bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C66: Establishing clinically relevant in vitro models of prostate cancer
Authors: Abou-Kheir Wassim , Hynes Paul , Martin Philip , Yin JuanJuan , Liu Yen-Nien , Seng Victoria , Lake Ross , Spurrier Joshua , Kelly Kathleen 
Published: May 2013

Abstract
Prostate cancer is the most commonly diagnosed cancer in men. PTEN and/or TP53 deletions in prostate cancer are associated with aggressiveness, castration-resistance, and poor prognosis. One origin of progressive, treatment-resistant prostate cancer has been hypothesized to be androgen-independent, prostate cancer stem cells. In order to investigate molecular mechanisms linking specific gene mutations to tumorigenic properties, we have established and characterized two prostate luminal epithelial cell lines with Pten/TP53 deletions, derived from a prostate epithelial stem/progenitor-enriched cell population and maintained in a serum-free media.
Normal mouse prostate epithelium containing floxed Pten and TP53 alleles was subjected to CRE-mediated deletion in vitro followed by serial propagation as protospheres. A polyclonal cell line was established from dissociated protospheres and subsequently a clonal daughter line was derived. Both lines demonstrate a mature luminal phenotype in vitro. The established lines contain a stable minor population of progenitor cells with protosphere-forming ability and multi-lineage differentiation capacity. Both lines formed orthotopic adenocarcinoma tumors with metastatic potential to lung. Intracardiac inoculation resulted in brain and lung metastasis, while intra-tibial injection induced osteoblastic bone formation, recapitulating the bone metastatic phenotype of human prostate cancer. The cells showed androgen receptor dependent growth in vitro. Importantly, in vivo, the deprivation of androgens from established orthotopic tumors resulted in tumor regression and eventually castration-resistant growth. Cells derived from orthotopic tumors have been isolated to develop androgen-dependent versus androgen-independent model. These data suggest that transformed prostate progenitor cells preferentially differentiate toward luminal cells and recapitulate many characteristics of the human disease.
Citation Format: Wassim Abou-Kheir, Paul Hynes, Philip Martin, JuanJuan Yin, Yen-Nien Liu, Victoria Seng, Ross Lake, Joshua Spurrier, Kathleen Kelly. Establishing clinically relevant in vitro models of prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C66.
Abstract IA14: Novel therapeutic targets in prostate cancer
Authors: Chinnaiyan Arul M. 
Published: May 2013

Abstract
Recurrent fusions of ETS genes are considered driving mutations in a diverse array of cancers, including Ewing's sarcoma, acute myeloid leukemia, and prostate cancer. We investigate the mechanisms by which ETS fusions mediate their effects, and find that the product of the predominant ETS gene fusion, TMPRSS2:ERG, interacts in a NA-independent manner with the enzyme poly (ADP-ribose) polymerase 1 (PARP1) and the catalytic subunit of DNA protein kinase (DNAPKcs). ETS gene-mediated transcription and cell invasion require PARP1 and DNAPKcs expression and activity. Importantly, pharmacological inhibition of PARP1 inhibits ETS-positive, but not ETS-negative, prostate cancer xenograft growth. Finally, overexpression of the TMPRSS2:ERG fusion induces DNA damage, which is potentiated by PARP1 inhibition in a manner similar to that of BRCA1/2 deficiency.
Citation Format: Arul M. Chinnaiyan. Novel therapeutic targets in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA14.
Abstract IA15: Context-specific oncogenesis by ETS-family transcription factors
Authors: Chen Yu , Shukla Shipra , Chi Ping , Carver Brett , Sawyers Charles L. 
Published: May 2013

Abstract
Recurrent translocation involving ETS-family transcription factors including ERG and ETV1, ETV4, and ETV5 occur in over half of prostate cancers, implicating them as driver oncogenes in prostate tumorigenesis. Two observations pose important questions. 1) The same ETS factors aberrantly expressed in prostate cancer can be endogenously highly expressed in other tissues to modulate normal physiology (e.g., ERG expression in endothelial cells and ETV1 expression in neurons). 2) Forced overexpression in prostate model systems such as immortalized human primary prostate epithelial cells and mouse prostate yields minimal phenotype. These observations indicate that ETS mediated oncogenesis is highly dependent on the cellular context, which is mediated by the cell/tissue type and cooperating lesions. We asked how cellular context affects the DNA binding, transcriptional output, and phenotype of ETS proteins. We compared human ETS dependent tumor cell lines from two lineages, prostate cancer and gastrointestinal stromal tumor and show that ETS binding is largely tissue specific. Further, we have generated genetically engineered mouse models that express ETS in different tissues, within different compartments of the prostate gland, and with different cooperating lesions. We show that ERG binding to genomic DNA is largely similar in PTEN intact and PTEN null mouse prostates. Yet, ERG can only mediate a transcriptional program that mediates an aggressive phenotype in PTEN null prostates. These data suggests that cellular context is critical for ETS transcription factor function.
Citation Format: Yu Chen, Shipra Shukla, Ping Chi, Brett Carver, Charles L. Sawyers. Context-specific oncogenesis by ETS-family transcription factors [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA15.
Abstract IA20: A bad influence: ERG, AR, and prostate cell differentiation
Authors: Pagliarini Raymond A. 
Published: May 2013

Abstract
Aberrant expression of oncogenic ETS transcription factors such as ERG (via the TMPRSS2:ERG fusion) plays a key role in the development of a significant fraction of prostate cancers. However, the underlying biology of ERG's function in prostate cancer is incompletely understood, with a growing number of potential effector pathways implicated. To better understand the “ERG pathway”, we have worked towards elucidating the mechanism of ERG function in prostate cancer using a variety of in vitro and in vivo models. We observe that potent ERG inhibition (using inducible shRNA constructs) inhibits the proliferation of TMPRSS2:ERG positive VCaP prostate cancer cells. A number of phenotypic findings in this model suggest that ERG knockdown causes growth arrest by inducing aspects of prostate cell differentiation. In particular, the most significant transcriptional response to ERG inhibition was an upregulation of Androgen Receptor (AR)-dependent genes expressed in normal prostate lumenal epithelium. We validated these findings in additional in vitro models, and showed that recruitment of ERG to AR target genes attenuates recruitment of AR, even when ERG and AR are not bound to adjacent regions of the target gene. From these findings, we hypothesize that the main role of ERG in prostate cancer is to prevent AR-mediated cell differentiation signals, while still allowing AR-dependent proliferation. We are currently working to further elucidate the mechanism of how ERG controls AR recruitment to its target genes; in particular, whether any ERG-interacting proteins with enzymatic function (i.e., “druggable pockets”) mediate this effect. We are also working to build more robust in vitro models of AR-dependent prostate cell differentiation, in order to better assess how perturbing ERG function, as well as the function of other signaling pathways, affects this biology.
Citation Format: Raymond A. Pagliarini. A bad influence: ERG, AR, and prostate cell differentiation [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA20.
Abstract IA21: Transcriptional programs directed by the androgen receptor splice variants
Authors: Hu Rong , Lu Changxue , Mostaghel Elahe A. , Yegnasubramanian Srinivasan , Gurel Meltem , Tannahill Clare , Edwards Joanne , Isaacs William , Nelson Peter S. , Bluemn Eric , Plymate Stephen R. , Luo Jun 
Published: May 2013

Abstract
Continued androgen receptor (AR) signaling is an established mechanism underlying castration-resistant prostate cancer (CRPC), and suppression of AR signaling remains a therapeutic goal of CRPC therapy. Constitutively active androgen receptor splice variants (AR-Vs) lack the AR ligand-binding domain (AR-LBD), the intended target of androgen deprivation therapies (ADT) including new CRPC therapies such as abiraterone and MDV3100. Transcriptional programs directed by the canonical full-length AR (AR-FL) are well characterized, but those directed the AR-Vs are not well understood. In addition, AR-FL and AR-Vs are both increased in CRPC, underscoring the critical importance of dissecting the complex interplay between AR-FL and AR-Vs. In this study, we employed a set of detection and targeting tools that differentiate the AR-FL and AR-Vs to investigate the functional distinctions between AR-FL and AR-V. We show that suppression of endogenous AR-FL signaling by targeting AR-LBD leads to increased AR-V expression in two cell line models of CRPC. Importantly, treatment-induced AR-Vs activate a distinct expression signature enriched for cell cycle genes without requiring the presence of AR-FL. Conversely, activation of AR-FL signaling suppresses the AR-V-mediated transcriptional programs but activates genes mainly associated with macromolecular synthesis, metabolism, and differentiation. In prostate cancer cells and CRPC xenografts treated with MDV3100 and abiraterone, increased expression of two constitutively active AR-Vs, AR-V7 and ARV567ES, but not AR-FL, parallels increased expression of the AR-driven cell cycle gene UBE2C. In addition, protein expression of AR-V7, but not AR-FL, is positively correlated with UBE2C in clinical CRPC specimens. The cumulative in vitro and in vivo evidence support an adaptive shift toward AR-V-mediated signaling in at least a subset of CRPC tumors as the AR-LBD is rendered inactive, suggesting a functional dichotomy between AR-FL and AR-Vs in a therapeutic setting. The dynamic interplay between AR signaling mediated by AR-FL and AR-V should be further explored in rational development of novel CRPC therapies and multipurpose biomarkers for CRPC.
Citation Format: Rong Hu, Changxue Lu, Elahe A. Mostaghel, Srinivasan Yegnasubramanian, Meltem Gurel, Clare Tannahill, Joanne Edwards, William Isaacs, Peter S. Nelson, Eric Bluemn, Stephen R. Plymate, Jun Luo. Transcriptional programs directed by the androgen receptor splice variants [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA21.
Abstract IA4: Outcome prediction from the pattern of aberrations in prostate cancer genomes
Authors: Taylor Barry S. , Hieronymus Haley , Schultz Nikolaus , Sawyers Charles L. ,   on behalf of the MSKCC Prostate Cancer Oncogenome Group
Published: May 2013

Abstract
One of the greatest challenges in prostate cancer care is distinguishing men with high-risk disease requiring aggressive therapy from those who can be managed with active surveillance. Therefore, we are pursuing an ongoing integrative genomic analysis of human primary and metastatic prostate cancers. We explore the clinical importance and pathogenicity of genomic lesions and their association with canonical features of prostate cancer biology. Previously, we found that global patterns of DNA copy number alterations (CNAs) in primary tumors were associated with disease recurrence after radical prostatectomy. Here, we will discuss our efforts to extend this discovery by validating the clinical importance of CNAs and structural rearrangements in independent cohorts, at multiple scales, and with orthogonal methods. Our principal goal is to deliver a clinical diagnosis informed by genomic abnormalities that impacts definitive treatment decisions in men diagnosed with prostate cancer.
Citation Format: Barry S. Taylor, Haley Hieronymus, Nikolaus Schultz, Charles L Sawyers, on behalf of the MSKCC Prostate Cancer Oncogenome Group. Outcome prediction from the pattern of aberrations in prostate cancer genomes [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA4.
Abstract IA6: Cell cycle progression genes differentiate indolent from aggressive prostate cancer
Authors: Stone Steven ,   On behalf of the Transatlantic Prostate Group, Cuzick Jack , Berney Dan , Reid Julia , Fisher Gabrielle , Lanchbury Jerry , Gutin Alexander , Swanson Greg 
Published: May 2013

Abstract
Background: In cancers with variable natural history, prognostic biomarkers are needed for selecting patients for therapeutic intervention. This is particularly true for prostate cancer, where many screen-detected cases are indolent and predicting adverse outcomes is difficult. Therefore, we developed an expression signature composed of genes involved in cell cycle progression (CCP) and tested its utility in prostate cancer.
Methods: We developed a 46-gene prognostic RNA signature that is based on measuring the expression of CCP genes. The expression score (CCP score) is derived as the normalized mean expression all CCP genes in the signature.
Results: The prognostic utility of the CCP score has been tested in both multiple clinical settings and patient populations. First, it was tested in a post-prostatectomy cohort from the U.S. where the CCP score predicted biochemical recurrence in univariate (χ2 = 34.0, 1df, p = 5·6 × 10-9) and multivariate analysis (χ2 = 21.65, 1df, p = 3.3 × 10-6). CCP score and PSA were the dominant variables in the best predictive model and were much more significant than any other clinical measure. Second, it was tested in a conservatively managed TURP cohort from the UK where the CCP score was the dominant variable for predicting death from prostate cancer in both univariate (χ2 = 92.7, 1df, p = 6.1 × 10-22) and multivariate analyses (χ2 = 42.2, p = 8.2 × 10-11). Third, it was tested in a conservatively managed needle biopsy cohort from the UK where the CCP score was a better univariate predictor of prostate cancer death than any other variable (χ2 = 37·6, 1df, p = 8.6 × 10-10). The best multivariate model from this study included Gleason and PSA, but CCP dominated (HR for one unit increase = 1.65, 95% CI (1.31, 2.09) χ2 = 17.7, P = 3 × 10-5) with Gleason score (χ2 = 12.1, P = 5 × 10-4) and baseline PSA (χ2 = 5.7, P = 0.017) providing significant, but smaller additional contributions.
Conclusions: A CCP expression signature is prognostic in prostate cancer patients at diagnosis and after prostatectomy. It consistently provides information beyond clinical and pathological variables to help differentiate aggressive from indolent disease. Studies aimed at expanding the clinical utility of this signature are warranted and ongoing.
Citation Format: Steven Stone, On behalf of the Transatlantic Prostate Group, Jack Cuzick, Dan Berney, Julia Reid, Gabrielle Fisher, Jerry Lanchbury, Alexander Gutin, Greg Swanson. Cell cycle progression genes differentiate indolent from aggressive prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA6.
Abstract IA7: Development of integrated diagnostic methods for tissue testing
Authors: Pestano Gary A. 
Published: May 2013

Abstract
Identification of patients who will benefit from targeted therapies, or who have highly aggressive disease courses are among the more difficult questions in disease management. We continue to address these questions in ongoing studies that include the development of integrated diagnostic test methods as IVD assays. These tests may better account for tissue heterogeneity, assess multiple gene re-arrangements, protein over-expression, and nuclei change parameters in individual transformed nuclei.
Specific results from studies will be discussed for the prostate. The ETS rearranged genes are the most common in prostate cancer, but it is expected men with diagnosed prostate cancer will have harbor additional genetic rearrangements that may be also reflected by alterations in nuclear morphology. In addition, prostate cancers with productive gene fusions results in the over-expression of oncogenic transcription factors, including in ERG. Alterations in nuclear morphology, gene fusion status, and the downstream factors they impact may serve as potential therapeutic targets, or may be linked to poor disease prognoses.
We describe an integrated testing strategy that can be applied to various stages of disease progression from an initial diagnosis on biopsy for PIN and low-risk disease, to advanced disease involving extra-capsular penetration and recurrence.
Note: This abstract was not presented at the conference because the presenter was unable to attend.
Citation Format: Gary A. Pestano. Development of integrated diagnostic methods for tissue testing [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA7.
Raw Garlic Consumption as a Protective Factor for Lung Cancer, a Population-Based Case–Control Study in a Chinese Population
Authors: Jin Zi-Yi , Wu Ming , Han Ren-Qiang , Zhang Xiao-Feng , Wang Xu-Shan , Liu Ai-Ming , Zhou Jin-Yi , Lu Qing-Yi , Zhang Zuo-Feng , Zhao Jin-Kou 
Published: May 2013

Abstract
Protective effect of garlic on the development of cancer has been reported in the in vitro and in vivo experimental studies; however, few human epidemiologic studies have evaluated the relationship. A population-based case–control study has been conducted in a Chinese population from 2003 to 2010, with the aim to explore the association between raw garlic consumption and lung cancer. Epidemiologic data were collected by face-to-face interviews using a standard questionnaire among 1,424 lung cancer cases and 4,543 healthy controls. Unconditional logistic regression was used to estimate adjusted ORs and their 95% confidence intervals (CI), and to evaluate ratio of ORs (ROR) for multiplicative interactions between raw garlic consumption and other risk factors. After adjusting for potential confounding factors, raw garlic consumption of 2 times or more per week is inversely associated with lung cancer (OR = 0.56; 95% CI, 0.44–0.72) with a monotonic dose–response relationship (Ptrend &lt; 0.001). Furthermore, strong interactions at either additive and/or multiplicative scales were observed between raw garlic consumption and tobacco smoking [synergy index (SI) = 0.70; 95% CI, 0.57–0.85; and ROR = 0.78; 95% CI, 0.67–0.90], as well as high-temperature cooking oil fume (ROR = 0.77; 95% CI, 0.59–1.00). In conclusion, protective association between intake of raw garlic and lung cancer has been observed with a dose–response pattern, suggesting that garlic may potentially serve as a chemopreventive agent for lung cancer. Effective components in garlic in lung cancer chemoprevention warrant further in-depth investigation. Cancer Prev Res; 6(7); 711–8. ©2013 AACR.
Should Bilateral Internal Thoracic Artery Grafting Be Used in Elderly Patients Undergoing Coronary Artery Bypass Grafting?
Authors: Medalion Benjamin , Mohr Rephael , Frid Osnat , Uretzky Gideon , Nesher Nachum , Paz Yosef , Kramer Amir , Pevni Dmitry 
Published: May 2013

Background—
Although bilateral internal thoracic artery grafting is associated with improved survival, the use of this technique in the elderly is controversial because of their increased surgical risk and shorter life expectancy. The purpose of this study was to evaluate the effect of age on outcome of patients undergoing bilateral internal thoracic artery grafting.

Methods and Results—

Between 1996 and 2001, 1714 consecutive patients underwent skeletonized bilateral internal thoracic artery grafting, of whom 748 were ≤65 years of age, 688 were between 65 and 75 years of age, and 278 were ≥75 years of age. Operative mortality of the 3 age groups (1.2%, 4.1%, and 5.8%, respectively) was lower than the logistic EuroSCORE predicted mortality (3.9%, 6.5%, and 9.3%, respectively;
P
<0.001). There were no significant differences among the groups in occurrence of sternal infection (1.3%, 2.6%, and 1.4%, respectively;
P
=0.171). Mean follow-up was 11.5 years. Kaplan–Meier 10-year survival for patients ≤65, 65 to 75, and >75 years of age was 85%, 65%, and 40%, respectively (
P
<0.001). These rates were better than the corresponding predicted Charlson Comorbidity Index survival rates (68%, 37%, and 20%, respectively;
P
<0.001 for all age groups), approaching survival of the sex- and age-matched general population (90%, 70%, and 41%, respectively). Age ≤65 years (hazard ratio, 0.232; 95% confidence interval, 0.188–0.288) and age 65 to 75 years (hazard ratio, 0.499; 95% confidence interval, 0.414–0.602) were independent predictors of improved survival (Cox model).

Conclusions—
Bilateral internal thoracic artery grafting should be considered in patients >65 years of age because of the significant survival benefit obtained with this surgical technique with no additional risk of sternal wound infection related to age.
High Proficiency in a Second Language is Characterized by Greater Involvement of the First Language Network: Evidence from Chinese Learners of English
Authors: Cao Fan , Tao Ran , Liu Li , Perfetti Charles A. , Booth James R. 
Published: May 2013

Abstract
The assimilation hypothesis argues that second language learning recruits the brain network for processing the native language, whereas the accommodation hypothesis argues that learning a second language recruits brain structures not involved in native language processing. This study tested these hypotheses by examining brain activation of a group of native Chinese speakers, who were late bilinguals with varying levels of proficiency in English, when they performed a rhyming judgment to visually presented English word pairs (CE group) during fMRI. Assimilation was examined by comparing the CE group to native Chinese speakers performing the rhyming task in Chinese (CC group), and accommodation was examined by comparing the CE group to native English speakers performing the rhyming task in English (EE group). The CE group was very similar in activation to the CC group, supporting the assimilation hypothesis. Additional support for the assimilation hypothesis was the finding that higher proficiency in the CE group was related to increased activation in the Chinese network (as defined by the CC &gt; EE), including the left middle frontal gyrus, the right inferior parietal lobule, and the right precuneus, and decreased activation in the English network (as defined by the EE &gt; CC), including the left inferior frontal gyrus and the left inferior temporal gyrus. Although most of the results support assimilation, there was some evidence for accommodation as the CE group showed less activation in the Chinese network including the right middle occipital gyrus, which has been argued to be involved in holistic visuospatial processing of Chinese characters.