(s): Fujii K, Karpova M, Cheng P, Kanekura T, Iwatsuki K, Dummer R, Urosevic-Maiwald M.
  • Organizer: The 39th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 大阪（Hotel Hankyu Expopark)
  • Year and Date: 2014-12-12 – 2014-12-14
• [Presentation] 蛍光標識二次元電気泳動法によるHDAC阻害剤の治療抵抗性原因タンパク質の同定 (2014)
  • Author(s): 藤井一恭、鈴木規弘、近藤 格、金蔵拓郎、岩月啓氏
  • Organizer: 第65回日本電気泳動学会総会
  • Place of Presentation: 横浜（横浜情報文化センター）
  • Year and Date: 2014-10-24 – 2014-10-25
• [Presentation] HSPA1A inhibits histone deacetylase inhibitor-induced apoptosis through mitochondrial apoptotic pathway. (2014)
  • Author(s): Fujii K, Idogawa M, Kondo T, Iwatsuki K, Kanekura T.
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜（PACIFICO YOKOHAMA)
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] HSP72 is a possible target for combination therapy with HDAC inhibitor (2014)
  • Author(s): Fujii K, Suzuki N, Idogawa M, Kondo T, Iwatsuki K, Kanekura T.
  • Organizer: 44th Annual Meeting of the European Society for Dermatological Research
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 2014-09-10 – 2014-09-13
• [Presentation] 疣贅状外観を呈した乾癬 (2014)
  • Author(s): 藤井一恭、馬場淳徳、有村亜希子、多田浩一、東 裕子、松下茂人、金蔵拓郎
  • Organizer: 森田栄伸教授・山元 修教授就任10周年記念日本皮膚科学会第128回山陰・第24回島根合同開催地方会
  • Place of Presentation: 松江（松江テルサ）
  • Year and Date: 2014-08-30 – 2014-08-31
• [Presentation] がん細胞の薬剤抵抗性分子機序：HDAC阻害剤を例として (2013)
  • Author(s): 藤井一恭
  • Organizer: 第65回日本皮膚科学会西部支部学術大会
  • Place of Presentation: かごしま県民交流センター
• [Presentation] Phenotypic analysis of dendritic cell polarization in the skin-draining lymph nodes of mycosis fungoides/ Sézary syndrome (2012)
  • Author(s): T. Hamada, K. Tada, K. Asagoe, H. Umemura, M. Otsuka, O. Yamasaki, Y. Aoyama, K. Fujii, K. Iwatsuki
  • Organizer: SID 72nd Annual Meeting
  • Place of Presentation: Raleigh, North Carolina
• [Presentation] ターゲット型紫外線療法は治療抵抗性ヘイリー・ヘイリー病に有用である (2012)
  • Author(s): 濱田利久、梅村啓史、池田佳寿子、藤井一恭、青山裕美、岩月啓氏
  • Organizer: 第111回日本皮膚科学会総会
  • Place of Presentation: 京都
• [Presentation] 菌状息肉症の皮膚病変における樹状細胞の検討 (2012)
  • Author(s): 池田佳寿子、濱田利久、多田光太郎、藤井一恭、青山裕美、岩月啓氏
  • Organizer: 第111回日本皮膚科学会総会
  • Place of Presentation: 京都
• [Presentation] EBウイルス関連疾患の予後に関する追跡調査 (2012)
  • Author(s): 三宅智子、山本剛伸、平井陽至、藤井一恭、岩月啓氏
  • Organizer: 第111回日本皮膚科学会総会
  • Place of Presentation: 京都
• [Presentation] 頭頸部血管肉腫の3例 (2012)
  • Author(s): 平井陽至、加持達弥、藤井一恭
  • Organizer: 第257回日本皮膚科学会岡山地方会
  • Place of Presentation: 岡山
• [Presentation] Analysis of lymphangiogenic markers in erythrodermic cutaneous T-cell lymphomas (2012)
  • Author(s): Karpova MB, Fujii K, Jenni D, Dummer R, Urosevic-Maiwald M
  • Organizer: EROTC CLTF 2012
  • Place of Presentation: Vienna, Austria
• [Presentation] The role of versican isoforms in skin homing of Sézary cells (2012)
  • Author(s): Karpova MB, Fujii K, Georgiev O, Dummer R, Urosevic-Maiwald M
  • Organizer: EROTC CLTF 2012
  • Place of Presentation: Vienna, Austria
• [Presentation] HSP 70 kDa protein 1A inhibits histone deacetylase inhibitor-induced apoptosis (2012)
  • Author(s): Fujii K, Suzuki N, Kaji T, Hamada T, Idogawa M, Kondo T, Iwatsuki K
  • Organizer: EROTC CLTF 2012
  • Place of Presentation: Vienna, Austria
• [Presentation] Comparative proteomic analysis identified HSPA1A as a candidate target for enhancing apoptosis induced by HDAC inhibitor (2012)
  • Author(s): Fujii K, Idogawa M, Kondo T, Iwatsuki K
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] Cell biologic and in situ studies for better understanding of blistering mechanisms of unusual mucosal pemphigus demonstrating no detectable serum anti-desmoglein 3 antibodies by routine tests (2012)
  • Author(s): K Kamiya, Y Aoyama, A Ukida, K Noda, T Hamada, K Fujii and K Iwatsuki
  • Organizer: 42nd Annual ESDR Meeting
  • Place of Presentation: Venice, Italy
• [Presentation] Versican as regulator of skin homing of Sézary cells (2012)
  • Author(s): MB Karpova, K Fujii, O Georgiev, R Dummer and M Urosevic-Maiwald
  • Organizer: 42nd Annual ESDR Meeting
  • Place of Presentation: Venice, Italy
• [Presentation] HSP 70 kDa protein 1A inhibits histone deacetylase inhibitor-induced apoptosis through mitochondrial pathway (2012)
  • Author(s): Fujii K, Suzuki N, Kaji T, Hamada T, Idogawa M, Kondo T, Iwatsuki K
  • Organizer: The 37th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 沖縄
• [Presentation] Multicentric Castleman’s disease（MCD）の一例
  • Author(s): 吉岡愛育、藤井一恭、濱田利久、岩月啓氏、野田和代、宮原信明
  • Organizer: 第259回日本皮膚科学会岡山地方会
  • Place of Presentation: 岡山コンベンションセンター
• [Presentation] Mタンパク血症を背景とし、深部静脈血栓症と皮膚随伴症状を伴った２例
  • Author(s): 梅村啓史、浅越健治、光井聖子、瀧口徹也、藤井一恭、岩月啓氏
  • Organizer: 第260回日本皮膚科学会岡山地方会
  • Place of Presentation: 岡山コンベンションセンター
• [Presentation] 帯状疱疹発症後に一時軽快したHIV関連乾癬
  • Author(s): 藤井一恭、竹原彩、青山裕美、岩月啓氏
  • Organizer: 岡山県医師会皮膚科部会・岡山市医師会皮膚科・泌尿器科専門医部会学術講演会
  • Place of Presentation: 岡山衛生会館
• [Presentation] Sezary細胞におけるVersicanの発現とその生物学的意義
  • Author(s): 藤井一恭
  • Organizer: 第32回岡山研究皮膚科フォーラム
  • Place of Presentation: 岡山コンベンションセンター
• [Presentation] TNF阻害剤による薬剤性障害の2例
  • Author(s): 深松紘子、濱田利久、藤井一恭、青山裕美、岩月啓氏、西田圭一郎、若林宏、川畑智子、高橋義雄
  • Organizer: 日本皮膚科学会第368回福岡地方会
  • Place of Presentation: ホテルニューオータニ博多
• [Book] 今日の処方 改訂第5版 (2013)
  • Author(s): 浦部晶夫、大田健、川合眞一、島田和幸、菅野健太郎 編集、藤井一恭他
  • Total Pages: 1198
  • Publisher: 南江堂
• [Book] 抗がん薬の臨床薬理 (2013)
  • Author(s): 相羽惠介 編、藤井一恭、岩月啓氏他
  • Total Pages: 731
  • Publisher: 南山堂