bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C118: TERT promoter mutations in human gliomas.
Authors: Lima Jorge , Reis Rui M. , Catarino Telmo , Peixoto Joana , Vinagre Joao , Batista Rui , Castro Ligia , Pardal Fernando , Sobrinho-Simoes Manuel , Maximo Valdemar , Soares Paula 
Published: August 2014

Abstract
Reactivation of telomerase has been implicated in human tumorigenesis, but the underlying mechanisms remain poorly understood. Recently, two mutations (-124G&gt;A and -146G&gt;A) in the promoter region of the telomerase catalytic subunit (TERT) were found in a significant proportion of human tumors, including gliomas, thyroid carcinomas, bladder carcinomas and melanomas. These mutations resulted in increased expression of telomerase, both in vitro and in vivo. In order to further characterize the prevalence of TERT mutations in human tumors, we screened a cohort of 273 human gliomas and found an overall TERT mutation frequency of 50%. TERT mutations were most commonly found in high grade tumors such as glioblastoma multiforme (GBM) and gliosarcoma (65% and 89%, respectively), whereas low grade tumors such as pilocytic astrocytoma and diffuse astrocytoma showed a low frequency of TERT mutations (6% and 16%, respectively). Oligodendrogliomas (grade II) and anaplastic oligodendrogliomas (grade III) also harbored a high frequency of TERT mutations (44% and 52%, respectively). In GBM patients, the presence of TERT mutations was significantly associated with a higher mean age at diagnosis (p&lt;0.0001) and worse survival (p=0.006). Our results show that TERT promoter mutations are frequent in human GBM and oligodendrogliomas and are associated with worse survival in GBM patients.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C118.
Citation Format: Jorge Lima, Rui M. Reis, Telmo Catarino, Joana Peixoto, Joao Vinagre, Rui Batista, Ligia Castro, Fernando Pardal, Manuel Sobrinho-Simoes, Valdemar Maximo, Paula Soares. TERT promoter mutations in human gliomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C118.
Abstract C135: AZ’4425 is a potent, selective, and orally bio-available progesterone receptor antagonist that has shown anti-tumor activity and inhibition of cancer stem cell proliferation.
Authors: Chresta Christine M. , Alferez Denis , Cerillo Georgia , Still Emma , Hughes Adina , Walker Graeme , Kendrew Jane , Sadler Claire , Harris Jayne , Simpson Iain , Thomas Andrew P. , Rabow Al , Clarke Robert , Howell Sacha , Richmond Graham 
Published: August 2014

Abstract
Progesterone is an important hormone in breast cancer; the paracrine mediator of the progesterone receptor, RANKL plays a critical role in cancer stem cells, metastasis and tumorigenesis. Steroidal inhibitors of PR have shown modest clinical activity but have been limited by toxicity. AZ’4425 is a novel, potent non-steroidal progesterone receptor (PR) antagonist which selectively inhibits PR compared to other steroid hormone receptors (∼ 1000-fold ER, MR, GR, AR). AZ’4425 competitively inhibits progesterone binding, thus preventing progesterone-induced phosphorylation of PR, nuclear translocation and PR-induced transcription with an IC50 of 26nM. Anchorage independent growth of T47D cells is similarly inhibited with an IC50 of 25nM. Using cancer stem cell (CSC) assays (mammosphere formation and ALDH positivity) we have shown broad cellular activity in both ER/PR positive tumor cell lines and early and late stage clinical samples. Furthermore, AZ’4425 prevents the increase in CSCs, and miRNA changes (miR221/2 and miR200c) induced by anti-estrogen therapies, suggesting a potential role in prevention of acquired resistance. In vivo, the PR antagonist inhibits transcription of progesterone-induced genes including RANKL and SGK1. Notably, AZ’4425 results in significant inhibition of new tumor formation and results in stasis and regression of DMBA-induced tumors, both as monotherapy and in combination with letrozole.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C135.
Citation Format: Christine M. Chresta, Denis Alferez, Georgia Cerillo, Emma Still, Adina Hughes, Graeme Walker, Jane Kendrew, Claire Sadler, Jayne Harris, Iain Simpson, Andrew P. Thomas, Al Rabow, Robert Clarke, Sacha Howell, Graham Richmond. AZ’4425 is a potent, selective, and orally bio-available progesterone receptor antagonist that has shown anti-tumor activity and inhibition of cancer stem cell proliferation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C135.
Abstract C219: Novel MET/FGFR/AXL kinase inhibitor S49076 exerts radiosensitizing activity in vitro and in vivo.
Authors: Chargari Cyrus , Clémenson Céline , Mondini Michele , Ferte Charles , Jacquet-Bescond Anne , Cattan Valérie , Depil Stéphane , Deutsch Eric 
Published: August 2014

Abstract
Background: S49076 was developed as an oral ATP-competitive inhibitor of MET receptor and of other kinases involved in tumor development. It is being assessed as single agent in phase I study. We examined its potential as a radiosensitizer in non-MET dependent tumor models.
Experimental Procedures: Cell viability and clonogenic survival assays were performed in two non small-cell lung carcinoma (NSCLC) cells (H460 and A549) and in breast cancer cells MDA-MB-231. Then, the drug was tested in combination with ionizing irradiation (IR) in vitro. The combination was assessed in subcutaneous tumor xenografts and in NSCLC orthotopic models of luciferine-expressing H460luc and A549luc tumors. Immunohistochemical correlates were performed and the activity of S49076 was assessed in a lung metastases model of intravenous injections of A549 cells.
Results: The drug as single agent inhibited proliferation (IC50 ranging from 0.50 μM to 1.1 μM) and clonogenic survival (IC50 ranging from 0.34 μM to 0.86 μM). Transcriptomic analyses showed that antitumor effect was associated with modulation of molecular pathways involved in radiation response (p53 and ATM). S49076 and IR inhibited synergistically clonogenic survival in H460 cells: sensitivity enhancement ratio at 0.6 μM was 2 for a single radiation dose of 2 Gy. Combination was additive in A549 and MDA-MB-231 cells. S49076 at 50 mg/kg twice daily enhanced radiation-induced growth delay in subcutaneous tumor xenografts, accompanied with an increase in TUNEL staining. Dose enhancement factors were 3.2 and 1.6 in H460 and A549 tumors, respectively. In lung orthotopic models, S49076 generated significant delay in time course of bioluminescent signal and improved median estimated survival, with significant benefit of combination over either IR or S49076 alone. Finally, treatment with S49076 improved significantly median survival in the lung metastases model (14 versus 22 days, p &lt; 0.001).
Conclusions: Altogether, these data suggest that S49076 has a potential as radiosensitizer in non MET-dependent cell lines, and that this effect is accompanied with a modulation of apoptosis.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C219.
Citation Format: Cyrus Chargari, Céline Clémenson, Michele Mondini, Charles Ferte, Anne Jacquet-Bescond, Valérie Cattan, Stéphane Depil, Eric Deutsch. Novel MET/FGFR/AXL kinase inhibitor S49076 exerts radiosensitizing activity in vitro and in vivo. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C219.
Abstract CN06-01: Cancer stem cells and the EMT.
Authors: Weinberg Robert A. 
Published: August 2014

Abstract
The epithelial-mesenchymal transition (EMT) is a cell-biological program that enables both normal and neoplastic epithelial cells to acquire mesenchymal characteristics. In the case of carcinoma cells, this enables them to invade and to disseminate. In addition, once disseminated, the EMT enables carcinoma cells to extravasate and to establish an initial foothold in the parenchyma of distant organs. Of note, the EMT may be triggered in carcinoma cells by signals that they receive from the adjacent activated stroma, and the proclivity of primary carcinoma cells to activate the EMT program in response to such signals may be an indication of their eventual tendency to invade and metastasize. In addition, activation of the EMT program empowers carcinoma cells to enter into the stem cell state, as defined by their tumor-initiating potential. Importantly, however, cells that have passed through an entire EMT program and become entirely mesenchymal are not qualified to enter into the CSC state and seed metastases. Hence, partial activation of this program would be appear to be optimal for entrance into this state and acquisition of tumor-initiating potential.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN06-01.
Citation Format: Robert A. Weinberg. Cancer stem cells and the EMT. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr CN06-01.
Abstract PL02-01: The metabolic phase of the cell cycle.
Authors: Gottlieb Eyal 
Published: August 2014

Abstract
Due to the nature of tumorigenesis, cancer cells constantly encounter environments in which nutrient and oxygen availability is severely compromised. In order to survive these harsh conditions, cancer cell transformation is often coupled with large changes in metabolism necessary to satisfy the exigencies for energy and biomass imposed by continued cellular proliferation. These variations often involve increases in the consumption and metabolism of extracellular resources, such as glucose, amino acids, and lipids. We were particularly interested in investigating the role of lipid metabolism in cancer cell growth. A siRNA screen against a panel of genes involved in lipid metabolism, specifically identified acetyl-coA synthetase as a critical enzyme for the growth of breast and prostate cancer cells. Bioinformatics analyses revealed that acetyl-coA synthetase 2 (ACSS2) was indeed amplified in a subset of invasive breast carcinomas. Furthermore, we characterized the contribution of acetate to lipid metabolism through liquid chromatography/mass spectrometry-based metabolomics and lipidomic approaches. Induced silencing of ACSS2 reduced cell growth of both breast and prostate cancer cells and revealed a heretofore unappreciated role of acetate as an anabolic precursor for de novo lipid biogenesis and cell growth.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL02-01.
Citation Format: Eyal Gottlieb. The metabolic phase of the cell cycle. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL02-01.
Abstract PL07-04: Engineered T cell transfer for cancer immunotherapy in the era of synthetic biology: Challenges and opportunities.
Authors: June Carl H. 
Published: August 2014

Abstract
Adoptive T cell transfer for cancer and chronic infection is an emerging field that shows promise in recent trials. Synthetic-biology-based engineering of T lymphocytes to express high-affinity antigen receptors can overcome immune tolerance, which has been a major limitation of previous immunotherapy-based strategies. Advances in cell engineering and culture approaches to enable efficient gene transfer and ex vivo cell expansion have facilitated broader evaluation of this technology, moving adoptive transfer from a "boutique"’ application to the cusp of a mainstream technology. Recent observations from ongoing clinical trials in patients with leukemia and carcinomas will be discussed. The major scientific challenge currently facing the field is identification of cancer specific targets to avoid on-target, off-tissue toxicity. As the field of adoptive transfer technology matures, the major engineering challenge is the development of automated cell culture systems, so that the approach can extend beyond specialized academic centers and become widely available.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL07-04.
Citation Format: Carl H. June. Engineered T cell transfer for cancer immunotherapy in the era of synthetic biology: Challenges and opportunities. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL07-04.
Abstract PR08: Loss of oncogenic Notch1 signaling contributes to PI3 kinase inhibitor resistance in T lineage leukemia.
Authors: Dail Monique 
Published: August 2014

Abstract
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer for which current therapies are toxic and frequently ineffective. Mutations that activate the Notch1 and Ras/PI3K/Akt signaling pathways are common in T-ALL and often coexist. Thus, inhibiting these pathways alone and in combination is a rational therapeutic strategy. Notch1 inhibition with a gamma-secretase inhibitor (GSI) was recently evaluated in patients with disappointing results. PI3K inhibitors are just entering Phase I clinical trials. GDC-0941 is a potent PI3K inhibitor that is currently advancing in clinical development that we evaluated for efficacy and mechanisms of drug resistance both in cell lines and primary murine T-ALLs. Cell lines are uniformly sensitive to GDC-0941, however gradual dose escalation results in resistant lines. In vivo, GDC-0941 is active against primary T-ALLs, but treated mice invariably relapse with drug resistant clones. Unexpectedly, a majority of GDC-0941-resistant cell lines and primary leukemias showed reduced levels of activated Notch1 protein, down-regulate many Notch1 target genes, and display cross-resistance to γ secretase inhibitors (GSIs). In multiple cases, Notch1 mutations that were present at enrollment were absent at relapse. Importantly, resistant clones that emerge both in vitro and in vivo up-regulate PI3K signaling indicating an “on pathway” mechanism of resistance. Consistent with these data, inhibition of Notch1 signaling promotes GDC-0941 resistance and enhances PI3K signaling, whereas expression of activated Notch1 increases the GDC-0941 sensitivity of mouse and human T-ALL cell lines. Thus, oncogenic Notch1 mutations that promote clonal outgrowth during malignant transformation unexpectedly undergo negative selection during treatment with GDC-0941. These studies validate PI3K as an important therapeutic target in T-ALL and raise the unexpected possibility that administering Notch1 and PI3K inhibitors in combination will accelerate drug resistance.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PR08.
Citation Format: Monique Dail. Loss of oncogenic Notch1 signaling contributes to PI3 kinase inhibitor resistance in T lineage leukemia. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PR08.
Abstract 3960: MicroRNA-23b targeting urokinase-type plasminogen activator facilitates human papillomavirus type 16 E6 induction of cervical cancer cell migration
Authors: Yeung Chi Lam Au , Tsang Tsun Yee , Yau Pak Lun , Kwok Tim Tak 
Published: August 2014

Abstract
Aberrant expression of microRNA in human cervical cancer is associated frequently with human papillomavirus (HPV) integration. MicroRNA-23b (miR-23b) is often down-regulated in HPV-associated cervical cancer. Also, urokinase-type plasminogen activator (uPA), a target of miR-23b, is reported to be over-expressed in cervical cancer. Thus, in the present study, the functional role of miR-23b in HPV-16 E6 associated cervical cancer development was investigated.
Knockdown of oncoprotein E6 by E6 siRNA in HPV-16 positive human cervical carcinoma SiHa cells and CaSki cells led to an increase in the expression of miR-23b and a decrease in the expression of uPA as assessed by quantitative RT-PCR and Western blot analyses. Besides, uPA is confirmed to be the target of miR-23b as transient transfection of SiHa cells with miR-23b precursor vector repressed uPA expression and also the activity of luciferase reporter carrying the 3’UTR of uPA mRNA. uPA is known to be involved in cell migration and cell invasion. By wound healing assay, the cell migration rate of SiHa cells was reduced upon E6 as well as uPA knockdown. Moreover, the effect of E6 siRNA on cell migration was offset upon transfection with anti-miR-23b inhibitor. The results indicate that HPV-16 E6 may regulate cell migration through miR-23b/uPA pathway. Furthermore, p53 is a well-known gene target of HPV-16 E6. Knockdown of p53 by p53 siRNA decreased the miR-23b expression and increased the uPA expression. This shows that p53 may mediate the E6 effect on miR-23b/uPA expressions and thus cell migration of human cervical cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3960. doi:10.1158/1538-7445.AM2011-3960
Abstract LB-180: Epigenetic portraits of human breast cancers
Authors: Dedeurwaerder Sarah , Desmedt Christine , Calonne Emilie , Singhal Sandeep K. , Haibe-Kains Benjamin , Defrance Matthieu , Michiels Stefan , Volkmar Michael , Deplus Rachel , Luciani Judith , Lallemand Françoise , Larsimont Denis , Toussaint Jérôme , Haussy Sandy , Rothé Françoise , Rouas Ghizlane , Metzger Otto , Majjaj Samira , Saini Kamal , Putmans Pascale , Hames Gérald , van Baren Nicolas , Coulie Pierre G. , Piccart Martine , Sotiriou Christos , Fuks François 
Published: August 2014

Abstract
Background:
Understanding the diversity of breast cancer is essential to improving diagnosis and optimising treatment. Both genetic and acquired epigenetic abnormalities participate in cancer, but information is scant on the involvement of the epigenome in breast cancer and its contribution to the complexity of the disease. Our goal was to explore the DNA methylation landscapes of phenotypically heterogeneous tumours, to relate this diversity to landscape features, and extract biological and clinical meaningful information.
Methods:
We performed comprehensive DNA methylation profiling to assess the methylomes of two independent sets of frozen breast tissue samples: a “main set” of 123 samples (4 normal and 119 infiltrating ductal carcinomas, IDCs), and a “validation set” of 125 samples (8 normal and 117 IDCs). We used the recently developed Illumina's Infinium Methylation Assay, that allows to assess the methylation status of more than 27,000 CpGs corresponding to over 14,000 genes.
Results:
Firstly, it emerged that the two major phenotypes of breast cancers determined by ER status are widely epigenetically controlled. Secondly, we have distinguished, and validated in an independent set of tumours, 6 methylation-profile-based tumour groups, some coinciding with known “expression subtypes” but also new entities that may provide a meaningful basis for refining breast tumour taxonomy. Thirdly, we showed that DNA methylation profiling can reflect the cell type composition of the tumour microenvironment. Lastly, we highlighted an unexpectedly strong epigenetic component in the regulation of key immune pathways, revealing a set of immune genes having high prognostic value in specific tumour categories.
Conclusions:
In this study, we have generated the largest and most comprehensive DNA methylation data set for human breast tumor tissues. Several novel findings and original concepts for breast cancer emerge, that previous RNA expression profiling has not highlighted. By laying the ground for better understanding of breast cancer heterogeneity and improved tumor taxonomy, the precise epigenetic portraits drawn in our work should contribute to better management of breast cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-180. doi:10.1158/1538-7445.AM2011-LB-180
Abstract LB-194: Phosphorylation-dependent dimerization of forkhead-associated domain regulates MDC1 function in response to DNA damage
Authors: Liu Jinping , Luo Shukun , Stern David , Ye Keqiong , Xu Xingzhi 
Published: August 2014

Abstract
MDC1 is a key mediator of DNA damage response in mammals. Here, we show that the N-terminal FHA domain of MDC1 mediates regulated dimerization in response to DNA damage. DNA damage induces phosphorylation of threonine 4 of MDC1 and FHA binds reciprocally to phospho-threonine-4 (pT4) from the other molecule. We determined the crystal structures of the MDC1 FHA domain in the free state and in complex with a pT4 peptide. FHA forms a dimer with pseudo 2-fold symmetry and face-to-face β-sheet contact. The FHA dimer is marginally stable, but is greatly stabilized in vitro and in vivo by the intermolecular binding between FHA and the preceding pT4 peptide. Forms of MDC1 with FHA deletion or mutations compromising dimerization are defective in foci formation at the sites of DNA damage, but could be largely rescued by an artificial dimerization module. Our results support a novel regulation mechanism of MDC1 function through T4 phosphorylation and FHA-mediated dimerization.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-194. doi:10.1158/1538-7445.AM2011-LB-194