Cancer Science

Cover image for Vol. 106 Issue 4

Early View (Online Version of Record published before inclusion in an issue)

Edited By: Yusuke Nakamura

Impact Factor: 3.534

ISI Journal Citation Reports © Ranking: 2013: 68/203 (Oncology)

Online ISSN: 1349-7006

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  1. 1 - 33
  1. Original Articles

    1. You have full text access to this OnlineOpen article
      High levels of DJ-1 protein and isoelectric point 6.3 isoform in sera of breast cancer patients

      Takahiko Kawate, Keiichi Iwaya, Kayoko Koshikawa, Tomoyuki Moriya, Tamio Yamasaki, Sho Hasegawa, Hiroshi Kaise, Tomoyuki Fujita, Hirotaka Matsuo, Takahiro Nakamura, Takashi Ishikawa, Sadayuki Hiroi, Sanae M.M. Iguchi-Ariga, Hiroyoshi Ariga, Keiichi Murota, Minoru Fujimori, Junji Yamamoto, Osamu Matsubara and Norio Kohno

      Article first published online: 6 MAY 2015 | DOI: 10.1111/cas.12673

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      In order to determine the clinical significance of DJ-1 protein in the sera of breast cancer patients, multicenter study was performed. The presence of the DJ-1 isoform at pI 6.3 could clearly differentiate breast cancer from non-cancerous state in patients with high levels of DJ-1 in the serum, which reflect cellular oxidative damage, a major factor of age-related diseases (cancer, neurodegenerative disorder, cardiovascular disease, diabetes, etc.).

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      Time-lapse imaging assay using the BioStation CT: A sensitive drug-screening method for three-dimensional cell culture

      Ruriko Sakamoto, M. Mamunur Rahman, Manami Shimomura, Manabu Itoh and Tetsuya Nakatsura

      Article first published online: 6 MAY 2015 | DOI: 10.1111/cas.12667

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      Novel anticancer drug screening technique.

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      Antitumor activity of the MEK inhibitor trametinib on intestinal polyp formation in ApcΔ716 mice involves stromal COX-2

      Teruaki Fujishita, Rie Kajino-Sakamoto, Yasushi Kojima, Makoto Mark Taketo and Masahiro Aoki

      Article first published online: 1 MAY 2015 | DOI: 10.1111/cas.12670

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      We found the MEK/ERK signaling was activated not only in adenoma epithelial cells, but also in tumor stromal cells of ApcΔ716 mice, a colon cancer mouse model. Eight-week treatment of ApcΔ716 mice with the MEK inhibitor trametinib reduced the number of polyps in the large size class. Trametinib treatment reduced the cyclooxygenase-2 (COX-2) level in ApcΔ716 tumors in vivo, as well as in primary culture of intestinal fibroblasts, suggesting that the MEK/ERK signaling plays key roles in intestinal adenoma formation partly through COX-2 induction in tumor stromal cells.

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      Association between serum ligands and the skin toxicity of anti-epidermal growth factor receptor antibody in metastatic colorectal cancer

      Naoki Takahashi, Yasuhide Yamada, Koh Furuta, Kengo Nagashima, Akiko Kubo, Yusuke Sasaki, Hirokazu Shoji, Yoshitaka Honma, Satoru Iwasa, Natsuko Okita, Atsuo Takashima, Ken Kato, Tetsuya Hamaguchi and Yasuhiro Shimada

      Article first published online: 29 APR 2015 | DOI: 10.1111/cas.12642

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      We evaluated the associtation between serum levels of ligands and grade of skin toxicity by anti-EGFR antibody treatment in metastatic clorectal cancer patients. Serum levels of HGF, EREG and AREG were inversely proportional to grades of skin toxicity as determined by the Cochran–Armitage test (P = 0.019, P = 0.047, P = 0.021, respectively). Our study indicated that serum levels such as HGF, EREG and AREG may be significant markers to predict the grade of skin toxicity and the prognosis of anti-EGFR antibody treatment.

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      Expression of ribosome-binding protein 1 correlates with shorter survival in Her-2 positive breast cancer

      Xiaoshuan Liang, Shanshan Sun, Xianyu Zhang, Hao Wu, Weiyang Tao, Tong Liu, Wei Wei, Jingshu Geng and Da Pang

      Article first published online: 27 APR 2015 | DOI: 10.1111/cas.12666

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      RRBP1 is a valuable prognostic factor in Her-2 positive breast cancer patients, indicating RRBP1 may be a potentially important target for the prediction of prognosis.

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      ADIPOQ polymorphism rs182052 is associated with clear cell renal cell carcinoma

      Guiming Zhang, Chengyuan Gu, Yao Zhu, Lei Luo, Dahai Dong, Fangning Wan, Hailiang Zhang, Guohai Shi, Lijiang Sun and Dingwei Ye

      Article first published online: 24 APR 2015 | DOI: 10.1111/cas.12664

      In this case–control study, we examined the frequency of single nucleotide polymorphisms (rs182052G>A, rs266729C>G, and rs3774262G>A) in the adiponectin gene (ADIPOQ) in 1004 patients with clear cell RCC (ccRCC) compared with a group of healthy subjects (n = 1108). Fasting serum adiponectin concentrations were also examined. Fasting serum adiponectin was lower in subjects carrying minor alleles of rs182052 in both ccRCC patients (β = −0.399, P = 0.018) and healthy controls (β = −0.371, P = 0.024). These results suggest that ADIPOQ rs182052 is significantly associated with ccRCC risk.

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      BRCA/Fanconi anemia pathway implicates chemoresistance to gemcitabine in biliary tract cancer

      Shinsuke Nakashima, Shogo Kobayashi, Hiroaki Nagano, Akira Tomokuni, Yoshito Tomimaru, Tadafumi Asaoka, Naoki Hama, Hiroshi Wada, Koichi Kawamoto, Shigeru Marubashi, Hidetoshi Eguchi, Yuichiro Doki and Masaki Mori

      Article first published online: 22 APR 2015 | DOI: 10.1111/cas.12652

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      We demonstrated that up-regulation of the BRCA/Fanconi anemia pathway was one mechanism of chemo-resistance to gemcitabine. GEM exposure would lead to enrichment of the CD24+/44+ cells highly-expressing BRCA/FA in BTC, which would cause co-resistance to GEM and CDDP. Inhibiting the BRCA/FA pathway decreased the CD24+/44+ population and restored chemo-resistance in GEM resistant BTC cells.

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      Correlation between the International Neuroblastoma Pathology Classification and genomic signature in neuroblastoma

      Atsuko Nakazawa, Chizuko Haga, Miki Ohira, Hajime Okita, Takehiko Kamijo and Akira Nakagawara

      Article first published online: 22 APR 2015 | DOI: 10.1111/cas.12665

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      Among GGP subtypes in UH NB. GGP2s and GGP3s showed significantly poorer prognosis (OS = 18%) than GGP4s (OS = 80%) which, together with GGWs, had better survival rate (P = 0.02).

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      Adaptor protein CRK induces epithelial–mesenchymal transition and metastasis of bladder cancer cells through HGF/c-Met feedback loop

      Ryuji Matsumoto, Masumi Tsuda, Lei Wang, Nako Maishi, Takashige Abe, Taichi Kimura, Mishie Tanino, Hiroshi Nishihara, Kyoko Hida, Yusuke Ohba, Nobuo Shinohara, Katsuya Nonomura and Shinya Tanaka

      Article first published online: 22 APR 2015 | DOI: 10.1111/cas.12662

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      CRK elimination decreases primary tumor growth and completely abolished metastasis. UM-UC-3 bladder cancer cells labeled with tdTomato-luc2 (control; empty, CRK depletion; CRKi-3) were orthotopically injected under the bladder muscle layer in athymic mice. Tumor growth and metastasis were monitored weekly by bioluminescence imaging system.

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      Human leukocyte antigen-E alleles and expression in patients with serous ovarian cancer

      Hui Zheng, Renquan Lu, Suhong Xie, Xuemei Wen, Hongling Wang, Xiang Gao and Lin Guo

      Article first published online: 13 APR 2015 | DOI: 10.1111/cas.12641

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      In this study, we found the frequency of HLA-E*0103 allele was increased in patients with serous ovarian cancer, and HLA-E*0103/peptides complex was stable. Thus, the elevated expression of total and cell surface HLA-E molecule with HLA-E*0103 allele increased the inhibitory effect on NK cell lysis, rendering tumor cells escape from NK immune surveillance. This study is the first one to evaluate the correlation between HLA-E alleles and serous ovarian cancer.

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      Validation study of the combined repeated-dose toxicity and genotoxicity assay using gpt delta rats

      Jun-ichi Akagi, Takeshi Toyoda, Young-Man Cho, Yasuko Mizuta, Takehiko Nohmi, Akiyoshi Nishikawa and Kumiko Ogawa

      Article first published online: 10 APR 2015 | DOI: 10.1111/cas.12634

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      To support development of a combined assay for general toxicity and genotoxicty by using transgenic rodents, we provide evidences that indicate equivalence of gpt delta rats, which carry reporter genes to detect in vivo genotoxicity, to their parental wild type in terms of toxicological responses. DEN- or DEHP- treated F344 and SD strains of gpt delta rats display comparable general toxicity and genotoxicity to wild type. Our results indicate that the combined assay using gpt delta rats was applicable for simultaneous detection of both general toxicity and genotoxicity for short durations of administration.

    12. You have full text access to this OnlineOpen article
      Phase I study of weekly nab-paclitaxel combined with S-1 in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer

      Junji Tsurutani, Katsumasa Kuroi, Tsutomu Iwasa, Masaki Miyazaki, Shinichi Nishina, Chihiro Makimura, Junko Tanizaki, Kunio Okamoto, Toshinari Yamashita, Tomoyuki Aruga, Takashi Shigekawa, Yoshifumi Komoike, Toshiaki Saeki and Kazuhiko Nakagawa

      Article first published online: 9 APR 2015 | DOI: 10.1111/cas.12658

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      Weekly nab-paclitaxel plus S-1 in patients with MBC.

    13. You have full text access to this OnlineOpen article
      Phase I study of tivantinib in Japanese patients with advanced hepatocellular carcinoma: Distinctive pharmacokinetic profiles from other solid tumors

      Takuji Okusaka, Takeshi Aramaki, Yoshitaka Inaba, Shinichiro Nakamura, Manabu Morimoto, Michihisa Moriguchi, Takashi Sato, Yuta Ikawa, Masafumi Ikeda and Junji Furuse

      Article first published online: 7 APR 2015 | DOI: 10.1111/cas.12644

      This would be one of the first manuscripts demonstrating that the recommended dose of an anti-cancer agent for patients with hepatocellular carcinoma (HCC) could be distinct from its recommended dose for patients with other solid tumors.

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      Cadmium-coordinated supramolecule suppresses tumor growth of T-cell leukemia in mice

      Xiaoping Zhou, Yukio Koizumi, Muxin Zhang, Miyuki Natsui, Souichi Koyota, Manabu Yamada, Yoshihiko Kondo, Fumio Hamada and Toshihiro Sugiyama

      Article first published online: 6 APR 2015 | DOI: 10.1111/cas.12651

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      We found that thiacalixarene-cadmium complex has an anti-proliferative effect against T-cell leukemia cells, with no cytotoxicity in epithelia-derived cancer cells in vitro and minimum accumulations of cadmium in mice. In xenograft tumor model, cadmium-complex treatment significantly suppressed tumor growth of Jurkat cells in mice. These results suggest that thiacalixarene-cadmium complex may have therapeutic potential for treatment of T-cell leukemia.

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      Prediction of desmoid tumor progression using miRNA expression profiling

      Armelle Dufresne, Marie Paturel, Laurent Alberti, Heloise Philippon, Adeline Duc, Anne-Valerie Decouvelaere, Philippe Cassier and Jean-Yves Blay

      Article first published online: 6 APR 2015 | DOI: 10.1111/cas.12640

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      This study was conducted to define the potential predictive and/or prognostic value of a miRNA expression profile of desmoid tumors. The results bring the first demonstration of the prognostic value of miRNA profile in DT. The results were obtained in a cohort of patients included in a clinical phase II trial and validated in an independent cohort. The implication of such a discovery will be important in the management of patients with tumors particularly over-treated.

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      Phase II trial of chemoradiotherapy with S-1 plus cisplatin for unresectable locally advanced head and neck cancer (JCOG0706)

      Makoto Tahara, Naomi Kiyota, Junki Mizusawa, Kenichi Nakamura, Ryuichi Hayashi, Tetsuo Akimoto, Yasuhisa Hasegawa, Shigemichi Iwae, Nobuya Monden, Kazuto Matsuura, Hirofumi Fujii, Yusuke Onozawa, Akira Homma, Akira Kubota, Haruhiko Fukuda and Masato Fujii

      Article first published online: 1 APR 2015 | DOI: 10.1111/cas.12657

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      Based on previous our phase I study (Tahara M et al., Cancer Science 2011; 102: 419–424), we conducted a phase II study to evaluate the efficacy and safety of concurrent chemoradiotherapy with S-1 plus cisplatin for patients with unresectable locally advanced squamous cell carcinoma of the head and neck. Results of this phase II study showed that this combination resulted in promising efficacy with acceptable toxicities.

  2. Review Articles

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      Targeting the canonical Wnt/β-catenin pathway in hematological malignancies

      Eishi Ashihara, Tetsuya Takada and Taira Maekawa

      Article first published online: 1 APR 2015 | DOI: 10.1111/cas.12655

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      The canonical Wnt/ß-catenin pathway has been investigated extensively as a target in cancer treatment and several specific inhibitors of this signaling pathway have been identified through high-throughput screening. In this review, the significance of the canonical Wnt/ß-catenin pathway in hematological carcinogenesis and screening methods for specific inhibitors are discussed.

  3. Original Articles

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      Therapeutic advances in BIG3-PHB2 inhibition targeting the crosstalk between estrogen and growth factors in breast cancer

      Tetsuro Yoshimaru, Masato Komatsu, Yasuo Miyoshi, Junko Honda, Mitsunori Sasa and Toyomasa Katagiri

      Article first published online: 1 APR 2015 | DOI: 10.1111/cas.12654

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      The specific disruption of BIG3-PHB2 complex, which is a critical modulator in estrogen signaling, leads to a novel therapeutic approach for endocrine-resistance in breast cancer cells activated by signaling crosstalk between estrogen and growth factors or HER2 amplification, especially in premenopausal women.

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      Suppression of silent information regulator 1 activity in noncancerous tissues of hepatocellular carcinoma: Possible association with non-B non-C hepatitis pathogenesis

      Hideyuki Konishi, Ken Shirabe, Hidekazu Nakagawara, Norifumi Harimoto, Yo-Ichi Yamashita, Toru Ikegami, Tomoharu Yoshizumi, Yuji Soejima, Yoshinao Oda and Yoshihiko Maehara

      Article first published online: 1 APR 2015 | DOI: 10.1111/cas.12653

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      Hepatic SIRT1 activity was repressed in non-B non-C patients, and low activity of SIRT1 may lead to hepatic inflammation and carcinogenesis in non-B non-C patients.

  4. Review Articles

    1. You have full text access to this OnlineOpen article
      Cancer immunotherapy using novel tumor-associated antigenic peptides identified by genome-wide cDNA microarray analyses

      Yasuharu Nishimura, Yusuke Tomita, Akira Yuno, Yoshihiro Yoshitake and Masanori Shinohara

      Article first published online: 1 APR 2015 | DOI: 10.1111/cas.12650

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      We attempted to identify TAAs-derived LPs encompassing both LPs-specific Th1 cells and CTLs epitopes in order to further improve TAAs-derived peptides-based cancer immunotherapy. We have succeeded in identification of highly immunogenic TAAs-derived LPs activating both promiscuous HLA class II-restricted Th1 cells and CTLs specific to SPs crosspresented from LPs by DCs.

  5. Original Articles

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      Expression and regulatory effects on cancer cell behavior of NELL1 and NELL2 in human renal cell carcinoma

      Ritsuko Nakamura, Takeru Oyama, Ryosuke Tajiri, Atsushi Mizokami, Mikio Namiki, Masaru Nakamoto and Akishi Ooi

      Article first published online: 26 MAR 2015 | DOI: 10.1111/cas.12649

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      We found that the down-regulation of NELL1 and NELL2 in renal cell carcinoma (RCC) is in part due to the hypermethylation of CpG islands in their putative promoter regions. Furthermore, we found that NELL1 suppresses and NELL2 partially suppresses RCC cell migration, and NELL1 further inhibits RCC cell adhesion.

  6. Review Articles

    1. You have full text access to this OnlineOpen article
      Pharmacokinetics, dynamics and toxicity of docetaxel: Why the Japanese dose differs from the Western dose

      Hirotsugu Kenmotsu and Yusuke Tanigawara

      Article first published online: 25 MAR 2015 | DOI: 10.1111/cas.12647

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      Docetaxel has been one of the most important chemotherapeutic drugs for cancer treatment, but a practical problem is discrepancy in standard dose between Japan and Western countries. This article reviews extensively the pharmacokinetic, pharmacodynamic and toxicological profiles of docetaxel, and explains why there exists an ethnic difference in dose, and further discusses which direction we should go forward to solve this problem.

  7. Original Articles

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      Catechol-O-methyltransferase, a new target for pancreatic cancer therapy

      Wenming Wu, Qiao Wu, Xiafei Hong, Li Zhou, Jie Zhang, Lei You, Wenze Wang, Huanwen Wu, Hongmei Dai and Yupei Zhao

      Article first published online: 25 MAR 2015 | DOI: 10.1111/cas.12648

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      Catechol-O-methyltransferase (COMT) serves as a tumor-suppressor for pancreatic cancer. Higher COMT levels in the surgical specimens predict longer survival. COMT also inhibits pancreatic cell growth, increases gemcitabine-induced apoptosis and inhibits invasion.

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      Enhanced antitumor effect of anti-tissue factor antibody-conjugated epirubicin-incorporating micelles in xenograft models

      Yoshiyuki Yamamoto, Ichinosuke Hyodo, Yoshikatsu Koga, Ryo Tsumura, Ryuta Sato, Toshihumi Obonai, Hirobumi Fuchigami, Fumiaki Furuya, Masahiro Yasunaga, Mitsunori Harada, Yasuki Kato, Atsushi Ohtsu and Yasuhiro Matsumura

      Article first published online: 23 MAR 2015 | DOI: 10.1111/cas.12645

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      Considering its possible clinical use, our anti-TF-NC-6300 may continue to exert a high antitumor activity despite the existence of the tumor stromal barrier, since anti-TF-NC-6300 was capable of suppressing tumor growth associated with damage to the tumor vessels and the death of cancer cells in humans.

  8. Review Articles

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      Intracellular signals of lung cancer cells as possible therapeutic targets

      Kiyomichi Tanaka, Keiki Kumano and Hiroo Ueno

      Article first published online: 20 MAR 2015 | DOI: 10.1111/cas.12643

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      In recent years, several molecularly targeted therapies have been developed as part of lung cancer treatment and produced dramatically good results. However, among the many oncogenes that have been identified to be involved in the onset of lung cancers, a number of oncogenes are not covered by these advanced therapies. In this article, we discuss major causal genes of lung cancers and intracellular signaling pathways involving those genes, and review studies of origin cells and stem cells of lung cancers, as well as the possibility of developing molecularly targeted therapies based on these studies.

  9. Original Articles

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      Advanced human T-cell leukemia virus type 1 carriers and early-stage indolent adult T-cell leukemia-lymphoma are indistinguishable based on CADM1 positivity in flow cytometry

      Seiichiro Kobayashi, Eri Watanabe, Tomohiro Ishigaki, Nobuhiro Ohno, Koichiro Yuji, Kazumi Nakano, Tadanori Yamochi, Nobukazu Watanabe, Arinobu Tojo, Toshiki Watanabe and Kaoru Uchimaru

      Article first published online: 20 MAR 2015 | DOI: 10.1111/cas.12639

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      The CADM1 vs. CD7 plot (flow cytometry) for CD4+ cells from peripheral blood revealed the diversity of disease stages in asymptomatic HTLV-1 carriers (AC) as well as ATL, and will help us to identify advanced AC with a similar disease status to indolent ATL patients at an early stage. Some cases of smoldering ATL and AC could not be distinguished; therefore, a new clinical category that includes these cases is warranted.

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      Prognosis of Japanese patients with previously untreated metastatic renal cell carcinoma in the era of molecular-targeted therapy

      Nobuo Shinohara, Wataru Obara, Katsunori Tatsugami, Sei Naito, Tomomi Kamba, Masayuki Takahashi, Sachiyo Murai, Takashige Abe, Koji Oba and Seiji Naito

      Article first published online: 19 MAR 2015 | DOI: 10.1111/cas.12646

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      The present study showed for the first time the prognosis of Japanese patients with metastatic renal cell carcinoma in the era of molecular-targeted therapy. The JMRC prognostic classification may be clinically useful as a prognostic model.

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      High expression of interleukin-11 is an independent indicator of poor prognosis in clear-cell renal cell carcinoma

      Deng Pan, Le Xu, Haiou Liu, Weijuan Zhang, Weisi Liu, Yidong Liu, Qiang Fu and Jiejie Xu

      Article first published online: 16 MAR 2015 | DOI: 10.1111/cas.12638

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      High IL-11 expression in ccRCC tissues is associated with a greater risk of recurrence and reduced survival in patients with ccRCC, especially in early-stage patients. And high IL-11 expression is an independent predictor of poor clinical outcome in patients with ccRCC. It may help identify patients who could benefit from additional treatments and closer follow-up.

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      Epidermal growth factor receptor and AKT1 gene copy numbers by multi-gene fluorescence in situ hybridization impact on prognosis in breast cancer

      Jiao Li, Wei Su, Sheng Zhang, Yunhui Hu, Jingjing Liu, Xiaobei Zhang, Jingchao Bai, Weiping Yuan, Linping Hu, Tao Cheng, Anders Zetterberg, Zhenmin Lei and Jin Zhang

      Article first published online: 16 MAR 2015 | DOI: 10.1111/cas.12637

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      Alterations of EGFR and AKT1 gene copy numbers in breast cancer cells detected by M-FISH.

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      Immunotherapy based on bispecific T-cell engager with hIgG1 Fc sequence as a new therapeutic strategy in multiple myeloma

      Jianxuan Zou, Dan Chen, Yunhui Zong, Sisi Ye, Jinle Tang, Huimin Meng, Gangli An, Xingding Zhang and Lin Yang

      Article first published online: 13 MAR 2015 | DOI: 10.1111/cas.12631

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      The world's first CD138/CD3 BiTE-hIgFc targeting T cells, natural killer cells and multiple myeloma cells simultaneously has nanomolar-level affinity to recombinant hCD138 protein and has shown potent antitumor activity against RPMI-8226 tumor cells in vitro and in vivo.

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      Activation of AMP-activated protein kinase by retinoic acid sensitizes hepatocellular carcinoma cells to apoptosis induced by sorafenib

      Naoki Ishijima, Keita Kanki, Hiroki Shimizu and Goshi Shiota

      Article first published online: 9 MAR 2015 | DOI: 10.1111/cas.12633

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      To improve the outcome of cancer chemotherapy, the strategies to enhance the efficacy of anticancer drugs are required. Suppression of glycolysis by retinoic acid sensitized hepatocellular carcinoma cells to apoptosis induced by sorafenib via AMPK activation. Our findings suggest that ATRA is useful for enhancing the cytotoxicity of sorafenib against HCC cells by regulating energy metabolism of HCC cells.

  10. Review Articles

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      Epithelial–mesenchymal transition is regulated at post-transcriptional levels by transforming growth factor-β signaling during tumor progression

      Masao Saitoh

      Article first published online: 9 MAR 2015 | DOI: 10.1111/cas.12630

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      The key EMT regulators modify expressions of EMT marker proteins at the posttranscriptional, transcriptional, and epigenetic levels. TGF-β, probably secreted from cancer cells, regulates expression of the key EMT regulators and plays a role in tumor progression in cooperation with additional signals from other factors secreted from cells in the tumor microenvironment.

  11. Original Articles

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      Sirtuin 6 promotes transforming growth factor-β1/H2O2/HOCl-mediated enhancement of hepatocellular carcinoma cell tumorigenicity by suppressing cellular senescence

      Xin-Xia Feng, Jing Luo, Mei Liu, Wei Yan, Zhen-Zhen Zhou, Yu-Jia Xia, Wei Tu, Pei-Yuan Li, Zuo-Hua Feng and De-An Tian

      Article first published online: 9 MAR 2015 | DOI: 10.1111/cas.12632

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      Although the function of SIRT6 could be tumor-promoting or tumor-suppressing, TGF-β1/H2O2/HOCl-mediated up-regulation of SIRT6 in HCC cells was tumor-promotional, but not tumor-suppressing. Suppressing the up-regulation of SIRT6 enabled TGF-β1/H2O2/HOCl to induce cellular senescence, thereby abrogating the enhancement of HCC cell tumorigenicity by TGF-β1/H2O2/HOCl.

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