bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 965: Exosome-derived microRNAs contributes to prostate cancer chemoresistance
Authors: Li JIng , Xu Xiaozhen , Guan Hao , Mizokami Atsushi , Keller Evan T. , Yang Xin , Liu Xia , Tan Jiyong , Hu Longyuan , Lu Yi , Zhang Jian 
Published: July 2016

Abstract
Accumulating evidence has demonstrated that certain miRNAs play important roles in cancer cell chemoresistance. However, the pleotropic functions of exosome-derived miRNAs on developing chemoresistance remain unknown. In this study, we aimed to build potential networks of miRNAs, which derived from the exosome of chemoresistant prostate cancer (PCa) cells, with their known target genes using miRNA expression profiling and bioinformatic tools. Global miRNA expression profiles were measured by microarray. Twelve miRNAs were initially selected and validated by qRT-PCR. Known targets of deregulated miRNAs were utilized using DIANA-TarBase database v6.0. The incorporation of deregulated miRNAs and target genes into KEGG pathways were utilized using DIANA-mirPath software. To construct potential miRNA regulatory networks, the overlapping parts of two selected KEGG pathways were visualized by Cytoscape software. We identified 29 deregulated miRNAs, including 19 up and 10 down, in exosome samples derived from two kinds of paclitaxel resistance PCa cells (PC3-TXR and DU145-TXR) compared with their parental cells (PC3 and DU145). The enrichment results of deregulated miRNAs and known target genes showed that a few pathways were correlated with several critical cell signaling pathways. We found that hub hsa-16-5p, hsa-miR-3915, hsa-miR-488-3p, hsa-miR-5004-5p, hsa-miR-23c, hsa-miR-3673, hsa-miR-3654, and hsa-miR-32-5p were potential targets to hub androgen receptor (AR) and phosphatase and tensin homolog (PTEN). Hub TCF4 target genes were mainly regulated by hub hsa-miR3176, hsa-miR-141-3p, hsa-miR-606, hsa-miR381, and hsa-miR-429 miRNAs. These results may provide a linkage between PCa chemoresistance and exosome regulatory networks and thus lead us to propose that PTEN and TCF4 genes may be the important genes which regulated by exosome miRNAs in chemoresistance cancer cells. Supported by NSFC Key Project 81130046; NSFC Project 81171993 and NSFC81272415; Guangxi Key Projects 2013GXNSFEA053004 and 2012GXNSFCB053004; Guangxi Ministry of Education grants 201202ZD022 and 201201ZD004.
Citation Format: JIng Li, Xiaozhen Xu, Hao Guan, Atsushi Mizokami, Evan T. Keller, Xin Yang, Xia Liu, Jiyong Tan, Longyuan Hu, Yi Lu, Jian Zhang. Exosome-derived microRNAs contributes to prostate cancer chemoresistance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 965.
Abstract 982: Long non-coding RNA PICSAR promotes growth of cutaneous squamous cell carcinoma by regulating ERK1/2 activity
Authors: Piipponen Minna , Nissinen Liisa , Farshchian Mehdi , Riihilä Pilvi , Kivisaari Atte , Kallajoki Markku , Peltonen Juha , Peltonen Sirkku , Kähäri. Veli-Matti 
Published: July 2016

Abstract
Keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer, and its incidence is increasing globally. Long non-coding RNAs (lncRNAs) are involved in various biological processes, and their role in cancer progression is emerging. The aim of this study was to find and characterize new biomarkers for evaluating the risk of progression and metastasis of cSCC and identify novel therapeutic targets for recurrent and metastatic cSCC. RNA-sequencing of cSCC cells (n = 8) and normal human epidermal keratinocytes (NHEKs, n = 4) revealed overexpression of a previously uncharacterized long intergenic non-coding RNA (lincRNA), LINC00162 in cSCC cells. Analysis of tissue sections by RNA in situ hybridization showed that LINC00162 is specifically expressed by tumor cells in cSCCs but not by keratinocytes in normal skin in vivo. The expression of LINC00162 in cSCC cells was upregulated by inhibition of the p38α and p38δ MAPKs using BIRB796 or p38α and p38δ specific siRNAs. Knockdown of LINC00162 inhibited proliferation and migration of cSCC cells, and suppressed the growth of human cSCC xenografts in vivo. Furthermore, knockdown of LINC00162 inhibited ERK1/2 activity and upregulated expression of dual specificity phosphatase DUSP6 in cSCC cells. Based on these observations, LINC00162 was named PICSAR (P38 Inhibited Cutaneous Squamous cell carcinoma Associated lincRNA). Our results provide mechanistic evidence for the role of PICSAR in promoting cSCC progression via activation of ERK1/2 signaling pathway by downregulating DUSP6 expression. These results also identify PICSAR as a novel biomarker and putative therapeutic target in cSCC.
Citation Format: Minna Piipponen, Liisa Nissinen, Mehdi Farshchian, Pilvi Riihilä, Atte Kivisaari, Markku Kallajoki, Juha Peltonen, Sirkku Peltonen, Veli-Matti Kähäri. Long non-coding RNA PICSAR promotes growth of cutaneous squamous cell carcinoma by regulating ERK1/2 activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 982.
Abstract 986: Long noncoding RNA CCAT2 cooperates with miR-145 and miR-21 to regulate colon cancer stem cells
Authors: Yu Yingjie , Nangia-Makker Pratima , Farhana Lulu , Majumdar Adhip P. N. 
Published: July 2016

Abstract
Colon cancer-associated transcript-2 (CCAT2), a long noncoding RNA (lncRNA), has been reported to be over-expressed in colorectal cancer to promote tumor growth and metastasis and also reduces sensitivity to chemotherapy, a property related to cancer stem cells (CSCs). MicroRNAs, small endogenous noncoding RNAs, negatively control the expression of target genes by cleaving mRNA or through translation repression. We have recently reported cooperation of miR-21 and miR-145 to regulate colon CSCs proliferation and differentiation. Down-regulation of miR-21 enhances CSC enriched chemo-resistant colon cancer cells’ susceptibility to chemo- therapeutic regimens. Although both CCAT2 and miR-21 increase WNT signaling activity and reduce chemosensitivity to 5-FU, a critical evidence on how CCAT2 regulates stemness leading to chemo-resistance is lacking. The primary goal of this investigation was to examine whether CCAT2 associates with miR-145 and miR-21 and whether this association plays a role in regulating stemness of colon cancer cells. We have observed that CCAT2 transcript level is dependent on p53 expression and activity, as evidenced by a marked increase in CCAT2 expression in p53 wild type harboring HCT-116 colon cancer cells compared with p53 null HCT-116 and p53 mutant HT-29 cells. We further revealed that knockdown of CCAT2 increased the expression of miR-145 and negatively regulates miR-21 in HCT-116 cells and impairs proliferation and differentiation of these cells. On the other hand, upregulation of CCAT2 induces proliferation of HCT-116 cells and also increases the expression of CSC markers CD44 and CD166. We have also observed that miR-145 and miR-21 cooperation plays a role in regulating colon cancer stem cells by down-regulating Sox2 and increased activity of Wnt/β-catenin pathway. Our current results suggest that lncRNA CCAT2 cooperates with miR-145 and miR-21 to regulate colon cancer stem cells, which provides a potential therapeutic target for chemoresistance in colorectal cancer.
Citation Format: Yingjie Yu, Pratima Nangia-Makker, Lulu Farhana, Adhip P. N. Majumdar. Long noncoding RNA CCAT2 cooperates with miR-145 and miR-21 to regulate colon cancer stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 986.
Abstract 998: LncRNA WDFY3-AS2 contributes to the EMT and metastasis in breast cancer
Authors: Richards Edward , Challa Sridevi , Li Yajuan , Permuth-Wey Jennifer , Bui Marilyn , Coppola Domenico , Sellers Thomas , Cheng Jin 
Published: July 2016

Abstract
The role of TGFβ in promoting mammary cell EMT and breast cancer metastasis was well established. However, the involvement of long non-coding RNA (lncRNA) in this process remains elusive. Here we demonstrated that mouse lncRNA BB179049 and its human ortholog WDFY3-AS2 were significantly increased upon TGFβ-induced EMT. WDFY3-AS2 was frequently elevated in invasive, metastatic and triple-negative breast cancer. Depletion of WDFY3-AS2 abrogated TGFβ-induced EMT and breast cancer metastasis. WDFY3-AS2 positively regulates STAT3 and WDFY3 through interaction with hnRNP-R. These data indicate that WDFY3-AS2 could play a pivotal role in TGFβ-induced EMT and metastasis and serves as a critical therapeutic target in aggressive breast cancer.
Citation Format: Edward Richards, Sridevi Challa, Yajuan Li, Jennifer Permuth-Wey, Marilyn Bui, Domenico Coppola, Thomas Sellers, Jin Cheng. LncRNA WDFY3-AS2 contributes to the EMT and metastasis in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 998.
Abstract CT029: The effect of tazemetostat on CYP3A-mediated metabolism of midazolam in patients with solid tumors
Authors: Smith Sherri , Suttle Benjamin , Waters Nigel L. , Ribrag Vincent , Italiano Antoine , Michot Jean-Marie , Postel-Vinay Sophie , Toulmonde Maud , Cousin Sophie , Roche Maria , Pimentel Patricia , Ho Peter 
Published: July 2016

Abstract
Background: Tazemetostat is a selective oral small molecule inhibitor of enhancer of zeste homolog 2 (EZH2). Results from in vitro studies using human liver microsomes, recombinant CYP isoforms, and hepatocytes demonstrated that tazemetostat is an inhibitor, inducer, and substrate of CYP3A4. Previous results indicated that systemic exposure to tazemetostat decreased after multiple dose administration in patients with cancer, consistent with net induction of CYP3A-mediated metabolism. Therefore, a drug-drug interaction sub-study was performed as part of the ongoing study E7438-G000-101 (NCT01897571).
Purpose: To investigate the effect of tazemetostat on CYP3A-mediated metabolism in patients with solid tumors using midazolam as a sensitive CYP3A probe substrate.
Methods: This was a single-sequence, open-label, crossover study. Patients with solid tumors (n = 13) received a single oral dose of 2 mg midazolam on Day -1 and on Day 15. Tazemetostat 800 mg twice daily (BID) was administered continuously starting on Day 1. Serial blood samples for the analysis of plasma midazolam and metabolites were collected over 24 h on Day -1 (midazolam alone) and Day 15 (midazolam plus tazemetostat).
Results: A summary of midazolam pharmacokinetic parameters after administration alone and with tazemetostat 800 mg BID in 12 evaluable patients is presented below: ParameterDay -1aDay 15aGLSMRb (90% CI)AUC(0-∞) ng*h/mL51.9 (87.2)31.1 (48.1)0.60 (0.46, 0.78)Cmax ng/mL16.5 (94.3)13.0 (48.3)0.78 (0.57, 1.08)t1/2 h5.67 (34.3)4.25 (32.4)NCaData presented as geometric mean (%CV)bGLSMR = geometric least squares mean ratioNC = not calculated
Plasma midazolam AUC(0-?) and Cmax decreased approximately 40% and 22%, respectively, after administration with tazemetostat 800 mg BID relative to administration of midazolam alone. Geometric mean t1/2 for midazolam decreased approximately 25%, after administration of midazolam with tazemetostat 800 mg BID relative to administration of midazolam alone.
Conclusions: Administration of tazemetostat 800 mg BID resulted in net induction of CYP3A-mediated metabolism in patients with cancer. Tazemetostat 800 mg BID resulted in a less than 50% decrease in midazolam AUC and therefore is a weak inducer of CYP3A-mediated metabolism.
Citation Format: Sherri Smith, Benjamin Suttle, Nigel L. Waters, Vincent Ribrag, Antoine Italiano, Jean-Marie Michot, Sophie Postel-Vinay, Maud Toulmonde, Sophie Cousin, Maria Roche, Patricia Pimentel, Peter Ho. The effect of tazemetostat on CYP3A-mediated metabolism of midazolam in patients with solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT029.
Abstract CT118: Efficient basket trial designs
Authors: Cunanan Kristen M. , Iasonos Alexia , Shen Ronglai , Hyman David , Begg Colin , Gonen Mithat 
Published: July 2016

Abstract
Background: Basket trials are used to study targeted treatments across a range of tumor sites. In these designs all patients have the same target altered and receive the same regimen but they are placed in baskets defined by the site of primary tumor. This design is particularly appealing since the prevalence of the target mutation is typically low in any given tumor site, and the drug sponsor is naturally interested in as broad an indication for use as possible. Given the multiple baskets, this design requires the investigation of whether the activity of the regimen applies uniformly to all baskets, i.e., homogeneity of treatment effect, and if not, which baskets show sufficient response. Many basket trial designs to date have resembled parallel phase II studies, using Simon's two-stage design separately for each basket. The inclusion of multiple baskets increases the overall false positive rate in the trial, an aspect that is commonly not taken into account in current designs. More importantly, the use of independent, parallel phase II trials fails to take advantage of the opportunity to combine baskets in the event that the interim results suggest common responsiveness across baskets, either common evidence of efficacy or common evidence of lack of efficacy.
Methods: We develop a novel, adaptive study design that makes use of an interim assessment of the heterogeneity of treatment effect across baskets to determine the most appropriate statistical analysis, while controlling the overall false positive rate in the trial. Our proposed design allows for aggregation of baskets in stage 2 when evidence points to a common effect of the drug, while retaining the option to maintain selected individual baskets in stage 2, if the interim evidence supports this strategy. Similar to conventional designs, our proposed design allows for early termination of baskets for lack of responsiveness. Using simulations we demonstrate the potential reduction in the number of patients required compared with the traditional strategy based on parallel Simon two-stage designs, while maintaining similar levels of Type I and II errors.
Citation Format: Kristen M. Cunanan, Alexia Iasonos, Ronglai Shen, David Hyman, Colin Begg, Mithat Gonen. Efficient basket trial designs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT118.
Abstract CT124: A phase II study of bevacizumab and irinotecan as second-line therapy for patients with metastatic colorectal cancer previously treated with fluoropyrimidine, oxaliplatin, and bevacizumab
Authors: Nakajima Go , Kuramochi Hidekazu , Ando Masayuki , Itabashi Michio , Kawakami Kazuyuki , Hamano Mie , Hirai Eiichi , Iino Takayuki , Yokomizo Hajime , Okuyama Ryuji , Araida Tatsuo , Yoshimatsu Kazuhiko , Kameoka Shingo , Hayashi Kazuhiko 
Published: July 2016

Abstract
Background: FOLFIRI plus bevacizumab (BV) is widely used as second-line chemotherapy for patients with metastatic colorectal cancer (mCRC) previously treated with FOLFOX/XELOX plus bevacizumab. However, there is insufficient data characterizing the effectiveness of administration of fluoropyrimidine beyond first disease progression. FOLFIRI requires using a CV catheter. Oral fluoropyrimidine may cause severe diarrhea when administered with irinotecan (CPT-11). CPT-11+BV may overcome those problems.
Methods: Patients with mCRC previously treated with at least four courses of fluoropyrimidine, oxaliplatin, and bevacizumab were designated to receive 150 mg/m2 of CPT-11 and 10 mg/kg of BV, every 2 weeks as second-line therapy. The primary endpoint was progression-free survival (PFS), and secondary endpoints included response rate (RR), overall survival (OS), and adverse events.
Results: Thirty patients from six institutes were enrolled from March 2011 to January 2014. Twenty-five (83.3%) patients were refractory to first-line therapy and eight patients (16.6%) were unable to tolerate first-line therapy. The median PFS was 5.7 months (95% CI; 4.2-7.3 months) and the RR was 6.7% (range, 0.8-22.1%. Grades 3-4 adverse events included leucopenia (36.7%), neutropenia (50%), thrombocytopenia (26.7%), anemia (30%), diarrhea (3.3%), anorexia (6.7%), and hypertension (3.3%). Relative dose intensities were 94.5% and 96.3% for CPT-11 and BV, respectively. Median OS was 11.8 months (6.3 months-not reached).
Conclusions: Administration of CPT-11 plus BV to patients with mCRC achieved comparable efficacy with relatively lower toxicities compared with the results of previous studies using FOLFIRI plus BV as second-line therapy. The dose intensity of CPT-11 was judged satisfactory. Clinical trial information: UMIN000005228
Citation Format: Go Nakajima, Hidekazu Kuramochi, Masayuki Ando, Michio Itabashi, Kazuyuki Kawakami, Mie Hamano, Eiichi Hirai, Takayuki Iino, Hajime Yokomizo, Ryuji Okuyama, Tatsuo Araida, Kazuhiko Yoshimatsu, Shingo Kameoka, Kazuhiko Hayashi. A phase II study of bevacizumab and irinotecan as second-line therapy for patients with metastatic colorectal cancer previously treated with fluoropyrimidine, oxaliplatin, and bevacizumab. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT124.
Abstract LB-003: Androgen-regulated proteome reveals a therapeutically relevant androgen receptor coactivator target in prostate cancer
Authors: Asim Mohammad , Massie Charlie , Warren Anne , Luko Katarina , Chohan Brinder , Menon Suraj , Baridi Ajoeb , Orafidiya Folake , Zhao Wanfeng , Escriu Carlos , Mohammed Hisham , D’Santos Clive , Yang Xiaoping , Taylor Chris , Qureshi Arham , Watt Kate , Zecchini Vincent , Selth Luke , Dehm Scott , Mills Ian , Carroll Jason , Tilley Wayne , McEwan Iain , Baniahmad Aria , Neal David 
Published: July 2016

Abstract
Resistance to androgen deprivation therapy (ADT) and the development of castration resistant prostate cancer (CRPC) remains a major challenge in the treatment of advanced prostate cancer (PCa). Elucidation of resistance mechanisms leading to CRPC is essential to develop novel therapeutic interventions. Using a systems biology approach, we interrogated the androgen-regulated proteome and identified a mitotic Kinase as a novel androgen regulated kinase in PCa. The kinase was shown to be androgen-regulated in PCa and its nuclear localisation significantly increased in CRPC and was associated with biochemical relapse. Interestingly, the Kinase interacted directly with the amino terminus transactivation and carboxy terminus ligand binding domain of androgen receptor (AR), resulting in stabilisation of AR protein and its activity. The AR-driven global transcriptional program was regulated by this coactivator kinase including pathways involved in tumour invasion and metastasis. The inhibition of the kinase function decreased AR levels and activity, and slowed growth of PCa cell lines and human PCa explants. Thus the mitotic kinase is a novel AR-Stablised kinase with potential for clinical applications as both a candidate biomarker of PCa progression and a therapeutic target in advanced disease.
Citation Format: Mohammad Asim, Charlie Massie, Anne Warren, Katarina Luko, Brinder Chohan, Suraj Menon, Ajoeb Baridi, Folake Orafidiya, Wanfeng Zhao, Carlos Escriu, Hisham Mohammed, Clive D’Santos, Xiaoping Yang, Chris Taylor, Arham Qureshi, Kate Watt, Vincent Zecchini, Luke Selth, Scott Dehm, Ian Mills, Jason Carroll, Wayne Tilley, Iain McEwan, Aria Baniahmad, David Neal. Androgen-regulated proteome reveals a therapeutically relevant androgen receptor coactivator target in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-003.
Abstract LB-006: Macrophage-dependent activation of Notch1 signaling regulates breast tumor cell intravasation
Authors: Pignatelli Jeanine , Bravo-Cordero Jose Javier , Roh-Johnson Minna , Gandhi Saumil , Wang Yarong , Singer Robert , Hodgson Louis , Oktay Maja , Condeelis John 
Published: July 2016

Abstract
The process of intravasation, a key component to the metastatic cascade, remains poorly understood. How the multi-cell type tumor microenvironment facilitates tumor cell intravasation is largely unknown. Intravital imaging of rodent mammary tumors has shown that direct contact between a Mena expressing tumor cell, a perivascular macrophage and an endothelial cell forms a microanatomical structure named TMEM (Tumor Microenvironment of Metastasis) which is the site where intravasation occurs in mammary tumors. Clinical studies have shown that the number of TMEM is correlated with increased risk of developing distant metastasis in breast cancer patients. While TMEM is an excellent prognostic marker for predicting metastasis, the mechanisms of TMEM assembly and function are not well understood. Recently, we showed that heterotypic cell contact between tumor cells and macrophages induces the formation of invadopodia in tumor cells, invasive structures necessary for matrix degradation and required for tumor cell intravasation. In further work we found that Notch1, a known receptor involved in heterotypic cell contact signaling, is involved. In the absence of Notch1 signaling, macrophage-induced invadopodium formation and tumor cell intravasation are abolished. This heterotypic tumor cell - macrophage interaction regulates the expression profile of Mena in the tumor cell. Upon touching, the transcription of Mena shows a rapid kinetic response, with detectable changes in single transcriptome activity within 1 hour. Inhibition of Notch1 in vivo results in decreased intravasation of mammary tumor cells. Our findings indicate that Notch1 signaling regulates heterotypic cell contact mediated invadopodium formation, transendothelial migration and intravasation and reveals a novel Notch1/Mena pathway as a molecular target to prevent TMEM function and therefore metastasis.
Citation Format: Jeanine Pignatelli, Jose Javier Bravo-Cordero, Minna Roh-Johnson, Saumil Gandhi, Yarong Wang, Robert Singer, Louis Hodgson, Maja Oktay, John Condeelis. Macrophage-dependent activation of Notch1 signaling regulates breast tumor cell intravasation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-006.