bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3922: 20(S)-protopanaxadiol-aglycone inhibition of the development and growth of castration-resistant prostate cancer
Authors: Cao Bo , Liu Xichun , Xiong Zhenggang , Zhao Lijuan , Zhang Haitao , Dong Yan 
Published: August 2012

Abstract
Recurrence with lethal castration-resistant prostate cancer after androgen deprivation therapy remains the major challenge in treatment of advanced prostate cancer. The main mechanism for the development of castration resistance is continuous androgen receptor signaling via promiscuous or hypersensitive androgen receptor, ligand-independent androgen receptor activation, expression of androgen receptor splice variants lacking the ligand-binding domain but remaining constitutively active, and/or de novo androgen synthesis in the prostate. Several new drugs targeting androgen receptor reactivation, such as abiraterone acetate, are showing benefit in prolonging survival in patients with castration-resistant prostate cancer. However, even this potent inhibitor of androgen synthesis has a relatively short time to disease progression. One potential mechanism is the prevalent upregulation of constitutively active, ligand-binding-domain-truncated androgen receptor splice variants in castration-resistant prostate cancer. Therefore, therapeutic approaches that can diminish the availability of both the full-length and the splice variants of androgen receptor should offer considerable benefit in preventing and inhibiting prostate cancer recurrence after androgen deprivation therapy. In the present study, we show that ginsenoside 20(S)-protopanaxadiol-aglycone (PPD), a steroidal saponin from ginseng, effectively downregulates the abundance and activity of both the full-length and the splice variants of androgen receptor. The effect is manifested by an immediate drop in androgen receptor proteins, followed by a reduction in androgen receptor mRNAs. The initial decrease in androgen receptor proteins could be attributed to PPD induction of proteasome-mediated degradation, possibly as a result of disrupted androgen receptor N-C interaction. Our xenograft studies show that PPD inhibits not only the development of castration-resistant prostate cancer after androgen deprivation but also the growth of prostate tumors that are already castration resistant. The inhibition is accompanied by a pronounced decrease of tumor androgen receptor and serum prostate-specific antigen levels. Our findings therefore provide strong justification and lay the groundwork for an effective treatment modality to improve the therapeutic outcome of androgen deprivation therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3922. doi:1538-7445.AM2012-3922
Abstract 3935: Microfluidic analysis of triple negative breast cancer epithelial cells in response to chemotherapeutic treatments coupled with oxygen gradients
Authors: Byrd Thomas F. , Seale Kevin 
Published: August 2012

Abstract
Multi-trap nanophysiometers (MTNPs) are used in trapping and studying very small numbers of cells. These precisely manufactured instruments, made of polydimethylsiloxane (PDMS), contain microfluidic channels and chambers that house arrays of three-sided cell traps. Trapped MCF7 breast cancer cells were perfused with media and gradients of chemotherapeutic agents specific to triple-negative breast cancer while oxygen levels were modulated within the device and quantified by the incorporation of an oxygen-sensing film. Rapid switching between perfusion channels and gas enabled precise dosing of cells with chemotherapeutic agents in a chamber simulating a variety of tumor microenvironments ranging from anoxic to normoxic. Preliminary results show a positive correlation between oxygen concentration and non-translational motion of trapped cells over a four hour time period.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3935. doi:1538-7445.AM2012-3935
Abstract 3939: Hypoxia-induced BRCA1 phosphorylation and degradation
Authors: Lu Yuhong , Glazer Peter Michael 
Published: August 2012

Abstract
Hypoxia is a key feature of tumor microenviroment. We have demonstrated that hypoxia downregulates BRCA1 at the transcriptional level through promoter binding by E2F4/p130 complexes and that hypoxia can produce BRCA1 gene silencing via epigenetic modifications. We also demonstrated that downregulation of BRCA1 by hypoxia leads to decreased DNA repair capacity, establishing a mechanism by which hypoxia can drive genetic instability in cancer cells. In addition to transcriptional regulation, BRCA1 has been found to be phosphorylated at S988 in a Chk2-dependent manner by both ionizing radiation and hypoxia exposure. In this study, we have been able to confirm that other residues of BRCA1 are phosphoylated during hypoxia exposure, including S1387, S1423, S1466, and S1524. Intriguingly, the phosphoryation of BRCA1 only happens under severe hypoxic condition, such as 0.01% oxygen, but not under moderate hypoxia (1% oxygen condition). Furthermore, the BRCA1 phosphoylation events induced by hypoxia can be attenuated by an ATM inhibitor, KU55933, indicating that ATM is playing a role in hypoxia-induced BRCA1 phosphorylation at multiple sites. We also observed that the decrease in BRCA1 protein levels in hypoxia is partially blocked by MG132, a proteasome inhibitor. Consistent with this, by transient transfection of exogenous BRCA1, we found that hypoxia induces BRCA1 unbiquitination in MCF-7 cells. Together, our data suggest that hypoxia-induced downregulation of BRCA1 is in part mediated through the ubiqutin-proteasome pathway. Our findings indicate a new mechanism of hypoxia induced regulation of BRCA1 by modulating its stability, suggesting that hypoxia-induced downregulation of BRCA1 is through multiple mechanisms. Future studies will investigate the mechanism of hypoxia-induced BRCA1 phophorylation and the relation between hypoxia-induced BRCA1 phosphorylation and BRCA1 degradation. To understand more about regulation of BRCA1 by hypoxia could lead to new therapies to target hypoxic tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3939. doi:1538-7445.AM2012-3939
Abstract 3946: Genome-wide characterization of hypoxic breast cancer transcriptome
Authors: Choudhry Hani , Oikonomopoulos Spyros , Harris Adrian , Ragoussis Ioannis 
Published: August 2012

Abstract
Hypoxia is a common feature of most solid tumors and is associated with poor prognosis in breast cancer. In the current study, we investigated the hypoxia transcription landscape of an ER positive breast cancer cell line [MCF7] using high throughput strand-specific total RNA sequencing (tssRNA-seq). MCF7 cells were grown under hypoxia and normoxia (24 hours, 1% O2), and we found about 7.3% of annotated genome got significantly differential expressed in hypoxic stress, which includes 79% (1293) up regulated and 21% (344) down regulated transcripts (P value of &lt;0.01, fold &gt;1.5). Analysis revealed deregulation of a range of non coding transcripts including piwiRNA (0.36%), miRNA (0.098%), sn/snoRNA (0.028%), tRNA (4.5%), lncRNA (6.5%) under hypoxia (P value of &lt;0.01, fold &gt;1.5). Many non-poly A transcripts and natural anti-sense transcripts (n=71) were detected and differently expressed in hypoxia. We characterized two significant up regulated natural anti-sense transcripts in hypoxia and found that these transcripts are long (&gt;200bp), lack of protein coding frames, localized in nucleus and found highly expressed (range fold &gt;5-15) in different hypoxic breast cancer cell lines. To define which hypoxic altered transcripts are dependent on, hypoxia-inducible factor (HIF), we suppressed HIF-alpha subunits in hypoxic MFC-7 cells using short interfering RNA and subjected them to mRNA-seq. Results revealed that HIF-1, HIF-2 and combined HIF-1/2 knockdown resulted in significant down-regulation of 179, 84 and 149 transcripts, respectively, which were up regulated in hypoxic MCF-7 cells. Despite detection of previously reported HIF dependent transcripts, we detected a substantial number of HIF dependent transcripts (n=64) that were not reported before as hypoxia regulated genes. To our understanding, this is first study to show hypoxia dependent natural anti-sense transcripts and genome-wide HIF dependent transcripts analysis at single base pair resolution in hypoxic tumors. These finding will open new avenues in our efforts to understand the hypoxia induced transcriptional response.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3946. doi:1538-7445.AM2012-3946
Abstract 3952: New advances in regulation of senescence by PML and the PML nuclear bodies
Authors: Aauino Mariana D. Acevedo , Bourdeau Véronique , Vernier Mathieu , Ferbeyre Gerardo 
Published: August 2012

Abstract
Senescence is a cellular defense mechanism activated by short telomeres, DNA damage or expression of oncogenes. The program includes the expression of high levels of the promyelocytic leukemia protein PML that form nuclear spherical bodies, known as PML-nuclear bodies (PML-NB). The expression of PML in normal fibroblasts is sufficient to induce senescence while genetic inactivation of PML inhibits the process. These results suggest that PML is a critical component of the senescence tumor suppressor mechanism. Accordingly PML is poorly expressed in malignant human tumors but highly expressed in benign tumors. We recently discovered a new mechanism of regulation of RAS-induced senescence by PML, which implicates the recruitment of the RB/E2F complex to the PML-NB via RB-PML interaction. This leads to inhibition of cell cycle and DNA repair genes, DNA damage, p53 activation and ultimately to senescence. We show now that the cyclin dependent kinase CDK4 blocks the ability of PML to regulate E2F gene expression and senescence and that CDK inhibitors potentiate the ability of PML to restore the senescence program in tumor cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3952. doi:1538-7445.AM2012-3952
Abstract 3956: BRCA1 chromatin dissociation induced by oncogene activation promotes formation of senescence-associated heterochromatin foci and senescence via chromatin remodeling factor BRG1
Authors: Tu Zhigang , Zhang Rugang 
Published: August 2012

Abstract
Background: Cellular senescence is a state of irreversible cell growth arrest that is an important tumor suppression mechanism in vivo. Activation of oncogenes such as Ras in primary mammalian cells typically triggers senescence and formation of senescence-associated heterochromatin foci (SAHF) that contributes to senescence-associated cell cycle exit. We have previously showed that dissociation of BRCA1 from chromatin induced by oncogenic Ras plays a key role in promoting cellular senescence by driving SAHF formation. However, the mechanism by which BRCA1 chromatin dissociation promotes SAHF formation and senescence remains to be determined. BRG1 is an ATP dependent SWI/SNF chromatin-remodeling factor that interacts with BRCA1. Components of SWI/SNF complex including BRG1 are often deregulated in human cancer. Here we examined the role of BRG1 in regulating formation of SAHF trigged by BRCA1 chromatin dissociation induced by oncogenic Ras. Results: We discovered that the interaction between BRG1 and BRCA1 is disrupted during oncogenic RAS induced senescence. Interestingly, BRG1 accumulates in chromatin fraction while BRCA1 becomes dissociated from chromatin. Notably, BRG1 knockdown suppresses formation of SAHF and senescence, while has no effects on BRCA1 chromatin dissociation in Ras-infected cells, suggesting that BRG1 functions downstream of BRCA1 chromatin dissociation in promoting SAHF formation and senescence. Indeed, BRG1 knockdown is sufficient to inhibit SAHF formation and senescence induced by BRCA1 knockdown. Conversely, BRG1 overexpression drives SAHF formation and senescence. Notably, senescence induced by BRG1 overexpression is independent of DNA damage response, further supporting the idea that BRG1 functions downstream of BRCA1 chromatin dissociation during Ras induced senescence. Mechanistically, chromatin immunoprecipitation analysis revealed that, in Ras-expressing or BRCA1 knockdown cells, there is an increased association of BRG1 with the promoters of p16INK4a and p21CIP, both of which are key regulators of SAHF formation and senescence. Significance: These studies revealed the molecular underpinning by which BRCA1 chromatin dissociation promotes SAHF formation and senescence. They also imply that BRG1 inactivation contributes to cancer development by suppressing cellular senescence. (R.Z. is an Ovarian Cancer Research Fund (OCRF) Liz Tilberis Scholar. This work was supported in part by a NCI FCCC-UPenn ovarian cancer SPORE (P50 CA083638) pilot project and SPORE career development award, a DOD ovarian cancer academy award (OC093420), and an OCRF program project.)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3956. doi:1538-7445.AM2012-3956
Abstract 396: Sequential metastases of colorectal cancer: Treatment, immunophenotypes and spatial distributions of infiltrating immune cells
Authors: Halama Niels , Keim Sophia , Zoernig Inka , Schirmacher Peter , Grabe Niels , Jaeger Dirk 
Published: August 2012

Abstract
The role of the immune system in the course of colorectal cancer has been elucidated in the last decade. While quantification of the immune cell infiltrates within the the resected specimen at diagnosis has a clear power to estimate the prognosis of the patient, the role within the metastatic situation and especially within the metastatic lesion itself remains largely unclear. Recent analyses of infiltrates in colorectal cancer liver metastases revealed a role for the infiltrate density not only for prognosis but also in the prediction of treatment response. This not only broadens the view on these infiltrates and indicates a systematic role of the local immunological microenvironment, but also raises the question how these infiltrates change during repeated courses of treatment (i.e. resection, chemotherapy etc.). To adress this question, multiple sequential lung or sequential liver metastases of colorectal cancer patients were analyzed using whole slide image quantification, using antibodies against CD3, CD8, FOXP3, CD68 and CD163. The clinical data and interventions were analyzed in association with the individual patient and the profiles of the metastatic lesions. The resulting cell densities reveal a heterogeneous profile: after successfull treatment of a metastatic lesion, the recurrent lesion can still have the same immunophenotype with similar cell distributions. In a situation of a favorable immune cell profile, this profile can return and apparently convey a similar favorable course of the disease. But also the opposite was found: the recurrent metastatic lesion could have a different profile with alterations in specific immune cell subsets. Treatment failure and a progression were observed after this change in immune cell composition. Further analyses are required to elucidate the different patterns and their associations to the treatment, the tumor cell phenotype and other factors. It is clear from this data however, that there is an immune cell plasticity during the course of the disease that needs to be analyzed and maybe has potential for improving therapeutic decisions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 396. doi:1538-7445.AM2012-396
Abstract 3960: Rapid and efficient large-scale somatic mutation validation approaches for cancer genome sequencing
Authors: Cibulskis Kristian , Sivachenko Andrey , Hammerman Peter , Imaz Ivan , Pugh Trevor , Sougnez Carrie , Winckler Wendy , Gabriel Stacey , Getz Gaddy 
Published: August 2012

Abstract
The landscape of somatic alterations in cancer is being rapidly uncovered by large-scale cancer genome sequencing projects in individual laboratories as well as consortia such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). The decreasing cost of sequencing has resulted in an increase in the number of cancer genomes that are being sequenced, and thus the numbers of candidate somatic mutations being identified are rapidly expanding. A single cancer genome from a cancer with an average mutation background rate, such as ovarian or breast cancer, will have 3000-6000 mutations. A high mutation rate cancer such as melanoma or colon cancer can have as many as 100,000 mutations/genome. Multiplying these numbers by the dozens of sequenced genomes and hundreds of sequenced exomes across a wide spectrum of tumor types yields a staggering number of candidate mutations. However, approaches for rapidly validating these findings at scale have been lagging behind. Current approaches, such as custom designed hybrid capture arrays followed by sequencing, can take months to complete and cannot begin until the initial sequencing is complete and mutations are called. This can lead to long delays in the interpretation and publication of biological findings. Here we describe the results of several approaches for rapid and efficient validation on large-scale projects, such as TCGA. We will share our approach and results using Fluidigm and PacBio sequencing for validation and sample extension at a small scale with rapid turnaround where we have validated PIK3CA and TP53 mutations in breast cancer samples of varying purity as well as significantly mutated genes in medulloblastoma. Ideally one could validate mutations and gene fusions concurrent with their discovery. To that end, we will also describe our validation results using RNA-Seq data, commonly produced concurrently with genome and exome sequencing, in lung squamous and renal cancer. Finally, we will explore an approach for instant-validation through simultaneous sequencing of barcoded discovery and cross-validation libraries.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3960. doi:1538-7445.AM2012-3960
Abstract 3967: The Cancer Genome Project high throughput analysis pipeline
Authors: Butler Adam P. , Teague Jon W. , Raine Keiran M. , Menzies Andrew , Jones David , Marshall John , Hinton Jon , Dronov Serge , Gamble John , Stebbings Lucy , Jayakumar Alagu , Leroy Catherine , McDermott Ultan , Stratton Michael R. , Campbell Peter , Futreal Andy 
Published: August 2012

Abstract
The Cancer Genome Project (CGP) was set up in 2000 to use systematic mutation screening methods to increase our understanding of human cancer. With the advent of next generation sequencing, and the large volumes of data that it generates, a new suite of software was required to rapidly and accurately screen these data for somatic changes. We have built an analysis pipeline to track and analyse large numbers of tumour samples, using in-house and externally available tools. The analysis pipeline is built around a ∼2,000 node compute farm and Lustre filesystem which outputs into our archive and data storage system, FileTrk. FileTrk holds the raw data files (BAM, CEL etc), the results of the analysis and any versioning information about the software used to generate these results. Sample lanes are aligned back to the genome using Burrows-Wheeler Aligner (BWA) and lane-to-lane comparisons are made to ensure data integrity. Lanes from each sample are merged into a single sample BAM file and once 30 - 40x coverage is reached and the lanes have been quality assessed the sample is locked and ready for analysis. Mutation callers detect point mutations (Caveman, in-house software), small insertions/deletions (Pindel), breakpoints (BRASS, in-house software) and copy number changes (ASCAT & PICNIC, in-house software). The resulting mutations are post-processed to remove false positives, annotated to the RNA and protein level using standard nomenclature (Vagrent, in-house software) and uploaded to a database. Interfaces have been developed to enable the selection of random sets of mutations for validation, the outcome of the validations is recorded so specificity can be calculated for each sample in the system. IT systems are being developed to automatically export lists of somatic changes to COSMIC, the ICGC data portal and raw data to the European Genome-Phenome Archive (EGA).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3967. doi:1538-7445.AM2012-3967