bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 416: Mammographic density and ECM stiffness
Authors: Acerbi Irene , Alfred Au , Lopez Jose , Hwang Shelley , Weaver Valerie 
Published: August 2014

Abstract
Breast tissue homoeostasis depends on the complex regulation of biochemical and biophysical factors present in the extra cellular matrix (ECM). Tumor tissue in mouse and human breast is characteristically stiffer than normal tissue, and changes to the ECM contribute to this phenotype. Breast density is associated with elevated collagen content, while increased deposition of collagen is known to augment ECM stiffness. Mammographic density imaging provides a qualitative description of breast density, and high mammographic density is associated with increased risk to malignancy. However, little is known about the correlation between ECM stiffness and the density in the breast image. Previously, we have used atomic force microscopy (AFM) to characterize the changes in breast tissue stiffness with cancer progression (Levental et al., Cell 2009). We hypothesized that mammographically dense breasts would be stiffer. To further understand the biophysical regulation of breast stiffness, we investigated whether mammographic density is a predictor of ECM stiffness. Towards this goal, we studied tissue samples from prophylactic mastectomies, from women with low versus high mammographic density. Tissue samples were obtained from the peripheral quadrants as well as from the retroareolar (nipple) regions, which are known to be of higher mammographic density. We performed AFM force mapping to characterize the ECM stiffness in the different regions. Our preliminary data indicate a heterogeneous pattern of stiffness within the breast. Moreover, we found that the peripheral terminal ductal lobuli have the most compliant ECM. By contrast, the stroma stiffness in the retroareolar region was 2-fold higher than in the peripheral quadrants. This work demonstrates the technical feasibility of measuring the mechanical properties as well as defined histological characteristics within the same patient specimen. The data suggest that ECM stiffness may be greater in breast tissue of high mammographic density. The correlation between mammographic density and ECM stiffness may reveal the role of collagen status in the risk to malignancy. (supported by W81XWH-05-1-0330 and R01 CA138818-01A1 to VMW, 1U01 ES019458-01 to VMW and ZW, and P50 CA 58207 to JG, VW, SH and LC.)
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 416. doi:10.1158/1538-7445.AM2011-416
Abstract 4162: The importance of age-related cytokines in chronic lymphocytic leukemia
Authors: Yoon Ju-Yoon , LaFarge Sandrine , Dawe David , Lakhi Sunjay , Kumar Rajat , Marshall Aaron , Gibson Spencer , Johnston James B. 
Published: August 2014

Abstract
Chronic lymphocytic leukemia (CLL) is a disease of the elderly with the median age at diagnosis being 72 years. Prognosis is highly variable with the relative survival progressively worsening after age 65 years. In this study we have evaluated whether the age-related cytokines, IL-6, IL-8 and TNF-alpha, play a role in the poor survival of elderly patients with CLL. The plasma levels and biological effects of the age-related cytokines, IL-6, IL-8 and TNF-alpha, were evaluated in 193 CLL patients of varying ages. Patients were chosen randomly to reflect the age spectrum and sex distribution of the Manitoban CLL population. As predicted from population studies, the survival of patients progressively worsened with age, with the primary causes of death being CLL or one of its complications (infection or second tumors). Cytokine levels were increased in CLL compared to 37 age- and sex-matched controls. A third of patients aged &lt;/=65 years had increased IL-6, compared to 10% in patients &lt; 65. A high correlation was found between the plasma levels of these three cytokines with age and Beta2-microglobulin (a measure of tumor burden). The plasma levels of the cytokines also correlated with each other, suggesting they increased in parallel. In contrast, the standard CLL prognostic markers IgVH mutational status, ZAP-70, CD38 and Rai stage did not correlate with cytokine levels or age. Patients with increased IL-6 or IL-8 had a poorer survival than those with normal levels. For IL-6, this difference was more marked for those &lt;/=65 years. Furthermore, focusing on older patients, multivariate analysis with backward selection of variables showed IL-6 and Beta2-microlgobulin to be significant predictors of survival, while the mutational status and Rai stage were not significant. The cause of death was due to CLL-related causes and not to frailty or cardiovascular disease. However, increased cytokine levels correlated with a higher lifetime incidence of cardiovascular disease. Thus, one source of cytokines may be cardiovascular disease, although CLL cells also secreted low amounts of IL-6 and IL-8. The two cytokines, in turn, significantly increased the adhesion of leukemic cells to stromal cells, suggesting that these cytokines may influence the microenvironment, which would contribute to poor survival.
In summary, IL-6 and IL-8 are predictors of survival in CLL, where IL-6 is a stronger predictor of survival in older patients than mutational status or Rai stage. Importance of IL-6 and IL-8 may be associated with their role in facilitating the leukemic-stromal cell interaction.
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 4162. doi:10.1158/1538-7445.AM2011-4162
Abstract 4169: Loss of GPR30 expression identifies estrogen receptor positive endometrial carcinoma patients with poor outcome
Authors: Krakstad Camilla , Trovik Jone , Wik Elisabeth , Engelsen Ingeborg B. , Øyan Anne M. , Stefansson Ingunn M. , Kalland Karl-Henning , Akslen Lars A. , Salvesen Helga B. 
Published: August 2014

Abstract
In industrialized countries, endometrial cancer is the most common pelvic gynecologic malignancy, with a 2% to 3% lifetime risk. Expression of estrogen receptor (ER) and progesterone receptor (PR) is known to be associated with good prognosis and response to anti-hormonal therapy. Still, up to 20% of receptor positive cancers recur. The G-protein coupled receptor GPR30 has been suggested as an alternative estrogen receptor. We have studied a prospective series of 472 endometrial cancer patients by immunohistochemistry and 76 for mRNA expression levels by oligonucleotide array. We identify that loss of GPR30 is significantly correlated with non-endometrioid histology and high histologic grade both at the mRNA and protein levels (all p-values≤0.006). In ER positive patients (n=363), loss of GPR30 significantly correlates with high FIGO stage, non-endometrioid histology and high histologic grade (all p-values≤0.005). Loss of GPR30 reduces the 5-year survival of ER positive patients from 93% to 76% (p=0.003) and identifies a subgroup of patients with poor prognosis that until now has been evaluated as favorable survivors. Examination of the gene expression profile for ER positive tumors with and without loss of GPR30, indicates mechanisms involved related to GPR30 expression.
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 4169. doi:10.1158/1538-7445.AM2011-4169
Abstract 4171: The role of ATM and 53BP1 as predictive markers and therapeutic targets in advanced stage cervical cancer
Authors: Roossink Frank , Wieringa Hylke W. , Noordhuis Maartje G. , Kok Mirjam , ten Hoor Klaske A. , de Bock Geertruida H. , de Jong Steven , van der Zee Ate G. J. , Schuuring Ed M.D. , Wisman G. Bea A. , van Vugt Marcel A.T.M. 
Published: August 2014

Abstract
Chemoradiation is the standard of care for advanced stage cervical cancer patients and induces cytotoxicity by inducing high levels of DNA breaks in the tumor. The ability of tumor cells to repair therapy-induced DNA damage may counteract the effects of chemoradiation. The pathway responsible for DNA double strand break repair is called the ‘DNA damage response’.
In vitro we observed robust radiation-induced G1 and G2 cell cycle arrests in cervical cancer cell lines, despite the expression of HPV oncogenes, which impact the DNA damage response through rapid p53 degradation. Moreover, the DNA damage checkpoint protein ATM and its substrate 53BP1 are required for proper induction of cell cycle checkpoint arrests. Yet, when long-term survival effects were measured, inhibition of ATM, but not 53BP1, strongly sensitized cervical cancer cells to irradiation. To validate the putative role of ATM and 53BP1 in advanced stage cervical cancer we investigated presence and activity of ATM as well as 53BP1 in relation to response-to-treatment in a large, well documented, series of advanced stage cervical cancer patients (n=375). We found that high levels of ATM were related to poor response to chemoradiation (P=0.013). Importantly, high phosho-ATM immunostaining, reflecting active ATM, predicted poor responses to chemoradiation even better (P=0.004). In addition, high phospho-ATM levels predicted shorter disease-specific survival (P=0.020).
Although presence of phosphorylated 53BP1 did relate to phospho-ATM (P=0.001), it was not significantly related to any clinicopathological features or survival.
Combined, our data suggest the prognostic value of ATM signaling for responses to chemoradiation and point at ATM inhibition as a potential therapeutic target to increase treatment efficacy in advanced stage cervical cancers.
Acknowledgements
This research is supported by the Dutch Cancer Society (RUG 2007-3719) and the Netherlands Organization for Scientific Research (NWO-VENI 916.76.062).
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 4171. doi:10.1158/1538-7445.AM2011-4171
Abstract 4174: Variation in UDP glucouronyltransferase (UGT) genes associated with prostate cancer mortality
Authors: Kohli Manish , Mahoney Douglas , Chai High , Hillman David , Rider David , Costello Brian , Cerhan James 
Published: August 2014

Abstract
Background: We investigated the association of germline genetic variation in hormone biosynthesis and metabolism genes with prostate cancer specific mortality in a cohort of advanced prostate cancer patients. Methods: We genotyped 852 single nucleotide polymorphisms (SNPs) from 97 genes in a cohort of 267 advanced prostate cancer patients at the time of progression to castration recurrence (CRPC) during on-going androgen ablation. Tagging SNPs with minor allele frequency (MAF) of &gt;5% and r2 ≥0.8 were selected from HapMap, NIEHS and Seattle SNP databases. Medical records were queried for cause of death. The primary endpoint of time to prostate cancer specific mortality (PCSM), was pre-defined as time from development of CRPC to death from prostate cancer progression. Principle components analysis was used for gene-levels tests, and to account for multiple testing, we calculated the false discovery rate (FDR). For SNP level results, Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using cox regression. Results: The median age of the cohort was 72 years at CRPC. 43% had a Gleason score (GS)=8-10, 33% a GS=7, and 24% a GS&lt;7. After a median follow up of 1.8 years (IQ range: 0.8-3.3 years), 139 patients died, of which 107 were due to prostate cancer progression. In unadjusted gene level analyses, UGT1A7 (p=0.0059; FDR=0.19), UGT1A10 (p=0.0017; FDR=0.17) and UGT1A3 (p=0.0037; FDR=0.18) were associated with PCSM. After adjusting for age and GS, SNPs strongly associated with PCSM are listed in the Table.

Conclusions: Variation in UGT genes involved in hormone metabolism yield prognostic information in CRPC. Further validation is needed to develop these as prognostic biomarkers.
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 4174. doi:10.1158/1538-7445.AM2011-4174
Abstract LB-179: The effects of hypoxia and reactive oxygen species on the methylation status of the polo-like kinases
Authors: Ward Alejandra , Hudson John W. 
Published: August 2014

Abstract
The family of polo-like kinases (Plks) consisting of five known members are key regulators of important cell cycle processes, such as mitotic entry, centrosome duplication, spindle assembly, and cytokinesis. Plk1 is typically overexpressed in many cancers, while Plks 2–4 deregulation is often associated with tumorigenesis and malignancy. Plk2 has been shown to be downregulated via promoter DNA hypermethylation in blood neoplasms. Furthermore, in hepatocellular carcinoma (HCC), we and others have shown Plks 2–4 are downregulated through epigenetic modifications, while concurrent decreased Plk 1 promoter methylation was correlated with increased expression. As changes in epigenetic modifications have been associated with external environmental stimuli, we hypothesized that the Plks may be important targets whose disregulation could contribute to malignancy. We therefore examined the status of promoter methylation and expression levels of the Plk family members under hypoxic conditions, and upon exposure to reactive oxygen species (ROS). Interestingly both wild-type and Plk4 heterozygous murine embryonic fibroblasts (MEFs) exposed to ROS displayed significant promoter methylation post treatment. Correspondingly, Plk4 transcript levels were reduced to 90% with no detectable Plk4 protein after exposure to ROS. Since ROS and hypoxic conditions are associated with liver function and normal metabolism, we next examined the promoter methylation status for the individual Plks and other markers in HepG2 and Hep3B liver cell lines. We found increased hypermethylation of the promoter region as well as decreased transcripts levels for both Plk1 and Plk4 post ROS treatment in both cell lines. No detectable methylation changes were detected in SAOS (bone sarcoma, p53 null) cells, while U2OS (p53 wild type) displayed increased methylation and decreased transcript levels. This suggests that the response to ROS might be dependent upon p53 status and origin of cell line. Similar to the case with ROS, hypoxia treatment also induced hypermethylation of Plk4 and decreased in transcripts in both HepG2 and Hep3B cells, while Plk1 levels were only reduced in HepG2 cells. Our results suggest that changes in the cellular environment may be a key regulator of Plk methylation status that in turn leads to deregulation. This has important implications in HCC and other cancers, where these epigenetic alterations could be contributing factors in tumourigenesis and disease progression.
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-179. doi:10.1158/1538-7445.AM2011-LB-179
Abstract LB-182: Preoperative serum level of homocysteine is associated with survival of breast cancer among Korean women
Authors: Lee Yunhee , Lee Sang-Ah , Lee Kyoung-Mu , Lee Ji-Young , Sung Hyuna , Li Lian , Park Sue K. , Yoo Keun-Young , Noh Dong-Young , Ahn Sei-Hyun , Choi Ji-Yeob , Kang Daehee 
Published: August 2014

Abstract
The serum level of homocysteine is suggested to be related to inflammation, cardiovascular disease, and cancer. This study aimed to evaluate preoperative serum homocysteine level as biomarker for breast cancer prognosis. We measured serum homocysteine levels using the fluorescence polarization in 370 participants who were newly diagnosed and histopathologically confirmed breast cancer from hospitals located in Seoul, Korea between 2004 and 2007. Univariate and multivariate analyses were used to investigate association between serum homocysteine level and disease free survival. The median concentration of homocysteine was 10.09 ng/mL and interquartile range was 8.4–12.6. Kaplan-Meier curves showed that the elevated concentration of homocysteine was associated with poor disease-free survival (log rank p = 0.02). In multivariate analysis using the Cox's proportional hazard regression model, patients with greater than median levels of homocysteine showed increased risk of breast cancer recurrence compared to the patients with lower levels of homocysteine after adjusting for factors related to prognosis (hazard ratio = 2.03; 95% confidence interval, 1.13–3.64; p = 0.02). These findings suggest that higher level of homocysteine may be associated with the poor prognosis of breast 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 LB-182. doi:10.1158/1538-7445.AM2011-LB-182
Abstract LB-183: Association of aberrant promoter methylation of novel genes with clinicalpathology and prognosis of urothelial carcinoma
Authors: Li Ching Fei , Lee Te-Chang , Wang Sheng-Shin Alexander , Pu Yeong-Shiau 
Published: August 2014

Abstract
DNA methylation profiles are one of valuable biomarkers to molecularly define cancer subtypes that may serve as better indicators for disease progression, treatment and prognosis. In the present study, we investigated the aberrant promoter methylation of 5 tumor-related genes, CCND1, CHFR, FAM51A1, LGALS4, and RBBP7, which were selected from pooled DNA methylation profiles of urothelial carcinoma (UC) with various clinicopathological parameters. DNA was extracted from 90 patients with confirmed UC and 10 adjacent non-tumor controls. Promoter aberrant methylation of these 5 genes was determined by quantitative methylation-specific PCR (qMSP). Our results showed that methylation levels were higher in UC as compared with controls in promoter of CHFR, FAM51A1, LGALS4, and RBBP7 (6.24 vs. 4.27; 0.66 vs. 0.01; 7.47 vs. 2.14; 0.45 vs. 0.01, respectively). Among UC patients, the levels of promoter methylation of CCND1, CHFR and LGALS4 were significantly associated with tumor stages (p&lt; 0.01), whereas that of FAM51A1 was inversely associated with tumor stages (p=0.012). Tumors with poor differentiation showed higher levels of promoter methylation on CCND1, CHFR and LGALS4 genes than tumors with moderate differentiation (p&lt;0.05). UC patients with highly methylated CCND1, CHFR, LGALS4 or RBBP7 tended to have a poor survival than patients with low levels of methylated gene (p&lt;0.02). This is the first report to show the association of promoter methylation of these 5 genes with UC tissues. We anticipate that the methylation status of these novel marker genes may have great clinical implications for further classifying UC 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-183. doi:10.1158/1538-7445.AM2011-LB-183
Abstract LB-184: Bmi1 regulates cell fate via tumor suppressor WWOX repression in small cell lung cancer cells
Authors: Kimura Masaki , Akita Nobuhiro , Takenobu Hisanori , Kimura Hideki , Nakagawara Akira , Kamijo Takehiko 
Published: August 2014

Abstract
Mortality from lung cancer is important worldwide. Recently, epigenetic aberration of lung cancer, not only genomic DNA methylation but also chromatin modification, has become an important target for lung cancer research, although previous research has demonstrated that lung cancer develops as a result of both environmental and genetic factors. Here, we demonstrated that an epigenetic regulator/polycomb group protein Bmi1 is more highly expressed in small cell lung cancer than in non-small-cell lung cancer by immunohistochemical analysis. In vitro experiments indicated that Bmi1 reduction by lentivirus-derived shRNA significantly suppressed proliferation, colony formation, and in vivo tumor formation. Importantly, apoptosis was induced by Bmi1 depletion in small cell lung cancer cells. Furthermore, a tumor suppressor WWOX was identified as a Bmi1 target in the cells by chromatin immunoprecipitation assay and quantitative real-time PCR assay; WWOX had a role as a tumor suppressor in SCLC cells; therefore, the Bmi1/WWOX pathway could be a new candidate for a new therapeutic approach for small cell lung 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 LB-184. doi:10.1158/1538-7445.AM2011-LB-184