bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3750: Functional analysis of the Fanconi Anemia pathway in primary lung tumors
Authors: Duan Wenrui , Gao Li , Wu Xin , Zhao Weiqiang , Leon Marino , Otterson Gregory A. , Villalona-Calero Miguel A. 
Published: February 2011

Abstract
The Fanconi Anemia (FA) pathway is a major mechanism of homologous recombination DNA repair in response to genotoxic insults. Lack of formation of FANCD2 foci has been reported as a predictor of cisplatin and mitomycin C (MMC) sensitivity in cancer cells. Given that this pathway plays essential roles in response to the DNA damage, cancers with defective FA pathway are expected to be more sensitive to DNA cross-link based therapy, or to treatments in which additional repair mechanisms are targeted.
We have developed a test to identify tumors with defective FA pathway using paraffin embedded tissues. Paraffin embedded lung primary cancer specimens were subjected to immunofluorescence microscopy (IF) analysis to evaluate the status of FancD2 subnuclear foci formation, Ki67 protein expression and DAPI staining of nuclei simultaneously in order to eliminate false negative tumor specimens due to absence of tumor cells or low proliferation. Additional validation using FA defective PD220 and PD20 cell-lines as well as fresh tumor tissues was done; IF analysis and Western blotting analysis of FDACD2 protein mono-ubiqutination were performed.
The ratio of FANCD2 foci negative tumor was 20% among 20 paraffin embedded non-small cell lung cancer samples analyzed. Histological characteristics of the defective tumors include large cell carcinoma and adenocarcinoma. The proposed immunofluorecence staining method evaluates functional status of FA pathway using paraffin embedded tissues even after long term storage. Given the clinical availability of agents targeting alternative mechanisms of repair, the status of FA pathway may be an important biomarker for personalized therapeutic treatment in patients with lung cancers. A clinical trial to validate this hypothesis is under way.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3750.
Abstract 3756: Prediction of xenograft response to MM-121, an anti-ErbB3 inhibitor, using computational modeling and measurements of five biomarkers
Authors: Onsum Matthew , Burenkova Olga , Fulgham Aaron , Nie Lin , Kalra Ashish , Xiao Dongmei , Grantcharova Viara , Adams Sharlene , Luus Lia , Paragas Violette , Bukhalid Raghida , Moulis Sharon , Wille Lucia , Garcia Gabriela , Moyo Victor , Schoeberl Birgit , Kubasek Bill , Nielsen Ulrik 
Published: February 2011

Abstract
One of the challenges faced by targeted therapeutics currently in the clinic is the relatively small population of patients who derive significant benefit from their use. We report the development of a preclinical classifier which can correctly predict xenograft response to MM-121, an anti-ErbB3 antibody, based on the measurement of a few key biomarkers in cell lysates.
Deregulation of the ErbB family receptors is common in many cancers. Using a combination of computational modeling and quantitative experiments we identified ErbB3 as a key mediator of mitogenic signaling downstream of the ErbB receptors. Based on these results, we developed MM-121, a first in class anti-ErbB3 monoclonal antibody that blocks heregulin-induced signaling and inhibits tumor growth in multiple xenograft models of human cancer.
Here we present our efforts to derive a predictive biomarker signature that identifies tumors that are responsive to MM-121. Using our computational model of the ErbB signaling pathway we identified the five most critical proteins for predicting activation of phospho-AKT - a key mediator of cell survival and apoptosis. These proteins include MM-121's target, ErbB3, and its ligand, heregulin. We profiled these biomarkers in a large panel of cancer cell lines, and using the measured effect of MM-121 on inhibiting tumor growth in eight xenograft tumor models, we determined a classification rule for predicting xenograft response. We subsequently used this classification rule to correctly predict a priori MM-121 response in 11 xenograft models.
These results suggest that our computationally-derived biomarker signature is sufficient for predicting response to MM-121 in xenografts, and could offer significant clinical benefit by helping select patients for MM-121 treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3756.
Abstract 3762: Automated analysis of breast cancer tissue microarrays to investigate etiologic heterogeneity in the Breast Cancer Association Consortium
Authors: Sherman Mark E. , Howatt William , Bolton Kelly , Pharoah Paul , Garcia-Closas Montserrat 
Published: February 2011

Abstract
Background: Data suggest that breast cancer risk factor associations vary by tumor marker expression. However, individual studies often lack the power required to assess these relationships and pooled analyses are limited by non-standardized scoring of tumor markers. To address these limitations, the Breast Cancer Association Consortium is assessing whether automated image analysis of immunohistochemically stained tissue microarrays (TMAs) can permit standardized scoring of tumor markers.
Methods: TMA sections prepared in 10 case-control studies containing up to 9,298 breast cancers stained for estrogen receptor (ER); progesterone receptor (PR); human epidermal growth factor receptor 2 (HER 2); epidermal growth factor receptor (EGFR) and cytokeratin 5/6 (CK 5/6) were scanned as digital images. Automated algorithms were used to score markers in tumor cells using the Ariol system. We are analyzing consistency of automated scores within individual studies; between studies; and against visual reads.
Results: Preliminarily, distributions of automated scores were generally similar across different TMA blocks within a study; however isolated blocks yielded disparate results related to low or high intensity staining for a marker or the counterstain across the entire slide. Distributions of scores varied between studies, suggesting the need for study-specific cutpoints for negative vs. positive. Analysis of receiver operator characteristic curves comparing automated analysis to independently recorded visual reads in two studies demonstrated areas under the curves of 0.90 and 0.93 for tumors classified visually as ER+/PR+ and 0.91 and 0.88 for tumors scored visually as ER-/PR-. Cores scored as negative for EGFR or CK 5/6 by automated methods agreed well with visual scores, but many tumors scored as positive by automated analysis were negative by visual review, irrespective of ER / PR status. Thus, restricting analyses to ER-/PR- tumors (a subset of interest) reduced the number of discrepancies. Ongoing analyses are comparing automated and visual scores for all markers / studies and are assessing risk factor associations for breast cancer by tumor marker expression (negative vs. positive and strength of expression) based on automated scores.
Conclusions: Automated analysis of immunohistochemically stained TMAs of breast cancers may be useful in standardizing high throughout characterization of cancer markers in multicenter studies and in consortia, although additional methodologic work is needed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3762.
Abstract 3766: Development of a model using genetics and PSA to reduce unnecessary prostate biopsies
Authors: Cross Deanna S. , McCarty Catherine , Reding Douglas J. 
Published: February 2011

Abstract
Background: Prostate cancer screening with PSA has decreased the average age of prostate cancer detection and increased the number of men who undergo prostate biopsies. Currently two thirds of the prostate biopsies performed due to a high PSA test are negative for prostate cancer leading to unnecessary expense and distress for the individual. One way to decrease the unnecessary procedures associated with PSA screening would be to identify individuals who are at higher or lower risk of prostate cancer using newly discovered genetic and environmental risk factors.
Aims: Using the males in the Personalized Medicine Research Project (PMRP) population that have had a PSA test, determine if genetic and environmental factors can be incorporated into the PSA screening model to better discriminate individuals who will have a diagnosis of prostate cancer from those with negative biopsies.
Methods: All men in PMRP who have had a PSA test (N=4659) were genotyped for 12 polymorphisms that have been associated with prostate cancer in GWAS studies and an additional 52 polymorphisms that were associated with a number of diseases. We also included dietary history, particularly dairy intake if available for the individual.
Results: A total of 935 of the 4659 men in the study have had a prostate biopsy with a positive biopsy rate of 34%. Using a panel of 12 previously identified polymorphisms; seven were significantly associated with prostate cancer in our population. Another three polymorphisms were found to be associated in our population (LPL rs328, NOS3 rs1799983, and PON2 rs7493). None of the tested polymorphisms were associated with the biopsy procedure. Individuals with 4 or fewer of the 10 associated risk alleles (17.33% of the population) were more likely to have a negative biopsy (OR 1.87 p=0.0017) while those individuals who have 8 or more associated risk alleles (11% of the population) were more likely to have a positive biopsy (OR 2.68).
Conclusions: The PMRP population that has experienced at least one PSA screen is a viable population for testing new screening algorithms that incorporate genetic and environmental factors for better identification of prostate cancer risk.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3766.
Abstract 3772: Lifestyle factors and global methylation in peripheral leukocyte DNA
Authors: Zhang Fang Fang , Morabia Alfredo , Carroll Joan , Gonzalez Karina , Fulda Kimberly , Kaur Manleen , Santella Regina M. , Cardarelli Roberto 
Published: February 2011

Abstract
Global hypomethylation is associated with genomic instability and may mediate the association between environmental and lifestyle factors and cancer risk. We examined the association between lifestyle factors and levels of genomic DNA methylation in the peripheral blood leukocytes of 160 participants in the North Texas Healthy Heart Study aged 45-75. We used in-person interviews for demographics and lifestyle factors, a self-administrated Block food frequency questionnaire for dietary data, bioelectrical impedance analysis (BIA) and CT-scan for body composition including fat mass % and areas of visceral and truncal subcutaneous adipose tissues at the L4L5 level. We measured genomic DNA methylation using bisulfite conversion of DNA and real time PCR (MethyLight) for SAT2-M1. The median level of global methylation was 61.3% in this cancer-free population. Male gender was positively associated with global hypomethylation (i.e. &lt; median) (OR=3.7, 95%CI: 1.4-9.7). Compared to Hispanics (n=58), non-Hispanic whites (n=33) and non-Hispanics blacks (n=68) had a significantly higher level of global hypomethylation (OR=8.4, 95%CI: 2.4-29.6 and OR=4.1, 95%CI: 1.5-11.2 respectively). Although the area of L4L5 subcutaneous adipose tissue was positively associated with DNA methylation in the univariate model (342 cm2 among subjects with methylation &lt; median vs. 395 cm2 among subjects with methylation ≥ median, p=0.04), none of the body composition measures were associated with DNA methylation in the multivariate model after adjusting for age, gender and ethnicity, nor were cigarette smoking, alcohol drinking, dietary folate intake and perceived stress. Although there was no association of lifestyle factors with genomic methylation in the peripheral leukocyte DNA, the strong association with gender and race/ethnicity indicates that interactions between these variables and lifestyle factors need to be explored in a larger sample before firm conclusions can be reached.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3772.
Abstract 3773: Ability to predict breast cancer in asian women using a polygenic susceptibility model
Authors: Hartman Mikael , Chen Suo , Miao Hui , Lim Wei-Yen , Koh Woon Puay , Teo Yik-Ying , Chia Kee Seng 
Published: February 2011

Abstract
Ability to predict breast cancer in Asian women using a polygenic susceptibility model
Background Recently identified susceptibility alleles from Genome wide Association Studies (GWAS) for breast cancer suggest a new venue to both prevention and treatment of the disease. Given variations in allele frequency between populations this ability may vary.
Methods We examined the possibility for individualized disease prevention and for population screening in Asian women based on common breast cancer risk alleles. We tested using simulations and available allele frequencies from the Singapore Genome Variation Project how these markers perform together with known environmental risk factors for the disease.
Results Our analysis suggests that the risk profile generated by 13 single nucleotide polymorphisms (SNP) as identified thru GWAS does not provide sufficient discrimination to warrant individualized prevention. They may however be useful in risk stratification for screening programs especially together with a few reproductive risk factors for disease in breast cancer prevention in the general population (Table 1).
Conclusions The clinical use of single, common, low-penetrance genes is limited, but 13 validated SNPs in combination with a few readily available reproductive factors may distinguish women who are at high risk for breast cancer from those who are at low risk, particularly in the context of population screening.
Table 1: Proportion of cases of breast cancer explained by the proportion of the population at highest risk for the disease. Estimates based on 13 currently known susceptibility alleles by ethnic group and number of SNPS.Proportion of general population at risk above a given level Proportion of Cases at risk above a given level Chinese 13 SNPsMalay 13 SNPsIndian 13 SNPsChinese 13 SNPs & Environment 20%30.6%30.9%32.2%33.5% 40%53.1%53.5%54.9%56.0% 60%71.9%72.4%73.5%74.2% 80%87.8%88.1%88.6%89.0%
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3773.
Abstract 3777: Diesel motor exhaust and lung cancer risk in a pooled analysis from case-control studies in Europe and Canada
Authors: Olsson Ann C. , Gustavsson Per , Kromhout Hans , Peters Susan , Vermeulen Roel C. H. , Brüske Irene , Pesch Beate , Brüning Tomas , Siemiatycki Jack , Pintos Javier , Wichmann Heinz-Erich , Consonni Dario , Plato Nils , Merletti Franco , Mirabelli Dario , Richiardi Lorenzo , Jöckel Karl-Heinz , Ahrens Wolfgang , Pohlabeln Hermann , Jolanta Lissowska , Szeszenia-Dabrowska Neonila , Adrian Cassidy , Zaridze David , Stücker Isabelle , Benhamou Simone , Bencko Vladimir , Foretova Lenka , Janout Vladimir , Rudnai Peter , Fabianova Eleonora , Mates Dana , Bueno-de-Mesquita Bas , Gross Isabelle , Benhaim-Luzon Veronique , Boffetta Paolo , Straif Kurt 
Published: February 2011

Abstract
Introduction: Diesel-motor exhaust (DME) is classified by IARC as probably carcinogenic to humans. The epidemiological evidence is evaluated as limited since many studies lack adequate information on tobacco smoking and only few studies reported on exposure-response relationships. Our objective is to investigate the risk of lung cancer following occupational exposure to DME, while controlling for smoking and potential occupational confounders.
Methods: The SYNERGY project pooled information on lifetime work histories and tobacco smoking from more than 13300 cases and 16300 controls from case-control studies conducted in 12 European countries and Canada. A job exposure matrix based on ISCO codes, assigning no (0), low (1) or high (2) exposure to DME was applied to determine level of exposure to DME. Cumulative exposure was defined as: ∑(level2 * duration). Odds ratios (OR) of lung cancer and 95% confidence intervals (CI) were estimated by unconditional logistic regression, adjusted for age, sex, study, pack-years and time since quitting smoking, and ever employment in a “Group A” job, i.e. occupations with established lung cancer risk.
Results: Workers exposed to low levels of occupational DME exposure had an increased risk of lung cancer after 40 years of exposure OR 1.31 (95% CI 1.14-1.51), while workers exposed to high DME levels experienced a similar risk already after short duration (&lt;10 years) OR 1.29, 95% CI 1.15-1.46. Cumulative DME exposure showed a significant exposure-response trend (p-value &lt;0.000) with an OR of 1.31 (95% CI 1.20-1.44) in the highest quartile. These results were similar in workers never employed in “Group A“ jobs, lending support to the assumption that confounding due to other occupational exposures was not responsible for the observed risk. Analyses in sub-populations of women and never-smokers also indicated an increased risk of lung cancer following occupational DME exposure.
Conclusion: Our results indicate that occupational exposure to DME is associated with an increased risk of lung cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3777.
Abstract 3781: 3,3′-diindolylmethane(DIM)-induced apoptosis in ovarian cancer cells is mediated by inhibition of EGFR-ERK pathway
Authors: Kandala Prabodh K. , Pramanik Kartick C. , Boreddy Srinivas Reddy , Srivastava Sanjay K. 
Published: February 2011

Abstract
Ovarian cancer is one of the leading causes of gynaecological deaths in the United States and several other countries. Genetic alterations including overexpression of EGFR (about 70% of ovarian tumors) play a crucial role in the signal transduction pathways that regulate key cellular functions such as cell survival and proliferation and are responsible for comprising traditional chemotherapy. Several epidemiological studies suggested a decreased risk of ovarian cancer in the population consuming Brassica vegetables. 3,3′-diindolylmethane (DIM) is an indole compound present in Brassica vegetables. In our previous studies, we have demonstrated that BR-DIM, a formulated version of DIM suppress the growth of ovarian cancer cells by causing cell cycle arrest. However, the exact mechanism by which DIM suppress the growth of ovarian cancer cells was not clear. In the present study, we delineated the mechanism of DIM in SKOV3, OVCAR-3 and TOV-21G human ovarian cancer cells. Our results show that DIM treatment induces apoptosis in all the cell lines in a dose-dependent manner, as analyzed by flow cytometry. Our western blot analysis reveals that DIM treatment causes significant down regulation of constitutive EGFR and HER2 protein level as well as phosphorylation of EGFR at Tyr992, Tyr845 and Tyr1173 in SKOV-3 and OVCAR-3 cells. To determine whether DIM can suppress the activation of EGFR by activating phosphorylation, cells were treated with EGF after DIM treatment. Our results reveal that DIM treatment block the activation of EGFR induced by EGF in OVCAR-3 and TOV-21G cells. In addition, DIM treatment drastically reduces the phosphorylation of ERK without affecting the protein level. DIM treatment also inhibits the kinase activity of ERK as observed by the down regulation of p-ELK in all the three ovarian cancer cell lines. ERK is known to be regulated by EGFR. Taken together our results indicate that DIM induces apoptosis in ovarian cancer cells by inhibiting EGFR-ERK pathway. Further mechanistic studies are in progress. [Supported in part by RO1 grants CA 106953 and CA129038 (to S.K.S) awarded by the National Cancer Institute].
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3781.
Abstract 3787: D, L-Sulforaphane inhibits constitutive and interleukin 6-induced activation of signal transducer and activator of transcription 3 in human prostate cancer cells
Authors: Hahm Eun-Ryeong , Singh Shivendra V. 
Published: February 2011

Abstract
D, L-Sulforaphane (SFN), a synthetic analogue of broccoli-derived L-isomer, inhibits viability of human prostate cancer cells in culture and in vivo. We also showed recently that oral administration of SFN prevents development of prostate cancer and pulmonary metastasis in a transgenic mouse model (TRAMP mice) by reducing cell proliferation and augmenting activity of natural killer cells. However, the mechanism underlying anticancer effect of SFN is not fully understood. We now demonstrate that SFN inhibits constitutive and interleukin 6 (IL6)-induced activation of signal transducer and activator of transcription 3 (STAT3), which is implicated in development and progression of prostate cancer. Growth suppressive concentrations of SFN (20 and 40 μmol/L) inhibited constitutive (DU145 cells) and IL6-induced (LNCaP cells) phosphorylation of STAT3 (Tyr705) as well as its upstream regulator Janus-activated kinase 2 (JAK2; Tyr1007/1008). Treatment of DU145 and LNCaP cells with SFN resulted in suppression of IL6-induced transcriptional activity of STAT3 as revealed by luciferase reporter assay and nuclear translocation of STAT3 as judged by immunofluorescence microscopy. The SFN-mediated inhibition of STAT3 activation was due to down-regulation of JAK2 mRNA expression in both cell lines. Levels of many STAT3-regulated gene products including Bcl-2, cyclin D1, and survivin were also down-regulated in SFN-treated cells. The IL6-mediated activation of STAT3 conferred partial but marked protection against SFN-induced apoptosis in LNCaP cells as evidenced by cleavage of poly-(ADP-ribose)-polymerase and caspase-3 and cytoplasmic histone-associated DNA fragmentation. In addition, siRNA knockdown of STAT3 in DU145 cells resulted in a modest yet statistically significant increase in SFN-induced apoptotic DNA fragmentation. The results of the present study demonstrate SFN-mediated inhibition of STAT3 activation in human prostate cancer cells. This investigation was supported by the National Cancer Institute grant CA115498-05.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3787.