bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 967: Establishing mechanisms of acquired resistance to Met inhibitor in Met-addicted gastric cancer cell lines.
Authors: Lai Andrea Z. , Thompson Crista , Cory Sean , Zhao Hong , Chughtai Naila , Hallett Michael , Park Morag 
Published: August 2014

Abstract
Signaling by the Met, hepatocyte growth factor (HGF) receptor tyrosine kinase (RTK) activates multiple downstream signaling pathways that promote cell migration and invasive growth. Cells that overexpress and are “addicted” to Met also require Met signaling to sustain cell survival. Thus, a number of specific small-molecule inhibitors have been developed to target Met in the clinic. Although several successes of RTK-targeted therapies are acknowledged, most have had limited long-term success clinically due to development of drug resistance.
As MET amplification occurs in 10-20% of gastric cancers, and MET-amplified cell lines are often exquisitely dependent on Met signaling for proliferation and survival, we established Met inhibitor-resistant clones derived from two different gastric cancer cell lines (MKN45 and KATO II) that are sensitive to Met inhibition. Treatment with a small-molecule inhibitor, PHA-665752 (PHA), specific to Met abrogates cell proliferation and anchorage-independent growth in these cells. In vitro selection of the most tumorigenic and resistant cells was performed by isolating colonies in anchorage-independent conditions with increasing PHA concentrations. Colonies were picked and expanded in 2D cell culture conditions and PHA concentration gradually increased until the cells were able to proliferate in a PHA concentration of &gt;1μM (10x greater than the dose required for abrogation of proliferation in the parental cell lines).
DNA, RNA, and protein have been isolated from each of the clones and sequencing, microarray analyses, phospho-RTK arrays, reverse-phase protein arrays (RPPA) have been utilized to identify the changes in signalling, protein and transcript expression that allow these cells to escape PHA inhibition. The analyses from these high-throughput assays will be presented here.
As several Met inhibitors are presently in all three phases of clinical trials, and Met signalling has emerged as a means of escaping treatment by other targeted small-molecule kinase inhibitors, there exists a great need to determine the mechanisms through which cells may circumvent Met inhibition. The identification of resistance mechanisms will be essential for developing multi-pronged therapeutic strategies that may prove more efficacious at combatting tumorigenesis.
Citation Format: Andrea Z. Lai, Crista Thompson, Sean Cory, Hong Zhao, Naila Chughtai, Michael Hallett, Morag Park. Establishing mechanisms of acquired resistance to Met inhibitor in Met-addicted gastric cancer cell lines. [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 967. doi:10.1158/1538-7445.AM2013-967
Abstract 980: PD173074, a selective FGFR inhibitor, reverses ABCB1-mediated drug resistance in cancer cells.
Authors: Patel Atish S. , Tiwari Amit , Chufan Eduardo , Singh Satyakam , Sodani Kamlesh , Anreddy Nagaraju , Talele Tanaji , Ambudkar Suresh , Stephani Ralph , Chen Zhe-Sheng 
Published: August 2014

Abstract
Multidrug resistance (MDR) through overexpression of ATP-binding cassette (ABC) transporters has long evaded chemotherapy in cancer patients. Specific tyrosine kinase inhibitors (TKIs) were recently reported to modulate these ABC transporters, leading to an increase in the intracellular concentration of their substrate drugs. Here, we report for the first time, PD173074 an inhibitor of the fibroblast growth factor receptor (FGFR), to selectively inhibit ABC subfamily B member 1 (ABCB1/P-glycoprotein) transporter. PD173074 significantly sensitized both ABCB1 transfected and drug selected cell lines overexpressing this transporter to anticancer drugs colchicine, paclitaxel, and vincristine. This effect of PD173074 is specific, as no significant interaction was detected with other ABC transporters such as ABCC1, and ABCG2. The observed inhibition was primarily due to the decreased active efflux of [3H]-paclitaxel in ABCB1 overexpressing cells. However, no significant change in the ABCB1 expression was observed when ABCB1 overexpressing cells were exposed to 5 μM PD173074 for up to 3 days thereby suggesting its role in modulating the function of the transporter. In addition, PD173074 stimulated the ATPase activity of ABCB1 in a concentration-dependent manner, indicating a direct interaction with the transporter. Interestingly, PD173074 did not inhibit the photolabeling of ABCB1 with [125I]-Iodoarylazidoprazosin (IAAP) showing that it binds at a site different from that of IAAP in the drug-binding pocket. In conclusion, PD173074 could selectively reverse ABCB1-mediated MDR by directly blocking the efflux function of ABCB1.
Citation Format: Atish S. Patel, Amit Tiwari, Eduardo Chufan, Satyakam Singh, Kamlesh Sodani, Nagaraju Anreddy, Tanaji Talele, Suresh Ambudkar, Ralph Stephani, Zhe-Sheng Chen. PD173074, a selective FGFR inhibitor, reverses ABCB1-mediated drug resistance in cancer cells. [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 980. doi:10.1158/1538-7445.AM2013-980
Abstract 990: Efficacy of various chemotherapeutic agents on 5-FU-resistant human gastric cancer cell lines and their mechanisms.
Authors: Nukatsuka Mamoru , Kobunai Takashi , Nakamura Ayako , Hayashi Kazuhiko , Takechi Teiji 
Published: August 2014

Abstract
Purpose: Four 5-fluorouracil (5-FU)-resistant human gastric cancer cell lines were established by the long-term exposure of parent cell lines (MKN45, MKN-74, KATO-III, and NCI-N87) to 5-FU. The cytotoxicity and mechanisms of several chemotherapeutic agents were then investigated using 5-FU-resistant gastric cancer cell lines.
Method: 5-FU-resistant cell lines were established by continuous exposure to escalating concentrations (1-5 μM) of 5-FU over a 1-year period. The sensitivities of the cell lines to chemotherapeutic agents (paclitaxel, docetaxel, cisplatin, oxaliplatin, epirubicin, and SN-38) were then evaluated using the WST-8 colorimetric assay. To elucidate the mechanisms of resistance, the gene expressions and copy numbers were measured using an Agilent Technologies whole human genome oligo DNA microarray and a CGH microarray. The protein and mRNA expressions of a target enzyme of 5-FU, thymidylate synthase (TS), were also investigated using western blotting and RT-PCR, respectively.
Results: The IC50 ratios of the 5-FU-resistant cell lines were 2.6 to 15.6 times higher than those of the parent cell lines in vitro. MKN-45/5-FU showed cross-resistance to cisplatin and oxaliplatin and KATO-III/5-FU showed cross-resistance to SN-38, while MKN-74/5-FU showed collateral sensitivities to docetaxel, cisplatin, and oxaliplatin, and NCI-N87/5-FU showed collateral sensitivities to cisplatin, oxaliplatin, SN-38, and epirubicin. RT-PCR showed that TS mRNA expression was higher in the parent cell lines than in the 5-FU-resistant cell lines, and the TS protein expression level was also higher in all the resistant cell lines. For MKN-45/5-FU and KATO-III/5-FU, not only the mRNA expression level but also the TS gene copy number was increased. Interestingly, the expression of MAP3K15, which is an apoptosis-facilitating factor, increased in NCI-N87/5-FU, which showed collateral sensitivity to cisplatin, oxaliplatin, SN-38, and epirubicin.
Conclusion: Analyzing the molecular mechanisms of 5-FU-resistant cell lines may be useful for the development of effective chemotherapy regimens for relapsed gastric cancer after 5-FU-based chemotherapy.
Citation Format: Mamoru Nukatsuka, Takashi Kobunai, Ayako Nakamura, Kazuhiko Hayashi, Teiji Takechi. Efficacy of various chemotherapeutic agents on 5-FU-resistant human gastric cancer cell lines and their mechanisms. [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 990. doi:10.1158/1538-7445.AM2013-990
Abstract 992: Regulation of ABCG2 lysosomal degradation by xanthines: Role of the PI3K/AKT pathway.
Authors: Ding Rui , Kamen Barton A. , Shi Jia , Scotto Kathleen W. 
Published: August 2014

Abstract
ABCG2 confers multidrug resistance to a wide range of structurally unrelated chemotherapeutic drugs, often resulting in the failure of cancer chemotherapy. Accordingly, the downregulation of ABCG2 expression and/or function has been proposed as part of a regimen to improve cancer therapeutic efficacy. Previously, we have reported that a group of xanthines including caffeine, theophylline and dyphylline can dramatically decrease ABCG2 protein in drug resistant cells, causing a significant increase in the intracellular retention of ABCG2 substrates and sensitization of the cells to chemotherapeutic agents (Ding et al., Mol Pharmacol 81:328-337, 2012). This downregulation of ABCG2 is due to a selective acceleration of its lysosomal degradation by xanthines. We now show that xanthines induce the endocytosis and subsequent degradation of ABCG2. In addition, PI3K/AKT/mTORC1 signaling was found to be involved in mediating the effect of xanthines on ABCG2, since both caffeine and theophylline strongly inhibited activation of AKT and mTORC1, and inhibition of both AKT and mTORC1 mimicked the effect of xanthines on ABCG2. Furthermore, adenosine, a nucleoside vital for purine metabolism and energy homeostasis, fully reversed the downregulation effect of caffeine on ABCG2. Interestingly, this adenosine-mediated effect occurs intracellularly and independent of adenosine receptor signalling, identifying a novel mechanism whereby the xanthine-degradation of ABCG2 is influenced by intracellular levels of adenosine. Importantly, adenosine also blocked the lysosomal degradation of ABCG2 that was induced by PI3K/AKT inhibition, indicating that the adenosine-mediated intracellular events cross-talk with the PI3K/AKT pathway in regulating ABCG2 degradation. This study enhances our understanding of the regulation of ABCG2 internalization and degradation, and identifies new targets for the development of ABCG2 expression/function modulating agents for chemosensitization.
Citation Format: Rui Ding, Barton A. Kamen, Jia Shi, Kathleen W. Scotto. Regulation of ABCG2 lysosomal degradation by xanthines: Role of the PI3K/AKT pathway. [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 992. doi:10.1158/1538-7445.AM2013-992
Abstract ADV08: Bridging the gaps in service.
Authors: Dauria Mary Kay 
Published: August 2014

Abstract
Susan's Rally is a Houston based 501c3 organization that started as a group supporting breast cancer research and has expanded to support services provided for those with all types of cancer. What began as a fun road rally for Bruce and Susan Roberson morphed into a fun-raising event for cancer after Susan was taken by breast cancer. For 17 years, Bruce and his friends have continued the rally in her honor and now the proceeds from the rally, golf tournament, and auctions are used to fight the disease and assist with providing patients support services.
Susan's Rally has raised over a million dollars in cash and in-kind donations utilizing all volunteer labor. Except for a few office supplies, postage and printing, all of Susan's Rally dollars go to fight cancer and support patients. Some of the programs supported included MD Anderson Patients Support Network, research at the Christus Stehlin Foundation for Cancer Research, provide diagnostic imaging for uninsured women at The Rose, counseling at Y-Me, and assists with making available low-cost short-term housing at The Sojourn House-Apartment, homes for cancer patients. In 2012 Susan's Rally also began funding “Dia De la Mujer community health festivals providing free breast exams, HIV testing an pap smears for women in need.
Citation Format: Mary Kay Dauria. Bridging the gaps in service. [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 ADV08. doi:10.1158/1538-7445.AM2013-ADV08
Abstract ADV09: Bladder cancer basics.
Authors: Hoffman Vanessa 
Published: August 2014

Abstract
The Bladder Cancer Advocacy Network's (BCAN) mission is to increase public awareness about bladder cancer, to advance bladder cancer research, and to provide educational and support services for the bladder cancer community. BCAN works to serve over 520,000 bladder cancer survivors and 73,000 newly diagnosed patients each year in the United States. BCAN engages in many initiatives and programs. BCAN's current initiatives include the Women's Outreach Initiative and Veterans’ Outreach Initiative, which are engaging national task forces to raise awareness of bladder cancer among these constituencies.
In patient education and support, BCAN's website: www/bacan.org- is one of the most comprehensive bladder cancer resources on the internet. BCAN also provides free bladder cancer patient education materials including patient tip sheets and a patient handbook-Bladder Cancer Basics for the Newly Diagnosed, which was revised this year and is now available in Spanish. BCAN offers Patient Insight Webinars throughout the year. BCAN also provides a free clinical trial matching service in coordination with Emerging Med, to help people obtain specific information about participating in bladder cancer research trials. BCAN staff answers patient calls and e-mails for more information, resources, and support. BCAN has facilitated the development of in-person bladder cancer support groups around the country and offers access to an online bladder cancer support community.
BCAN also offers the Young Investigator Awards, announced this year, for three awards of $100,000 over two years, to increase the understanding of bladder cancer risk, biology, prevention, and treatment while encouraging young investigators to pursue a career in bladder cancer research. BCAN is also engaged in advocacy with staff members and volunteers serving on panels and participating in coalitions. BCAN has coordinated Walks for Bladder Cancer to raise awareness of the disease since 2011, on the first Saturday in May. In 2012, the Walks for Bladder Cancer held on May 5 took place in 60 communities, had more than 5,000 participants and raised more than $275,000.
Citation Format: Vanessa Hoffman. Bladder cancer basics. [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 ADV09. doi:10.1158/1538-7445.AM2013-ADV09
Abstract LB-100: Exploring the mechanisms of resistance to Salinomycin, a cancer stem cell-specific agent, in budding yeast as a model.
Authors: Rozario Donald , Zeglam Sammer , Siede Wolfram 
Published: August 2014

Abstract
Introduction
The antibiotic salinomycin (SM) represents a selective potassium ionophore. It has recently attracted considerable attention due to its stem-cell specific mode of action that has been elucidated in a breast cancer stem cell model [1]. Further studies revealed additional benefits, e.g. the triggering of apoptosis in resistant cancer cell lines and reversal of multidrug resistance [2,3]. In budding yeast, we discovered that this agent prominently causes mitochondrial damage as revealed by the emergence of respiration-defective cells (“petites”), similar to nigericin. We also noted the frequent occurrence of SM-resistant clones - a possible obstacle in therapy.
Methods
We used the collection of systematic gene deletions in haploid Saccharomyces cerevisiae to characterize genes whose deletion confers SM sensitivity or resistance if a carbon source is provided (glycerol) that requires active respiration for growth. In parallel, the emergence of reactive oxygen species (ROS) was measured by flow cytometry. With this toxicogenomics approach in a model organism, we attempt to elucidate cancer-stem cell specific therapy targets and suggest strategies to avoid the development of salinomycin resistance.
Results and Conclusions
Among SM-sensitive deletion mutants, mutants that compromise vacuole/Golgi function and autophagy dominate. Novel genes which confer SM sensitivity if deleted were also uncovered, such as CAJ1, a heat shock protein of the dnaJ family. In almost all cases, a strong correlation between SM and nigericin sensitivity was observed.
Among the most SM-resistant mutants were deletions of the E2-ubiquitin conjugating enzymes Ubc13 and Mms2 as well as deletions of TOR pathway components Sch9 and Tco89. In the presence of SM, Sch9 (homolog of human Akt) underwent dephosphorylation; a deletion of Sch9 was shown to improve growth in glycerol media and to counteract petite induction in glucose media in SM-treated cells. The observed mitochondria-dependent ROS production by SM, however, was unaltered and we suggest that, while initial damage is not affected, cells acquire resistance to the consequences of such damage.
[1] Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, et al. (2009) Cell 138: 645-659. [2] Fuchs D, Heinold A, Opelz G, Daniel V, Naujokat C (2009) Biochem Biophys Res Commun 390: 743-749. [3] Fuchs D, Daniel V, Sadeghi M, Opelz G, Naujokat C (2010) Biochem Biophys Res Commun 394: 1098-1104.
Supported by Cancer Prevention and Research Institute of Texas.
Citation Format: Donald Rozario, Sammer Zeglam, Wolfram Siede. Exploring the mechanisms of resistance to Salinomycin, a cancer stem cell-specific agent, in budding yeast as a model. [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 LB-100. doi:10.1158/1538-7445.AM2013-LB-100
Abstract LB-108: Exosome profiling of mRNAs and miRNAs in serum samples from GBM patients .
Authors: Skog Johan , Bentink Stefan , LoGuidice Lori , Romain Charlotte , Belzer Susan , Noerholm Mikkel 
Published: August 2014

Abstract
Background: Biomarker discovery and development in oncology has traditionally required the use of tissue, either FFPE or frozen. In recent years, the use of Circulating Tumor Cells (CTCs), cell free DNA (cfDNA), and most recently, exosomes, has allowed biomarker research in biofluids to evolve. Exosomes contain mRNA, microRNA, DNA and protein in a protected, highly stable vesicle. Recently, we have shown that large panels of mRNA genes can be run on small samples of frozen, archived serum. The ability to assess the expressions patterns in blood represents a potentially important development for biomarker research and the development of non-invasive diagnostics.
Methods: Frozen, archived serum (2ml) was obtained from a glioblastoma clinical trial cohort, containing serum from both responders and non-responders to a novel therapy. We isolated the microvesicle fraction from the serum, extracted the RNA, and qualified the RNA using an Agilent 2100 Bioanalyzer on an Agilent 6000 RNA Picochip. A standard in-house control extraction was processed in parallel and subjected to quality control on the Bioanalyzer as well as RT-qPCR. The first cohort of samples (n = 60) were reverse transcribed to cDNA, and the cDNA was assayed on a human cancer mRNA panel Array by qPCR (Life Technologies).The cancer panel includes a total of 648 cancer related genes including endogenous controls. The second cohort of samples (n = 40) was reverse transcribed and analyzed by a miRNA panel of 758 different miRNA assays and controls.
Results: Our data clearly demonstrate the ability to detect relevant gene expression patterns in microvesicle RNA isolated from patient serum. High quality RNA was extracted from the samples received, and an average of 80% of the 648 cancer associated mRNA genes and 36% of the miRNAs were detected in the samples with the volumes used in this study. Data was demonstrated to be reproducible between and among samples and suggests a biological pattern of RNAs in serum exosomes that could be used to monitor response to treatment.
Conclusions: RNA isolated from the microvesicle fraction of serum contains abundant, high-quality RNA, including mRNA. The analysis of a large panel of genes from a small sample of serum is possible, demonstrating that RNA isolated from microvesicles from peripheral blood has the potential to be used as a source of genetic material for non-invasive diagnostic tests.
Citation Format: Johan Skog, Stefan Bentink, Lori LoGuidice, Charlotte Romain, Susan Belzer, Mikkel Noerholm. Exosome profiling of mRNAs and miRNAs in serum samples from GBM patients . [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 LB-108. doi:10.1158/1538-7445.AM2013-LB-108
Abstract LB-115: Cooperative activation of tissue specific genes by pRB and E2F1.
Authors: Flowers Stephen J. , Xu Fuhua , Moran Elizabeth 
Published: August 2014

Abstract
The retinoblastoma tumor suppressor protein pRB is conventionally regarded as an inhibitor of the E2F family of transcription factors. Conversely, pRB is also recognized as an activator of tissue-specific gene expression along various lineages including osteoblastogenesis. During osteoblast differentiation, pRB directly targets Alpl and Bglap, which encode the major markers of osteogenesis, alkaline phosphatase and osteocalcin. Surprisingly, p130 and repressor E2Fs were recently found to co-occupy and repress Alpl and Bglap in proliferating osteoblast precursors prior to differentiation. This raises the further question of whether these genes convert to E2F activation targets when differentiation begins, which would constitute a remarkable situation wherein pRB and E2F would be co-targeting genes for activation.Chromatin immunoprecipitation (ChIP) analysis in an osteoblast differentiation model shows Alpl and Bglap are indeed targeted by an activator E2F, i.e. E2F1. Promoter occupation of Alpl and Bglap by E2F1 occurs specifically during activation, and depletion of E2F1 severely impairs their induction. Mechanistically, promoter occupation by E2F1 and pRB is mutually dependent, and without this cooperative effect, activation steps previously shown to be dependent on pRB, including recruitment of RNA polymerase II, are impaired. Myocyte and adipocyte specific genes are also co-targeted by E2F1 and pRB during differentiation along their respective lineages. The finding that pRB and E2F1 cooperate to activate expression of tissue-specific genes is a paradigm distinct from the classical concept of pRB as an inhibitor of E2F1, but is consistent with the observed roles of these proteins in physiological models.
Citation Format: Stephen J. Flowers, Fuhua Xu, Elizabeth Moran. Cooperative activation of tissue specific genes by pRB and E2F1. [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 LB-115. doi:10.1158/1538-7445.AM2013-LB-115