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  • American Association for Cancer Research (AACR)  (33)
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  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 4 ( 2018-02-15), p. 865-876
    Abstract: Pancreatoblastoma is a rare pediatric pancreatic malignancy for which the molecular pathogenesis is not understood. In this study, we report the findings of an integrated multiomics study of whole-exome and RNA sequencing as well as genome-wide copy number and methylation analyses of ten pancreatoblastoma cases. The pancreatoblastoma genome was characterized by a high frequency of aberrant activation of the Wnt signaling pathway, either via somatic mutations of CTNNB1 (90%) and copy-neutral loss of heterozygosity (CN-LOH) of APC (10%). In addition, imprinting dysregulation of IGF2 as a consequence of CN-LOH (80%), gain of paternal allele (10%), and gain of methylation (10%) was universally detected. At the transcriptome level, pancreatoblastoma exhibited an expression profile characteristic of early pancreas progenitor-like cells along with upregulation of the R-spondin/LGR5/RNF43 module. Our results offer a comprehensive description of the molecular basis for pancreatoblastoma and highlight rational therapeutic targets for its treatment. Significance: Molecular genetic analysis of a rare untreatable pediatric tumor reveals Wnt/IGF2 aberrations and features of early pancreas progenitor-like cells, suggesting cellular origins and rational strategies for therapeutic targeting. Cancer Res; 78(4); 865–76. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1601-1601
    Abstract: Overcoming the treatment resistance of cancer is a problem to be solved in improving the prognosis of cancer patients. Recently, genome analysis has revealed that multiple clusters exist in one tumor, and it has been reported that intratumor heterogeneity causes treatment resistance even in lung cancer. However, the mechanism of intratumor heterogeneity has not yet been clarified. Previous studies of intratumor heterogeneity have mainly focused on analyzing cancer cells from patients, classifying clusters of different properties, and identifying factors that define their characteristics. Multiple clusters are present in the tumor tissue of a single patient, and analysis of multiple patients classifies them into even more clusters, but it is difficult to research all of them. To solve this problem, an early model of intratumor heterogeneity in which homogeneous cells become heterogeneous is needed.We hypothesized that intratumor heterogeneity cell model could be found in resistant strains.Alectinib was exposed in vitro to an ALK-positive lung cancer cell line (H2228) to create an alectinib-resistant cell line (H2228-AR1S). H2228-AR1S has two subpopulations that look different. Of the two subpopulations, the smaller cells have high CD47 expression (CD47 high subpopulation), and the scattered spindle-shaped cells have low CD47 expression (CD47 low subpopulation). Using flow cytometry, each subpopulation was isolated, and its properties were investigated. There was no difference in sensitivity to alectinib between the CD47 high subpopulation and the CD47 low subpopulation. In the low subpopulation of CD47, epithelial markers were decreased, and mesenchymal markers were increased using immunoblotting. It suggests that CD47 low subpopulation has undergone epithelial-mesenchymal transition (EMT). The CD47 high subpopulation had high sphere formation ability in vitro, and high tumorigenicity using Xenograft model. CD47 gene inhibition using siRNA reduced the sphere formation ability of the CD47 high subpopulation. This suggests that CD47 is involved in sphere formation.There have been no reports of CD47 being involved in the characteristics of intratumor heterogeneity. Furthermore, using intratumor heterogeneity cell model, we are exploring the mechanism that regulate division into two subpopulations. Citation Format: Tomoko Y. Funazo, Hiroaki Ozasa, Kentaro Hashimoto, Hiroshi Yoshida, Tatsuya Ogimoto, Kazutaka Hosoya, Hitomi Ajimizu, Takahiro Tsuji, Hironori Yoshida, Ryo Itotani, Yuichi Sakamori, Toyohiro Hirai. CD47 related to intratumor heterogeneity in alectinib-resistant ALK-rearranged lung cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1601.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5335-5335
    Abstract: Background: EGFR mutation-positive lung cancer has high response rates to EGFR-tyrosine kinase inhibitors (TKIs), but eventually acquires resistance to EGFR-TKIs. Acquired resistance mechanisms are diverse because of tumor heterogeneity, which makes it difficult to overcome acquired resistance. Initial resistance is the resistance mechanism of tumor cells that survive the initial treatment. If we could overcome the initial resistance, we could prevent cancer cells from developing various types of acquired resistance. We are now focusing on YAP1 and cancer stem cells, which have been also reported as acquired resistance mechanisms in various types of cancers. Methods: PC-9 cells and HCC827 cells which were EGFR mutation-positive lung cancer cell lines were mainly utilized in our experiments; they were purchased from ECACC and ATCC, respectively. We mainly utilized osimertinib as an EGFR-TKI and verteporfin as a YAP1 inhibitor. The nuclear translocation of YAP1 was confirmed by fluorescence immunostaining. siRNA was utilized to knock down YAP1. Cell viability assays were performed using CellTiter-Glo reagent. qRT-PCR was performed to confirm the gene expression of cancer stem cells. Results: YAP1 is activated by nuclear translocation. In PC-9 cells, YAP1 was localized in the nucleus after osimertinib exposure. In contrast, YAP1 was localized in the nucleus of HCC827 cells before osimertinib exposure and remained in the nucleus even after osimertinib exposure. These data suggest that YAP1 activation is correlated with initial resistance. Cell viability assay showed that both PC-9 cells and HCC827 cells became more sensitive to osimertinib with the knocking down of YAP1. In addition, cell viability assays using PC-9 cells with verteporfin and osimertinib showed increased sensitivity to osimertinib. The gene expression of ALDH1A1 and SOX2 which are involved in cancer stem cells were increased in PC-9 cells after osimertinib exposure. On the other hand, the gene expression of ALDH1A1 was up-regulated but SOX2 was down-regulated in HCC827 cells after osimertinib exposure. We hypothesized that increased gene expression of cancer stem cells occurred downstream of YAP1 followed by initial resistance, thus we are currently confirming the gene alteration of cancer stem cells associated with osimertinib exposure with the knocking down YAP1. We are also considering the investigation of combination therapy of EGFR-TKIs and YAP1 inhibitors in vivo studies. Conclusions: YAP1 and cancer stem cells may be involved in initial resistance mechanisms to EGFR-TKIs in EGFR mutation-positive lung cancer. Our results suggest that especially YAP1 can be a potential therapeutic target, thus we will continue additional studies of combination therapy of EGFR-TKIs and YAP1 inhibitors. In addition, we will continue to investigate whether the gene for cancer stem cells acts downstream of YAP1. Citation Format: Tatsuya Ogimoto, Hiroaki Ozasa, Kentaro Hashimoto, Hiroshi Yoshida, Kazutaka Hosoya, Masatoshi Yamazoe, Hitomi Ajimizu, Tomoko Funazo, Takahiro Tsuji, Hironori Yoshida, Ryo Itotani, Yuichi Sakamori, Toyohiro Hirai. Elucidation of initial resistance mechanisms in EGFR mutation-positive lung cancer focusing on YAP1 and cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5335.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 4
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    Online Resource
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1907-1907
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1907-1907
    Abstract: [Introduction] Tenascin-C (TN-C), an extracellular matrix molecules, is highly expressed in cancer stroma. Recent studies have demonstrated that cancer associated fibroblasts (CAFs) expressed TN-C in many tumors, including breast cancer. Here, we clarified the effects of TN-C on phenotype changes of the fibroblasts. [Methods] We examined the cell morphology, expression of CAFs markers, and contractile ability in the fibroblasts after TNC treatment in vitro, using human mammary gland fibroblasts (HMFs) and dermal ones (HDFs). We also investigated the correlation between the expression of the CAF markers and TNC deposition in human breast cancer tissues, using immunohistochemical staining. [Results] TN-C (10μg/mL) induced morphological changes of HMFs from spindle-shaped cells to stellate-shaped cells on plastic as well as on glass coverslips. After the treatment of TN-C, the protein expressions of α-SMA and calponin were significantly increased. Immunofluorescence analysis revealed TN-C increased the actin-stress fiber formation and the expression of α-SMA and calponin. Furthermore, TN-C promoted contraction of collagen gel by HMFs. These results indicated TN-C induces transformation of HMFs into high-contractile myofibroblasts. In human breast cancer tissues, α-SMA and calponin-positive fibroblasts were localized in TN-C-positive cancer stroma. Interestingly, calponin-expressing fibroblasts were not observed in the skin metastatic lesions of breast cancer. In addition, the increased expression of α-SMA and calponin after TN-C treatment in HDFs were significantly lower compared to HMFs in vitro. These results suggested the responses of TN-C on fibroblasts differs according to the residential tissues. Next, we examined the receptor to TNC and signaling pathway for TNC-induced change of HMFs. TN-C increased the colocalization of integrin αv and β1 in focal adhesion. Furthermore, phosphorylation of SMAD2 and SMAD3 were significantly increased and SMAD3 translocated from cytoplasm to nucleus after TN-C addition. Inhibition of TGF-β type I receptor (SB-505124) or SMAD3 (SIS3) suppressed the expression of α-SMA and calponin after TN-C treatment. [Conclusion] TNC could contribute cancer stroma formation characteristics of breast cancer tissues, following induction of phenotypical change to myofibroblasts and enhanced stromal contraction via integrin αvβ1/TGF-β/SMAD signaling. Phenotypic differences between HMFs and HDFs after TN-C administration may be present. Citation Format: Daisuke Katoh, Aya Noro, Kyoko Imanaka-Yoshida, Tomoko Ogawa, Toshimichi Yoshida. Tenascin-C promotes the activation of mammary fibroblasts to calponin-expressing myofibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1907.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 5
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 22, No. 12_Supplement ( 2023-12-01), p. A004-A004
    Abstract: Background: Studies of diacylglycerol kinase ζ (DGKζ) in DGKζ-knockout mice have revealed its role as an intracellular immune checkpoint in T cells. Although enhancing antitumor immunity by pharmacological inhibition of DGKζ is desirable, selective DGKζ inhibitors for clinical use remain largely unexplored. Here, we report a novel, small-molecule, DGKζ inhibitor—ASP1570—which is currently under phase 1 development (NCT05083481), and describe its nonclinical properties and potential application in cancer immunotherapy. Methods: ASP1570 was characterized by evaluating T cell receptor signaling and T cell function under immunosuppressive conditions relevant to the tumor microenvironment. Antitumor efficacy was evaluated in 2 types of syngeneic mouse models: anti-PD-1-antibody–sensitive MC38 and anti-PD-1-antibody–insensitive B16F1/F10. Results: ASP1570 enhanced T cell activation with increased diacylglycerol downstream signaling and released anergic T cells from their hyporesponsive state. Further, ASP1570 restored T cell functions suppressed by multiple immunosuppressive signals (TGF-β, prostaglandin E2, adenosine, PD-1, CTLA-4, and TIGIT) and induced tumor-growth inhibition in MC38 and B16F1/F10 syngeneic mouse models. The antitumor efficacy of ASP1570 was cancelled by CD8+ T cell depletion, indicating that its antitumor effect depends on CD8+ cytotoxic T cell activation. Conclusions: ASP1570 potentially improves antitumor efficacy in both anti-PD-1-therapy–resistant and anti-PD-1-therapy–responsive tumors by overcoming multiple immunosuppressive signals. Citation Format: Osamu Ikeda, Aya Kikuchi, Hirofumi Tsuzuki, Toshihiro Matsuda, Jane Weng, Tomoko Kawashima, Tetsuo Kiso, Atsushi Suzuki, Takeyuki Nagashima, Tomoyuki Suzuki, Kazuya Yamano, Taku Yoshida. Enhanced antitumor immunity by ASP1570 in mouse models: A novel DGKζ inhibitor offers a potential immunotherapy for treating cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A004.
    Type of Medium: Online Resource
    ISSN: 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 6
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    Online Resource
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 295-295
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 295-295
    Abstract: Lung cancer is the leading cause of cancer death. Small cell lung cancer (SCLC) is a histologic subtype of lung cancer and the proportion of SCLC is approximately 15%. New molecular targeted drugs and immune checkpoint inhibitors are successfully effective for non-small cell lung cancer. However, treatment of SCLC has not been improved over recent decades. It is important to explore new treatment strategies of SCLC. MCL1 is a member of the BCL-2 family, which regulates apoptosis. Targeting MCL1 represents a potential breakthrough of cancer treatment. We tested S63845, a MCL1 inhibitor, in four SCLC cell lines (DMS114, DMS53, SW1271, and NCI-H69) and, in addition, one patient derived SCLC cell (KTOR201). S63845 had greater efficacy in two of five SCLC cells (DMS114 and KTOR201). These two SCLC cells had higher expression of MCL1 and lower expression of BCL-XL, which is another member of the BCL-2 family. The other three SCLC cells (DMS53, SW1271 and NCI-H69) were resistant to S63845 and had a higher expression of BCL-XL or lower expression of MCL1. These data suggested that S63845 might be a powerful treatment of SCLC as a new therapeutic strategy. It is possible that the expressions of MCL1 and other members of the BCL-2 family predict the sensitivity of S63845. Citation Format: Yuto Yasuda, Hiroaki Ozasa, Takahiro Tsuji, Takashi Nomizo, Tomoko Funazo, Hironori Yoshida, Yuichi Sakamori, Toyohiro Hirai, Young Hak Kim. Efficacy of MCL1 inhibitor S63845 in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 295.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 7
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2604-2604
    Abstract: Treatment of lung cancer is improved recently, especially immune-check point inhibitors prolong progression-free survival (PFS) and overall survival (OS), however, Lung cancer is still leading cause of death worldwide. This is because of response rates in the treatment of non-small cell lung cancer (NSCLC) with combination platinum-based chemotherapy vary from 20% to 40%, and response rates of the treatment of NSCLC with nivolumab is around 20%, whereas with leaving a large number of patients with either stable or progressive disease. It is currently difficult to predict treatment response to chemotherapy and nivolumab since there are no precise biomarkers for it. Recently, we have reported that PD-L1 single nucleotide polymorphisms (SNPs) are associated with response to nivolumab treatment. This study was intended to determine the efficacy of platinum-based combination chemotherapy either in a doublet or triplet, and nivolumab treatment respect to PD-L1 SNPs among patients with NSCLC. A total of 139 patients with NSCLC were treated with platinum-based doublet or triplet chemotherapy, 73 patients treated with nivolumab and were also evaluated for PD-L1 SNPs from plasma DNA. We investigated the association among PD-L1 SNPs, objective response rate (ORR) and PFS. PD-L1 rs2282055 was associated with ORR and PFS in the patients treated with pulatinum-based chemotherapy and nivolumab. In the patients treated with nivolumab, the ORR was 24%, 12%, and 0% for the G/G, G/T and T/T genotypes of PD-L1 rs2282055, respectively. The G allele of PD-L1 rs2282055 was significantly associated with better clinical response compared with the T allele (P = 0.0056 [Cochran-Armitage trend test]). The median PFS time was 2.1 months (95% confidence interval [CI] , 1.8 months to 3.9 months) for the G/G and G/T genotypes and 2.2 months (95% confidence interval [CI], 0.9 months to 2.6 months) for the T/T genotype (P = 0.0210). On the other hand, The T allele of PD-L1 rs2282055 was significantly associated with better clinical response compared with the G allele in the patients treated with platinum-based combination chemotherapy either in a doublet or triplet (P = 0.0080 [Cochran-Armitage trend test] ). The median PFS time was 11.0 months (95% confidence interval [CI], 6.2 months to 16.3 months) for the T/T genotypes and 7.3 months (95% confidence interval [CI] , 6.0 months to 8.2 months) for the G/T and G/G genotype (P = 0.0284). In conclusion, these results suggest that the T/T genotype of PD-L1 SNP rs2282055 associated with the better treatment effect of platinum-based combination chemotherapy, on the contrary, the T/T of rs2282055 negatively associated with response to nivolumab treatment. It might be used as a biomaker for selection of the regimen of NSCLC treatment. Citation Format: Takashi Nomizo, Hiroaki Ozasa, Takahiro Tsuji, Tomoko Funazo, Yuto Yasuda, Hironori Yoshida, Yuichi Sakamori, Toyohiro Hirai, Yong Hak Kim. PD-L1 rs2282055 is associated with opposite treatment effect between platinum-based chemotherapy and nivolumab treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2604.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 8
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 9_Supplement ( 2015-05-01), p. P5-15-09-P5-15-09
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9_Supplement ( 2015-05-01), p. P5-15-09-P5-15-09
    Abstract: Background: Many breast cancer patients suffer hair loss due to chemotherapy, and not only scalp hair loss, but also eyebrow loss, eyelash loss and nail changes induced by chemotherapy are traumatic for patients. These side effects diminish self-esteem and greatly reduce quality of life. However, there has been little research in this field until now. To clarify the actual situation concerning appearance issues in breast cancer patients who received adjuvant chemotherapy, and to consider a support system for these patients, we conducted a questionnaire survey. Methods: Disease-free breast cancer patients who have received adjuvant chemotherapy containing anthracycline and/or taxane within 5 years were recruited from 47 hospitals or clinics in Japan from April to October 2013. The patients participating in this survey completed a 65-question questionnaire concerning appearance issues (48) and their perception of physical and non-physical side effects (17). The drugs administered and treatment period were filled out by their doctors beforehand. The completed questionnaires were mailed directly to the data center by the patients. Results: A total of 1511 patients returned the questionnaire to the data center with a response rate of 82% (1511/1853). Since 33 patients did not meet the entry criteria, the questionnaires returned by 1478 patients were analyzed in this survey. The mean age was 54.7 years (+-10.4, range 17-79). The distribution of the patients by time from the end of chemotherapy to this survey was as follows: & lt; 1 year: 28%; 1 to 2 years: 24%; 2 to 3 years: 19%; 3 to 4 years: 15%; 4 to 5 years: 13%. In this survey, the side effect that most patients (92%) considered traumatic was hair loss. The second most traumatic side effect was fatigue (83%), while the 7th place was taken by nail changes (72%) and nausea/vomiting was in the 10th place (56%). During chemotherapy, scalp hair loss occurred in 98% of patients. Eyebrows fell out in 90% and complete eyebrow loss occurred in 36%. Eyelashes fell out in 88% and complete eyelash loss occurred in 37%. Fingernail changes occurred in 77% and toenail changes in 62%. In 60-70%, scalp hair, eyebrow and eyelashes recovered to the original appearance by 1 to 1.5 years after chemotherapy, but in 3-7%, scalp and face hair loss did not recover at all by 1 to 1.5 years. This proportion remained almost the same for 1.5 to 5 years too. During or after chemotherapy, 84% of patients used wigs. This decreased to 47% by 1 year after chemotherapy and 15.2% by 1.5 years. However 10% of patients were still using a wig 4 to 5 years after chemotherapy. Approximately 30% of the patients had trouble using and selecting a wig. In 51% of the patients, sufficient information on scalp hair loss was obtained. However, sufficient information on eyebrow loss, eyelash loss and nail changes was only obtained from 28%, 25% and 31%, respectively. Conclusions: Our survey demonstrated the outline of hair loss and appearance issues in breast cancer patients who received chemotherapy. Hair loss is the most distressing and occasionally long-lasting side effect. Lack of information is a serious problem. These facts suggested a need for long-time and careful support of these patients. Citation Format: Takanori Watanabe, Hiroshi Yagata, Mitsue Saito, Hiroko Okada, Tomoko Takayama, Hirohisa Imai, Yuko Yoshida, Nao Tamai, Keiko Nozawa, Tamiko Yajima, Kojiro Shimozuma. National survey of chemotherapy-induced appearance issues in breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-09.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 9
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    Online Resource
    American Association for Cancer Research (AACR) ; 2013
    In:  Clinical Cancer Research Vol. 19, No. 23 ( 2013-12-01), p. 6473-6483
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 23 ( 2013-12-01), p. 6473-6483
    Abstract: Purpose: Cidofovir (CDV) is an U.S. Food and Drug Administration (FDA)-approved nucleoside antiviral agent used to treat severe human cytomegalovirus (HCMV) infection. Until now, no clear therapeutic effects of CDV have been reported outside of the setting of viral infection, including a potential role for CDV as an antineoplastic agent for the treatment of brain tumors. Experimental Design: We investigated the cytotoxicity of CDV against the glioblastoma cells, U87MG and primary SF7796, both in vitro and in vivo, using an intracranial xenograft model. Standard techniques for cell culturing, immunohistochemistry, Western blotting, and real-time PCR were employed. The survival of athymic mice (n = 8–10 per group) bearing glioblastoma tumors, treated with CDV alone or in combination with radiation, was analyzed by the Kaplan–Meier method and evaluated with a two-sided log-rank test. Results: CDV possesses potent antineoplastic activity against HCMV-infected glioblastoma cells. This activity is associated with the inhibition of HCMV gene expression and with activation of cellular apoptosis. Surprisingly, we also determined that CDV induces glioblastoma cell death in the absence of HCMV infection. CDV is incorporated into tumor cell DNA, which promotes double-stranded DNA breaks and induces apoptosis. In the setting of ionizing radiotherapy, the standard of care for glioblastoma in humans, CDV augments radiation-induced DNA damage and, further, promotes tumor cell death. Combination therapy with CDV and radiotherapy significantly extended the survival of mice bearing intracranial glioblastoma tumors. Conclusion: We have identified a novel antiglioma property of the FDA-approved drug CDV, which heightens the cytotoxic effect of radiotherapy, the standard of care therapy for glioblastoma. Clin Cancer Res; 19(23); 6473–83. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5541-5541
    Abstract: Although Nivolumab is one of the immune-checkpoint inhibitors that improves the prognosis of lung cancer, it is known to cause immune-related adverse events (irAEs). It has recently been reported that patients with irAEs have a longer progression-free survival (PFS) than those without irAEs. However, there are few detailed reports on irAEs in patients with NSCLC. We previously reported the association between single nucleotide polymorphisms (SNPs) of programmed death ligand 1 (PD-L1) and PFS for nivolumab treatment. Therefore, we hypothesized that the SNPs of programed death 1 (PD-1) and PD-L1 were associated with irAEs and PFS. Between January 2016 and March 2017, 95 consecutive patients with advanced NSCLC were treated with nivolumab and 80 of these patients participated in this study. Patients who did not provide informed consent, patients without follow-up blood tests, patients with double cancer history, and patients diagnosed with disease progression within 15 days were excluded. The prevalence of genotypes between patients with adverse events and those without adverse events was evaluated. PFS was calculated in 59 out of 80 patients excluding liver metastasis at baseline imaging. The response rate was 15% and the median PFS was 85 days in this cohort. For all adverse events, hypothyroidism, which is defined as a low free T4 level, was associated with SNPs of PD-L1: rs1411262 and rs822339. Moreover, patients with hypothyroidism had a significantly longer PFS than those without hypothyroidism (67 days vs N.R.; P= 0.0055). The T/T genotype of rs1411262 and the A/A genotype of rs822339 were significantly associated with longer PFS than the C/T and C/C genotypes of rs1411262, and the A/G and G/G genotypes of rs822339, respectively (82 versus 175 days; P = 0.0468). In conclusion, the T allele of rs1411262 and the A allele of rs822339 were significantly associated with hypothyroidism and longer PFS. SNPs of PD-L1 may be associated with functions of the PD-1 and PD-L1 pathway. Hypothyroidism and SNPs of PD-L1hypothyroidism (-)hypothyroidism (+)P value(n=7)(n=73)rs14112620190.0386CC336CT418TTrs822339AA0190.0386AG336GG418 Citation Format: Tomoko Funazo, Hiroaki Ozasa, Takashi Nomizo, Takahiro Tsuji, Yuto Yasuda, Hironori Yoshida, Yuichi Sakamori, Hiroki Nagai, Toyohiro Hirai, Young Hak Kim. Clinical impact of hypothyroidism and PD-L1 SNPs in patients having non-small cell lung cancer treated with nivolumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5541.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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