bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3939: Delineation of the ATM-Snail pathway in the DNA damage response
Authors: Boohaker Rebecca J. , Fried Joshua , Cui Xiaoli , Xu Bo 
Published: May 2015

Abstract
To cope with constant challenges toward the fidelity of genome by DNA damaging insults (both endogenous and exogenous), activation of the DNA damage response (DDR) is an essential step in preventing genomic instability. Studies of mammalian mechanisms have revealed that there are comprehensive, coordinated pathways that, when activated, serve to regulate the DDR. Recently, we have shown that hyperactive DDR mediated by the Ataxia-Telangiectasia Mutated (ATM) kinase is linked to activation of the Zinc finger protein SNAI1 (Snail). Activated Snail in metastasis is well-characterized by its role as transcriptional repressor of E-cadherin thereby inducing an epithelial-to-mesenchymal transition (EMT). Here we report that, in response to DNA damage, activation of the ATM-Snail pathway, mediated by Snail Serine 100 phosphorylation, also contributes to the regulation of the cellular sensitivity to ionizing radiation. Expression of a hyperactive Snail led to radioresistance. More interestingly, the Serine 100 to Glutamic Acid mutant variant of Snail displayed an enhanced invasion index after low dose radiation, independent of survival. Functional genomics and proteomics studies revealed downstream targets and interacting partners of Snail in the DDR. Together, we highlight the functional significance of the ATM-Snail pathway in the DDR.
Citation Format: Rebecca J. Boohaker, Joshua Fried, Xiaoli Cui, Bo Xu. Delineation of the ATM-Snail pathway in the DNA damage response. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3939. doi:10.1158/1538-7445.AM2014-3939
Abstract 3947: Radiation treatment solubilizes membrane receptors in meningioma cells
Authors: Gogineni Venkateswara Rao , Maddirela Dilip R. , Chetty Chandramu , Rao Jasti S. 
Published: May 2015

Abstract
In our earlier studies we reported that radio-resistance was associated with soluble uPAR and uPARAP in meningioma cells. In the present study we show solubilization of a broad range of membrane-bound receptors induced by radiation treatment. Although the increase in radiation dosage beyond 10Gy increased the release of receptors, cell proliferation was adversely affected. Further, fractionated dosages (5Gy+5Gy) or a single dose (10Gy) radiation showed a significant surge in soluble receptors after 36 hours of treatment. Correspondingly, an initial lag in proliferation with G2-M arrest and subsequent recovery was seen in irradiated cells. Pretreatment of meningioma cells with N-acetyl cysteine before radiation treatment significantly quenched the solubilization of receptors. Conditioned media collected from irradiated cells promoted invasiveness and migration of meningioma cells compared to the controls. Later, screening for cell-free receptors in the brain sections of tumor-bearing mice also showed an increased incidence in irradiated groups. In conclusion, our study reveals an additional niche of receptor functioning in meningioma.
Citation Format: Venkateswara Rao Gogineni, Dilip R. Maddirela, Chandramu Chetty, Jasti S. Rao. Radiation treatment solubilizes membrane receptors in meningioma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3947. doi:10.1158/1538-7445.AM2014-3947
Abstract 3950: Integrative analysis of acute and late radiotherapy effects using genome-wide transcriptomics and quantitative proteomics
Authors: Rackwitz Tilmann , Seidel Philipp , Winter Martin , Zhou Cheng , Mayer Ramona , Warnken Uwe , Hofner Peter , Debus Jürgen , Schnölzer Martina , Abdollahi Amir 
Published: May 2015

Abstract
Pulmonary microvascular endothelial cells are critically involved in development of radiation-induced acute inflammation and late fibrosis often limiting the delivery of sufficient dose to optimally treat lung cancer. Moreover, tumor-endothelium communication has emerged as a key target to augment radiotherapy by resensitizing endothelial-specific survival signals. Therefore, we aimed to employ high-throughput genome-wide gene expression and whole proteome analysis to uncover the molecular mechanisms governing tumor-vessel communication and radiation-induced normal tissue toxicity.
Human primary isolated pulmonary microvascular endothelial cells (HPMEC) were irradiated with 0 or 6Gy. Cells were harvested two hours (acute) and six days (late) after irradiation and proteins as well as RNA were extracted. Gene expression analysis was performed using 47k Illumina microarray (HumanHT-12 v4) platform. Mass spectrometry on an LTQ-Orbitrap instrument was employed for protein identification and relative quantification using label-free quantification techniques. An IMAC/TiO2 enrichment step to obtain phosphorylated peptides was carried out and analyzed by mass spectrometry as well. The regulation of candidate radiation-regulated genes and proteins were confirmed in-vitro and in irradiated lung specimen (C57BL/6 mouse) by real-time qRT-PCR, western blot and ELISA.
At the early timepoint a strong induction of genes involved in apoptosis and DNA-damage response such as GADD45A, PARP3 and DDB2 was identified. In contrast to the acute radiation response, cell adhesion (Integrins), pro-inflammatory (Interleukines), pro-angiogenic and matrix-remodeling related genes (MMPs, PDGFs, VEGFs) were induced late after irradiation. Integrative analysis of protein quantification, phosphorylation and gene-expression further revealed novel insights to an intricate gene/protein regulatory network underlying late radiation response in microvascular endothelium. The here identified genes and proteins involved in late radiation response constitute attractive targets for modulation of radiotherapy effects in tumor-endothelium or prevention of undesired radiotherapy-induced late side effects.
Citation Format: Tilmann Rackwitz, Philipp Seidel, Martin Winter, Cheng Zhou, Ramona Mayer, Uwe Warnken, Peter Hofner, Jürgen Debus, Martina Schnölzer, Amir Abdollahi. Integrative analysis of acute and late radiotherapy effects using genome-wide transcriptomics and quantitative proteomics. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3950. doi:10.1158/1538-7445.AM2014-3950
Abstract 3952: Recurrent prostate cancer genomic alterations predict response to brachytherapy treatment
Authors: Fontugne Jacqueline , Lee Daniel , Cantaloni Chiara , Barbieri Christopher E. , Orazio Caffo , Hanspeter Esther , Mazzoleni Guido , Palma Paolo Dalla , Rubin Mark A. , Fellin Giovanni , Mosquera Juan Miguel , Barbareschi Mattia , Demichelis Francesca 
Published: May 2015

Abstract
Background
Discovery of ERG rearrangements and recurrent associated molecular alterations, such as PTEN deletions, has helped understand prostate carcinogenesis. However, prostate cancer (PCa) molecular stratification has not been well studied in response to different treatment modalities. The objective of this study was to evaluate the association of ERG rearrangements and PTEN deletions with oncologic outcomes in PCa patients treated with brachytherapy.
Material and methods
Ninety-two men underwent I-125 brachytherapy with a 145Gy delivered dose between 2000 and 2008. Pre-treatment prostate biopsies were analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) for ERG rearrangement and overexpression, PTEN deletion and expression loss. Univariable and multivariable Cox-regression analyses evaluated association of ERG and PTEN status with biochemical recurrence (BCR).
Results
Within a median follow-up of 73 months, 11% of patients experienced BCR. Of 80 samples with both IHC and FISH performed for ERG, 46 (57.8%) demonstrated rearrangement by FISH and 45 (56.3%) by IHC. Of 77 samples with both IHC and FISH for PTEN, 14 (18.2%) had PTEN deletion by FISH and 22 (28.6%) by IHC. No significant associations were found between ERG, PTEN status and clinicopathologic features. Patients with concurrent ERG rearrangement and PTEN deletion demonstrated significantly worse relapse-free survival rates compared to those with ERG or PTEN wild-type (p&lt;0.01). In multivariable Cox regression analysis adjusted for the effects of standard clinicopathologic features, combined ERG rearranged and PTEN deletion was independently associated with BCR (HR 2.6, p=0.02).
Conclusions
Concurrent ERG rearrangement and PTEN loss was independently associated with time to BCR in patients undergoing brachytherapy. Identifying patients in this molecular subclass may improve treatment personalization. Future studies are needed to validate PCa molecular subtyping for risk-stratification.
Citation Format: Jacqueline Fontugne, Daniel Lee, Chiara Cantaloni, Christopher E. Barbieri, Caffo Orazio, Esther Hanspeter, Guido Mazzoleni, Paolo Dalla Palma, Mark A. Rubin, Giovanni Fellin, Juan Miguel Mosquera, Mattia Barbareschi, Francesca Demichelis. Recurrent prostate cancer genomic alterations predict response to brachytherapy treatment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3952. doi:10.1158/1538-7445.AM2014-3952
Abstract 3957: Analyzing the effects of radiotherapy on the metastatic phenotype: a role for combined therapeutic approaches incorporating Src and PI3K targeting
Authors: Rowling Emily J. , Telfer Brian , Elvin Paul , Williams Kaye J. 
Published: May 2015

Abstract
Background: Radiotherapy is used in the treatment of over 50% of cancer patients. Although seen as a positive intervention, there are reports of radiation enhancing the metastatic characteristics of cells. We have previously observed that radiotherapy activates a number of pathways associated with tumour metastases and aggressive phenotype including Src and phosphoinositide 3-kinase (PI3K). Here we wished to relate pathway activation to cellular phenotype and to investigate the impact of pharmacological inhibition on radiation response and metastases.
Methods: The effects of radiotherapy alone, and combined with Src (AZD0530) and/or PI3K (GDC-0941) inhibition, on cell adhesion, migration and clonogenic survival were assessed in vitro using well-characterised assays. Initial in vivo studies, using FTC133 xenografts, evaluated the effects of radiation treatment on the Src and PI3K pathways and inhibition thereof using pAKT (Ser473) and pFAK (Tyr861) as biomarkers. The effect of single versus combined pathway inhibition with radiation therapy (5x2Gy fractions) on primary tumour growth and lung metastasis (via ex vivo clonogenic assay) was then evaluated.
Results: In vitro, radiation combined with Src and/or PI3K inhibition resulted in a reduction in cell adhesion, cell spreading and cell migration compared to radiation alone, with the combined effects greater than either inhibitor alone. Radiation both in vivo and in vitro enhanced activity of the PI3K/AKT and the Src/FAK axis. In vivo, radiation combined with Src or PI3K inhibition showed little effect on tumour growth but did reduce metastatic lung colonisation, compared to radiation alone, with Src inhibition proving more efficacious. When radiation was combined with inhibition of both pathways a significant reduction in both primary tumour growth and metastatic lung colonisation was observed.
Conclusion: Radiation enhances multiple pathways, two predominant ones being PI3K and Src, and by using rationale drug combinations we saw improved local control and reduced metastatic spread. From these data we can suggest that the PI3K and Src pathways are involved in the radiation enhancement in metastatic phenotype and this provides potential for application of these therapies in the clinic.
Citation Format: Emily J. Rowling, Brian Telfer, Paul Elvin, Kaye J. Williams. Analyzing the effects of radiotherapy on the metastatic phenotype: a role for combined therapeutic approaches incorporating Src and PI3K targeting. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3957. doi:10.1158/1538-7445.AM2014-3957
Abstract 3994: Identifying molecular networks linked to colorectal liver metastasis progression during liver regeneration by RNA-seq
Authors: Simoneau Eve , Chicoine Jarred , Salman Ayat , Sladek Robert , Lazaris Anthoula , Amre Ramila , Metrakos Peter 
Published: May 2015

Abstract
The only potential cure for colorectal liver metastasis (CRCLM) is hepatic resection; portal vein embolization (PVE) is used as an adjunct to stimulate liver regeneration and increase the number of resectable patients. PVE has been shown to enhance CRCLM progression in most patients. The objective of this study is to determine the molecular networks involved in CRCLM progression during liver regeneration, by transcriptome analysis (RNA-Seq). CRCLM RNA was procured prospectively from patients prior to and after PVE. 14 patients with PVE underwent tumor volumetric analysis (blinded from the transcriptome analysis) to determine stable vs. progressive disease. A subgroup of 9 patients had tumor progression (median 45.3% (95%CI 10.6-192.5%) increase in tumor volume) while the remaining patients exhibited stable disease and continuous chemotherapy response (median 26.0%(95%CI -53.1-1.2%) decrease in tumor volume) (p=0.0121), which was consistent with our published series of 123 patients. RNA extracted from tumor tissue (pre and post PVE) in a subset (n=6) of patients (median RNA Integrity number (RIN) scores 7.1 (6.2 - 9.0)) was used to prepare Illumina rRNA-depleted TruSeq stranded cDNA libraries for HiSeq 100bp paired-end sequencing. An average of 150 million reads and 91.8% genomic alignment was achieved per sample. The analysis revealed that several genes known to act as tumor suppressors in CRC (e.g. NR1H4 and HRG) are consistently down regulated post-PVE in the progressive group. Several canonical pathways (including acute phase response, LXR/RXR signaling) showed statistical enrichment for transcripts that were differentially expressed in patients with disease progression. This work aims to establish a comprehensive view of the transcriptional changes associated with CRCLM progression during liver regeneration, to identify the molecular mechanisms that drive metastatic progression in this unique context. Highlighting such mechanisms is a critical first step towards developing targeted therapeutic strategies that may mitigate the unwanted effects of liver regeneration on tumor growth.
Citation Format: Eve Simoneau, Jarred Chicoine, Ayat Salman, Robert Sladek, Anthoula Lazaris, Ramila Amre, Peter Metrakos. Identifying molecular networks linked to colorectal liver metastasis progression during liver regeneration by RNA-seq. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3994. doi:10.1158/1538-7445.AM2014-3994
Abstract 3998: Network-based identification of gene signatures of epithelial-mesenchymal transition in breast cancer
Authors: CONG YANG , Zhan Ming , Wong Stephen T. 
Published: May 2015

Abstract
Metastasis is a major cause of death in breast cancer patients. Breast cancer cells at the primary site gain metastatic ability through epithelial-mesenchymal transition (EMT). During the process, cancer cells lose cell-cell adhesion mediated by E-cadherin repression and gain motility and invasive properties to penetrate the basement membrane and enter the bloodstream or lymphatic system in order to travel to distant metastatic sites. To investigate the underlying gene regulation mechanism of EMT, we established an EMT gene regulatory network. We first built and validated an EMT signal pathway by Ingenuity Knowledge Base, a repository of expertly curated biological interactions and functional annotations from literatures. Based on gene profiling data of 590 breast cancer patients from The Cancer Genome Atlas (TCGA) and over 370 breast cancer patients from Gene Expression Omnibus (GEO), we modeled the gene regulation mechanism of each gene and its expression regulators in the EMT signal pathway in a stochastic Markov Chain model. In order to identify biomarkers and to determine the dynamical transition process at molecular level during EMT, it is important to identify the corresponding gene expression patterns of epithelial and mesenchymal cells. Several studies have already demonstrated that stable gene expression patterns correspond to stable cell phenotypes. In this study, we reported a cost-efficient computational algorithm developed to identify these stable gene signatures and validate them with gene expression profiles of human mammary epithelial cells and transduced mesenchymal cells.
Citation Format: YANG CONG, Ming Zhan, Stephen T. Wong. Network-based identification of gene signatures of epithelial-mesenchymal transition in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3998. doi:10.1158/1538-7445.AM2014-3998
Abstract 4012: Large-scale characterization of DNA methylation changes in human gastric carcinomas with and without metastasis
Authors: Liu Zhaojun , Zhang Jun , Gao Yanhong , Pei Lirong , Hattori Naoko , Zhu Budong , Ji Jiafu , Yuasa Yasuhito , Kim Wooho , Ushijima Toshikazu , Shi Huidong , Deng Dajun 
Published: May 2015

Abstract
Metastasis is the leading cause of caner-related death for solid tumors including gastric carcinoma (GC). An epigenetic biomarker panel for prediction GC metastasis will have clinical impact on the care of GC patients. In order to characterize the methylation differences between GCs with and without metastasis, genome-wide DNA methylation profiles were compared between 4 metastatic and 4 non-metastatic GCs and their surgical margins (SM). The GC genome showed significantly higher proportions of hypomethylation in the promoter and exon-1 regions, as well as increased hypermethylation of intragenic fragments when compared to SMs. From the list of differentially methylated CpG islands (CGIs), 63 candidate genes and 10 known tumor-related genes were selected for further analysis based on their known functions. Significant differential methylation was validated in the CGIs of 15 genes (Ps&lt;0.05) and confirmed using bisulfite-sequencing. These genes included BMP3, BNIP3, CDKN2A, ECEL1, ELK1, GFRA1, HOXD10, KCNH1, PSMD10, PTPRT, SIGIRR, SRF, TBX5, TFPI2, and ZNF382. Hypermethylation of CGIs in several genes resulted in inactivation of their transcription; however, hypomethylation of GFRA1 correlated with an increase in expression. Most importantly, the prevalence of GFRA1, SRF, and ZNF382 methylation alterations were inversely and coordinately associated with GC metastasis and the patients' overall survival throughout discovery and validation cohorts in China (n=108 and 222), and two independent validation cohorts in Japan and Korea (n=129 and 153). Multivariate analysis showed that the number of combined methylation changes of GFRA1, SRF, and ZNF382 was an independent predictor of overall survival for GC patients in the above 4 patient cohorts (n=246) after adjusting for the pTNM stage, GC location, differentiation, vascular embolus, age, and sex (HR=0.753; 95%CI [0.584-0.972]). The metastasis-prediction values of GFRA1 and SRF methylation are stronger than those of MMP7. In conclusion, methylation changes of GFRA1, SRF, and ZNF382 may be a potential biomarker set for prediction of GC metastasis.
Citation Format: Zhaojun Liu, Jun Zhang, Yanhong Gao, Lirong Pei, Naoko Hattori, Budong Zhu, Jiafu Ji, Yasuhito Yuasa, Wooho Kim, Toshikazu Ushijima, Huidong Shi, Dajun Deng. Large-scale characterization of DNA methylation changes in human gastric carcinomas with and without metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4012. doi:10.1158/1538-7445.AM2014-4012
Abstract 4016: Serum proteomics uncover possible biomarkers associated with progression of metastatic breast cancer
Authors: AlZaabi Adhari A. , Hansen Marc , Graves Steven 
Published: May 2015

Abstract
Despite the recognized advances in the treatment of breast cancer, it still accounts for 15% of all cancer-related deaths. Ninety percent of breast cancer deaths are due to unpredicted metastasis. There is neither successful treatment for metastatic patients nor a specific test to predict or detect secondary lesions. Patients with primary tumor will be either overtreated with cytotoxic side effects or undertreated and risk recurrence. This necessitates the need for personalized treatment, which is hard to offer for such heterogeneous disease. Obstacles in treating breast cancer metastasis are mainly due to the gaps exist in the understanding of the molecular mechanism of metastasis. The linear model of metastasis is supported by several observations that reflect an early crosstalk between the primary and secondary tumor, which in turn makes the secondary microenvironment fertile for the growth of disseminated cells. This communication occurs through circulation and utilizes molecules which have not been identified to date. Identifying such molecules may help in detecting initial stages of tumor colonization and predict the target organ of metastasis. Furthermore, these molecules may help to provide a personalized therapy that aims to tailor treatment according to the biology of the individual tumor. Advances in proteomics allows for more reproducible and sensitive biomarker discovery. Proteomic biomarkers are often more translatable to the clinic compared to biomarkers identified using other -omics approaches. Further, protein biomarkers can be found in biological fluids making them a non invasive way to treat or investigate cancer patients. In this study we are screening serum samples of stage I and stage III breast cancer patients using cLC-MS/MS, with a focus on characterizing the differential expression of small peptide biomarkers. We typically analyze 2500 individual small peptide biomarkers in a single serum sample. Comparisons between different sample types (from stage I and III breast cancer patients in this case) allows for the detection of unique short peptide biomarkers present in one sample type. In our preliminary analysis of 6 patients of each type, we find roughly 64 short peptide biomarkers to be upregulated in patients with metastatic breast cancer. We also see the downregulation of an addition 92 short peptides in these same patients. The serum expression pattern and identity of peptides in metastatic patients may provide clues about the biology underlying tumor cell dissemination and colonization to specific sites.
Citation Format: Adhari A. AlZaabi, Marc Hansen, Steven Graves. Serum proteomics uncover possible biomarkers associated with progression of metastatic breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4016. doi:10.1158/1538-7445.AM2014-4016