bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 651: The clinical significance of tissue miR-124 methylation in sporadic and ulcerative colitis-associated colorectal cancer.
Authors: Toiyama Yuji , Hur Keun , Tanaka Koji , Inoue Yasuhiro , Nagasaka Takeshi , Kusunoki Masato , Boland C. Richard , Goel Ajay 
Published: August 2014

Abstract
Background: Growing evidence indicates that the expression of several miRNAs can be epigenetically regulated through methylation of their promoter CpG sequences. MiR-124 is one such tumor suppressive miRNA, which is expressed at lower levels in various human cancers due to methylation of its promoter region. The present study aimed to determine miR-124 methylation status and determine its clinical significance in sporadic and ulcerative colitis-associated colorectal cancer (CRC). Materials & Methods: We analyzed 579 colorectal tissues, which included 176 sporadic CRC and the corresponding adjacent normal colonic mucosa (NC), 57 colorectal adenomas and 20 normal colonic mucosae from non-cancer patients (NN). In addition, we also examined 135 normal mucosae (N-UC), 12 dysplasia(D-UC) and 12 colitic cancers (C-UC) from UC patients. We performed quantitative bisulfite pyrosequencing analysis to determine miR-124 promoter methylation levels. Results: MiR-124 methylation rate was significantly higher in CRCs and adenomas compared to NC or NN (P&lt;0.0001, CRC vs. NC; P&lt;0.0001, CRC vs. NN). Receiver operating characteristic (ROC) analysis revealed that methylation levels of miR-124 can robustly discriminate patients with CRC (AUC=0.977) and adenomas (AUC=0.985) from healthy controls. Kaplan-Meier survival analysis showed that patients with high miR-124 methylation demonstrated poor overall survival (p=0.001), and high miR-124 methylation was an independent prognostic factor of sporadic CRC (p=0.028). Similarly, miR-124 methylation was significantly higher in C-UC and D-UC compared to N-UC (p&lt;0.0001). ROC analysis showed that miR-124 methylation can successfully discriminate C-UC (AUC=0.978) and D-UC (AUC=0.884) from N-UC. Interestingly, high levels of miR-124 methylation in rectal specimens were an independent predictor for the development of UC-associated CRC. Conclusions: miR-124 methylation is an early event in sporadic, as well as ulcerative colitis-associated CRC. Since miR-124 methylation could robustly identify patients with colorectal adenomas and cancers, this miRNA has the potential to serve as a diagnostic marker in colorectal neoplasia.
Citation Format: Yuji Toiyama, Keun Hur, Koji Tanaka, Yasuhiro Inoue, Takeshi Nagasaka, Masato Kusunoki, C. Richard Boland, Ajay Goel. The clinical significance of tissue miR-124 methylation in sporadic and ulcerative colitis-associated colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 651. doi:10.1158/1538-7445.AM2013-651
Abstract 672: Histone deacetylase inhibition has potential to suppresse growth of androgen dependent and independent prostate cancer in vitro and in vivo.
Authors: Sato Shinya , Suzuki Shugo , Naiki-Ito Aya , Yamashita Yoriko , Asamoto Makoto , Shirai Tomoyuki , Takahashi Satoru 
Published: August 2014

Abstract
Histone acetylation plays an important role in chromatin remodeling and gene expression. Histone deacetylase (HDAC) inhibitors regulate gene expressions through the induction of histone acetylation and have been reported to suppress growth of several malignancies including lymphoma. In this study, we examined the effects of one example on androgen dependent and independent prostate cancer growth in vivo and in vitro. In in vitro study, androgen dependent and independent prostate cancer cell lines (LNCaP and VCaP) were used. The HDAC inhibitor, OBP-801 (Generously donated by Dr. Urata, Oncolys Biopharma), significantly suppressed cell proliferation with induction of G2/M arrest, and decreased expression of cdc2, androgen receptor (AR) and PSA protein in both cell lines. OBP-801 also significantly induced apoptosis with activation of caspase 3 in LNCaP. Next, we performed two in vivo experiments. First, we transplanted an androgen independent rat prostate cancer (PLS-P) into the femurs and backs of male F344 rats, and OBP-801 was administered intravenously at doses of 0, 2.5 and 5mg/kg every other day for 2 weeks. OBP-801 significantly reduced the volume of the transplanted tumor, while inducing cleaved caspase 3 protein expression. OBP-801 also suppressed bone destruction and induction of osteoclasts in xenografts transplanted to femurs. Second, we prepared male Transgenic Rat for Adenocarcinoma of Prostate (TRAP) rats which spontaneously develop androgen dependent rat prostate cancers, and OBP-801 was given intravenously at doses of 0, 0.5 and 2mg/kg once a week for 8 weeks. As a result, body weight loss was observed in treated groups, and numbers of carcinoma acini in the lateral and ventral prostates were significantly decreased compared with the control group values. In conclusion, the obtained data suggests that OBP-801 may be a candidate therapeutic or preventing agent for androgen dependent and independent prostate cancer, although side effects such as body weight loss may occur. Elucidation of mechanisms of HDAC underlying these effects is needed.
Citation Format: Shinya Sato, Shugo Suzuki, Aya Naiki-Ito, Yoriko Yamashita, Makoto Asamoto, Tomoyuki Shirai, Satoru Takahashi. Histone deacetylase inhibition has potential to suppresse growth of androgen dependent and independent prostate cancer in vitro and in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 672. doi:10.1158/1538-7445.AM2013-672
Abstract 674: The lysine demethylase KDM1 is a novel therapeutic target for the treatment of gliomas.
Authors: Sareddy Gangadhara R. , Saran Sandeep , Nair Binoj C. , Krishnan Samaya R. , Gonugunta Vijay K. , Brenner Andrew J. , Vadlamudi Ratna K. 
Published: August 2014

Abstract
Glioma development is a multistep process, involving alterations in genetic and epigenetic mechanisms. Understanding the mechanisms and enzymes that promote epigenetic changes in gliomas are urgently needed to identify novel therapeutic targets. In the present study we explored the significance of histone demethylase KDM1 in glioma progression. In order to know the status of expression of KDM1, we utilized glioma tissue microarrays which consist of different grades of astrocytomas, oligodendrogliomas, ependymomas and normal brain tissues. Immunohistochemical analysis showed that KDM1 expression is overexpressed in the gliomas compared to normal brain, and KDM1 expression levels were positively correlated with histological malignancy. KDM1 expression was also found to be elevated in various established glioma cell lines. To study the functional significance of KDM1 in gliomas, KDM1 expression was silenced using siRNA or its pharmacological inhibition using pargyline or NCL-1. Silencing of KDM1 or inhibition of its enzyme activity significantly reduced the proliferation and colony formation of glioma cells. Mechanistic studies showed that inhibition of KDM1 promoted the acetylation of p53 and up regulation of its target genes p21 and PUMA. Patient-derived primary GBM cells expressed high levels of KDM1 and pharmacological inhibition of KDM1 decreased their proliferation. Further, KDM1 inhibition reduced the expression of stemness markers CD133 and nestin in GBM cells. Mouse xenograft assays revealed that inhibition of KDM1 using pargyline significantly reduced U87 glioma xenograft tumor growth. Inhibition of KDM1 increased levels of H3K4-me2 and H3K9-Ac histone modifications, reduced H3K9-me2 modification and promoted expression of p53 target genes (p21 and PUMA), leading to apoptosis of glioma xenograft tumors. Our results suggest that KDM1 is overexpressed in gliomas and could be a potential therapeutic target for the treatment of gliomas.
Citation Format: Gangadhara R. Sareddy, Sandeep Saran, Binoj C. Nair, Samaya R. Krishnan, Vijay K. Gonugunta, Andrew J. Brenner, Ratna K. Vadlamudi. The lysine demethylase KDM1 is a novel therapeutic target for the treatment of gliomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 674. doi:10.1158/1538-7445.AM2013-674
Abstract 682: Synergistic effects of CG200745 combining with Gemcitabine and/or Erotinib in pancreatic cancer.
Authors: Ro Seonggu , Hong Jang-Won , Kwon Sool-Ki , Cha Hyunju , Jung Dong Sub , Chang Ho-Jin , Cho Joong Myung 
Published: August 2014

Abstract
CG200745 is a HDAC inhibitor at the final stage of phase I clinical trial. In the current human studies with patient with terminal solid tumors, CG200745 is showing highly desirable PK and safety profiles. Actually, the AUC/dose of CG200745 is the highest among all the clinical stage HDAC inhibitors. CG200745 is more distributed in tumor tissue that in plasma. Moreover, SD's (stable disease) were observed even in single dose study. Currently, we are planning phase II studies using regimens combining CG200745 and existing therapy in patients with solid tumors. As a choice of indications, pancreatic cancer was considered based on biological studies and observation in phase I clinical studies.Thus, cellular and xenograft studies of CG200745 using pancreatic cancer cell lines have been carried out in our laboratories. In these studies, treatments of CG200745 combining with gemcitabine and/or erotinib show clear synergistic effects. These results indicate that the combination of CG200745 with existing therapy can be a promising intervention for pancreatic cancer.
Citation Format: Seonggu Ro, Jang-Won Hong, Sool-Ki Kwon, Hyunju Cha, Dong Sub Jung, Ho-Jin Chang, Joong Myung Cho. Synergistic effects of CG200745 combining with Gemcitabine and/or Erotinib in pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 682. doi:10.1158/1538-7445.AM2013-682
Abstract 689: Methylation of miRNA genes is a useful biomarker for detection of bladder cancer.
Authors: Suzuki Hiromu , Shimizu Takashi , Nojima Masanori , Yamamoto Eiichiro , Maruyama Reo 
Published: August 2014

Abstract
Background and aim: Dysregulation of microRNAs (miRNAs) has been implicated in bladder cancer (BCa), though the mechanism is not fully understood. We aimed to explore the involvement of epigenetic alteration of miRNA expression in bladder cancer. Materials and methods: Two BCa cell lines (T24 and UM-UC-3) were treated with 5-aza-2’deoxycytidine (5-aza-dC) and 4-phenylbutyric acid (PBA), after which their miRNA expression profiles were analyzed using a TaqMan Array. Bisulfite pyrosequencing was used to assess miRNA gene methylation in 5 cancer cell lines, 83 primary tumors, and 120 preoperative and 47 postoperative urine samples. Receiver operating characteristic curve analysis was used to assess the diagnostic performance of the miRNA gene panel. Results: Of 664 miRNAs examined, 146 were upregulated by 5-aza-dC plus PBA. CpG islands were identified in the proximal upstream of 23 miRNA genes, and 12 of those were hypermethylated in cell lines. Among them, miR-137, -124-2, -124-3 and -9-3 were frequently and tumor-specifically methylated in primary cancers (miR-137, 68.7%; miR-124-2, 50.6%; miR-124-3, 65.1%; miR-9-3, 45.8%). Methylation of the same four miRNAs in urine specimens enabled BCa detection with 81% sensitivity and 89% specificity; the area under the ROC curve was 0.916. Ectopic expression of silenced miRNAs in BCa cells suppressed growth and cell invasion. Conclusions: Our results indicate that epigenetic silencing of miRNA genes may be involved in the development of BCa and that methylation of miRNA genes could be a useful biomarker for cancer detection.
Citation Format: Hiromu Suzuki, Takashi Shimizu, Masanori Nojima, Eiichiro Yamamoto, Reo Maruyama. Methylation of miRNA genes is a useful biomarker for detection of bladder cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 689. doi:10.1158/1538-7445.AM2013-689
Abstract 695: The generation of a mono-selective CDK7 inhibitor.
Authors: Eickhoff Jan E. , Zischinsky Gunther , Choidas Axel , Habenberger Peter , Wolf Alexander , Degenhardt Carsten , Baumann Matthias , Unger Anke , Ghallab Ahmad , Werchau Doreen , Hengstler Jan , Nussbaumer Peter , Klebl Bert M. 
Published: August 2014

Abstract
Cyclin-depending kinase (CDK) family members that trigger passage through the cell cycle have been considered as attractive cancer targets for at least two decdes Yet, the first generation of pan-specific CDK inhibitors failed to show clinical efficacy due to their small therapeutic window. CDK family members that control processes such as transcription have caught less attention, although experimental evidence for an involvement in different pathological processes is emerging. CDK7 (or CAK) has essential roles in both the cell-division cycle and transcription, and serves as a direct link between the regulation of basal transcription and the cell cycle. In addition to its role as a transcription activator, CDK7 has been reported to act on specific transcription events by phosphorylating a series of specific transcription factors, such as the estrogen receptor and p53. These findings indicate that CDK7 is a potential target for cancer therapy, and perhaps inflammation. The detailed molecular characterization of the biological role of CDK7, as well as its therapeutic validation, is dependent on the development of highly specific and potent CDK7 inhibitors. We have developed a series of CDK7 inhibitors with picomolar potency on CDK7, more than 1000-fold selectivity over any other CDK, and single digit nM inhibition of sensitive cancer cell lines. Interestingly, a broad screen of &gt;200 different tumor cell lines lead to the identification of responder and non-responder cell lines. Non-responder tumor lines, similar to primary cells are at least by a factor of 1000 less sensitive to the inhibition with the mono-selective CDK7 inhibitor. Our findings further indicate that CDK7 is neither essential for general transcription, nor for the progression through the cell cycle. It rather coordinates cell line specific biological processes. The effects of selective CDK7 inhibitors on tumor cell lines are clearly distinct from existing, nonselective pan-CDK inhibitors. The responder status for a subset of cancer cell lines can be predicted with a distinct biomarker. Chemical optimization of the selective inhibitor lead to a compound which shows dose-dependent pharmacological efficacy in mouse xenograft models after oral administration, with no signs of toxicity at the efficacious doses.
Citation Format: Jan E. Eickhoff, Gunther Zischinsky, Axel Choidas, Peter Habenberger, Alexander Wolf, Carsten Degenhardt, Matthias Baumann, Anke Unger, Ahmad Ghallab, Doreen Werchau, Jan Hengstler, Peter Nussbaumer, Bert M. Klebl. The generation of a mono-selective CDK7 inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 695. doi:10.1158/1538-7445.AM2013-695
Abstract 698: MCL1 dependent cells are sensitive to the CDK inhibitor Dinaciclib.
Authors: Hatch Harold , Booher Robert , Perera Samanthi , Nguyen Thi , Dolinski Brian , Al-Assaad Samer , Harmonay Lauren , Schuller Alwin , Angagaw Minilik , Long Brian , Qu Xianlu , Miselis Nathan , Ayers Mark , Nebozhyn Michael , Hirsch Heather , Greenawalt Danielle , Loboda Andrey , Graef Thorseten , Im Ellie , Blanchard Rebecca , Zawel Leigh , Strack Peter 
Published: August 2014

Abstract
Dinaciclib is a potent inhibitor of cyclin dependent kinases (CDKs) 1, 2, 5, and 9 and is currently in Phase 3 for the treatment of refractory chronic lymphocytic leukemia (CLL). To further understand the mechanism of action, identify predictive biomarkers, and find additional cancer types which may benefit from dinaciclib, we evaluated cell viability following 24 hours treatment across a panel of ∼500 cells lines. Hematopoietic cell lines were on average 3-times more sensitive than solid tumor lines. In agreement with previous findings, mRNA expression of the anti-apoptotic family member BCL-xL or the ratio of MCL1-to-BCL-xL continue to be the best predictor of dinaciclib sensitivity in both hematopoietic and solid tumor cell lines. MCL1 appears to be an important target of dinaciclib particularly in MCL1 amplified cell lines. Dependence on MCL1 was established in a panel of 19 breast, NSCLC and SCLC cell lines by depletion of the protein by either dinaciclib treatment or MCL1 RNAi. The NSCLC line H23 was highly dependent on MCL1, as RNAi knockdown decreased viability to &lt;20% and could be rescued by introduction of a non-targeted MCL1 expression construct. In the H23 xenograft, dinaciclib diminished MCL1 levels and induced tumor apoptosis resulting in &gt;80% tumor regression. Cell lines which lacked pro-apoptotic proteins BAX / BAK or harbored a BAX mutation were insensitive to the inhibitor. Using apoptosis defective lines we demonstrate that 24 hours of dinaciclib treatment still impacted cell count by blocking cell cycle progression as measured by FACS. These data demonstrate that both cell cycle block and induction of apoptosis contribute to dinaciclib's mechanism of action. However, the observation that MCL1 and BCL-xL were top genes associated with sensitivity suggests that induction of apoptosis is the predominant mechanism of dinaciclib's anti-tumor effect and warrants further investigation of MCL1 amplification as a predictive biomarker in future clinical studies.
Citation Format: Harold Hatch, Robert Booher, Samanthi Perera, Thi Nguyen, Brian Dolinski, Samer Al-Assaad, Lauren Harmonay, Alwin Schuller, Minilik Angagaw, Brian Long, Xianlu Qu, Nathan Miselis, Mark Ayers, Michael Nebozhyn, Heather Hirsch, Danielle Greenawalt, Andrey Loboda, Thorseten Graef, Ellie Im, Rebecca Blanchard, Leigh Zawel, Peter Strack. MCL1 dependent cells are sensitive to the CDK inhibitor Dinaciclib. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 698. doi:10.1158/1538-7445.AM2013-698
Abstract 701: Characterization of two novel quinoline derivatives that induce apoptosis in a cancer-specific manner.
Authors: Lindamulage Indeewari K. , Vu Hai-Yen , Lee Yi-Fang , Lee Hoyun , Trivedi Piyush 
Published: August 2014

Abstract
Many quinoline-based compounds possess pharmacological properties that are beneficial for the control of various human diseases, including microbial infections, inflammatory-related disorders, cardiovascular conditions, and cancer. The anticancer activities of quinoline compounds are often rendered by their property of inhibiting protein kinases, proteasome activity, tubulin polymerization/depolymerization and DNA repair. To further improve the efficacy and specificity, we created and characterized several quinoline derivatives, which led us to identify CTRI-17 and CTRI-20 as promising leads. We examined their anti-proliferative properties using three human breast cancer cell lines (MDA-MB-468, MDA-MB-231 and MCF-7) and two matching non-cancer breast cell lines (184B5 and MCF10A). In addition, we also examined their efficacy using one leukemic cell line (K-562) and one cervical cell line (HeLa). Data from this study showed that the IC50 values of CTRI-17 and CTRI-20 were 0.1-0.3 μM and 1.2-2.4 μM ranges on cancer and non-cancer cell lines, respectively. Thus, both CTRI-17 and CTRI-20 killed cancer cells 10-20 times more effectively than non-cancer cells. This differential cell killing effects on cancer and non-cancer cells is a highly desirable property for potential anticancer therapeutics. We further found that cancer cells treated with the two compounds resulted in increases of pro-apoptotic proteins such as p53 and Bax, and decreases of anti-apoptotic proteins such as Bcl-2 and survivin. Our data obtained from flow cytometry and confocal microscopy showed that CTRI-17 and CTRI-20 induced prolonged cell cycle arrest at G2/M phase prior to causing apoptosis in cancer cells. However, the two compounds neither induced substantial cell cycle arrest nor caused high levels of apoptosis in non-cancer cells at the same drug concentration. We are currently in the process of determining the detailed functional mechanisms of CTRI-17 and CTRI-20.
Citation Format: Indeewari K. Lindamulage, Hai-Yen Vu, Yi-Fang Lee, Hoyun Lee, Piyush Trivedi. Characterization of two novel quinoline derivatives that induce apoptosis in a cancer-specific manner. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 701. doi:10.1158/1538-7445.AM2013-701
Abstract 703: Caffeine modulates the cell cycle in cancer cells to enhance cisplatin efficacy.
Authors: Miwa Shinji , Yano Shuya , Hiroshima Yukihiko , Tome Yasunori , Uehara Fuminori , Mii Sumiyuki , Kimura Hiroaki , Hayashi Katsuro , Tsuchiya Hiroyuki , Digman Michelle , Gratton Enrico , Hoffman Robert M. 
Published: August 2014

Abstract
Caffeine has been shown to enhance the efficacy of chemotherapy, but the mechanism is not well understood. In this study, we investigated cell-cycle modulation induced by caffeine in combination with cisplatinum treatment of human cancer cells. Proliferation inhibition was determined with a clonogenic assay. Mitotic and apoptotic changes were observed by imaging of 143B dual-color cells, in which GFP is expressed in the nucleus and RFP in the cytoplasm. Modulation of the cell-cycle in combination with cisplatinum was observed using time-lapse imaging analyses of HeLa cells expressing a fluorescent cell-cycle indicator, FUCCI (Fluorescent Ubiquitination-based Cell Cycle Indicator). The clonogenic assay showed that caffeine increased the efficacy of cisplatin on inhibition of cell proliferation. Dual-color imaging demonstrated that cisplatin decreased mitosis and induced apoptosis in 143B cells. The combination of cisplatin and caffeine reduced the decrease of mitosis and increased apoptosis. Time-lapse FUCCI imaging showed that cisplatin strongly induced cell-cycle arrest at the S/G2/M phases in HeLa cells. Caffeine released the cell-cycle arrest induced by cisplatin, resulting in increased cell-killing efficacy. These data indicates that caffeine can effectively modulates the cell-cycle in cancer cells treated with cisplatin and possibly other drugs.
Citation Format: Shinji Miwa, Shuya Yano, Yukihiko Hiroshima, Yasunori Tome, Fuminori Uehara, Sumiyuki Mii, Hiroaki Kimura, Katsuro Hayashi, Hiroyuki Tsuchiya, Michelle Digman, Enrico Gratton, Robert M. Hoffman. Caffeine modulates the cell cycle in cancer cells to enhance cisplatin efficacy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 703. doi:10.1158/1538-7445.AM2013-703