bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR14: Germline submicroscopic chromosome imbalances in pediatric cancer
Authors: Cappeli Leonardo , Krepischi Ana C.V. , Heck Benjamin , Gonçalves Amanda , Brentani Ricardo R. , Costa Cecilia M.L. , de Camargo Beatriz , Rosenberg Carla 
Published: June 2012

Abstract
The development of cancer is a multi-step process and, therefore, the probability of cancer occurrence increases with age. Pediatric cancer then either involves a succession of infrequent events occurring in a short period of time, which supposedly only happens rarely, or alternatively, some of the steps required for cancer development are already present in the individuals' germlines. Support for the presence of genomic alterations in the germline of these patients is given by the association of pediatric cancer with congenital abnormalities, observed both as the frequent presence of congenital abnormalities among these patients and as an increase of cancer among children with congenital abnormalities. We investigated DNA copy number variations (CNVs) in a cohort of 55 pediatric cancer patients attending the AC Camargo Hospital, São Paulo, Brazil. In particular, we focused on those alterations not commonly found in the general population (rare CNVs). No selection criteria were used other than age at diagnosis &lt; 20 years and the families agreeing to participate in the study. In addition to CNV profiling by array-CGH (180K – Agilent Technologies), the patients were also physically examined by a clinical geneticist. Eighteen copy number alterations were detected in 16 patients; these rare CNVs included complex rearrangements and triplications, not often observed among common variants. The size of the alterations ranged from 58 to 2,600 Kb, with an average of 438 Kb, which is over twice the average length of rare copy number variations identified with the same array-CGH platform in a sample of 100 reference individuals studied in our laboratory. Many of the sixty-four genes mapping within the chromosome imbalances detected in patients represent good candidates for cancer manifestation and/or congenital abnormalities. Our results suggest that constitutive submicroscopic chromosome imbalances are a contributor to the etiology of pediatric cancer, that the combined presence of pediatric cancer and congenital abnormalities is strongly suggestive of constitutive chromosome imbalances being present, and that further CNV studies will lead finally to identification of genes involved in predisposition to pediatric cancer.
Funding: FAPESP; CNPq
This abstract is also presented as Poster B7.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr PR14.
Abstract A101: Metformin prevents mammary tumors in p53-null mammary gland mice
Authors: Mazumdar Abhijit , Hill Jamal L. , Zhang Yun , Kittrell Frances S. , Medina Daniel , Brown Powel 
Published: June 2012

Abstract
Background: Breast cancer prevention is now possible using antiestrogen drugs such as tamoxifen and raloxifene; however, antiestrogens are ineffective against estrogen receptor (ER)-negative breast cancers. Since ER-negative breast cancers are highly aggressive and particularly difficult to treat, preventive agents against these life-threatening cancers are urgently needed. Metformin, a first line treatment for adult-onset diabetes, recently was shown to be associated with reduced incidence of cancer (including breast cancer) in epidemiologic studies. Metformin activates AMP-dependent kinase (AMPK) and stimulation of AMPK by metformin reduces cell proliferation in both estrogen receptor alpha (ERa)-positive and -negative human breast cancer cell lines. We hypothesized that the metformin would effectively prevent the growth and development of ER-negative breast cancer. To test this hypothesis, we tested metformin's ability to prevent mammary tumors in two mouse models: the MMTV-erbB2 transgenic mouse model that develops ER-negative mammary tumors and the p53-null mammary gland mouse model that develops both ER-positive and ER-negative mammary tumors.
Methods: MCF7, BT474, MDA MB 468 and MDA MB 453 cells were treated with10mM metformin and cell proliferation was measured using an MTS assay. Virgin female MMTV-erbB2 mice (Jackson Lab) were housed in the institutional animal facilities and fed a purified diet (AIN-76A; Harlan Teklad). Mice were separated into 2 treatment groups: 1) Vehicle control (PBS via gastric gavage daily), 2) Metformin (250mg/kg via gastric gavage daily; from 3 months to 12 months of age). P53-null Balb/C mammary glands from donor mice were transplanted into both cleared inguinal mammary fat pads of Balb/C p53 wild-type mice. Mice were observed daily for tumor formation and the percentage of tumor free mice were recorded. Tumor incidence and time to tumor formation was visualized using Kaplan Meier curves and analyzed using the generalized Wilcoxon test.
Results: Metformin (at 10mM) significantly reduced proliferation of breast cancer cells irrespective to their ER, Her2 and p53 status. In the MMTV-erbB2 mice, metformin treatment did not prevent or delay mammary tumor formation. However, in p53-null mammary gland mice, metformin completely prevented mammary tumor formation.
Conclusions: Metformin treatment totally prevented mammary tumor development in p53-null mammary gland mice. These results suggest that metformin will be most useful in preventing breast cancers with P53 mutations such as occurs in Li-Fraumeni syndrome individuals or individuals with ERa-negative or “triple-negative” breast cancer. These results support testing metformin in clinical trials for the prevention of ER-negative and p53-mutant breast cancers. This research was supported by the NIH/NCI R01 CA78480 grant (PHB).
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A101.
Abstract A111: Endogenous conversion of n-6 PUFAs to n-3 PUFAs prevents progression of K-Ras activated pancreatic lesion development to pancreatic ductal carcinoma in Fat-1 transgenic mice
Authors: Mohammed Altaf , Janakiram Naveena B. , Brewer Misty , Duff Ashley , Lightfoot Stan , Brush Richard S. , Anderson Robert E. , Rao Chinthalapally V. 
Published: June 2012

Abstract
Developing novel strategies to prevent or delay the progression of pancreatic ductal adenocarcinoma (PDAC), a devastating disease with a dismal 5-year survival rate (&lt;5%), is of utmost importance. Preclinical studies suggest that omega-3 fatty acid (n-3 PUFA)-rich diets may be beneficial for pancreatic cancer prevention. Nutritional intervention studies are often complex and there is no clear evidence whether conversion of n-6 PUFAs to n-3 PUFAs in pancreatic tissues would provide protection without potential confounding factors of interference. Thus, experiments were designed using fat-1 transgenic (n-3 fatty acid desaturase) mice, which can convert n-6 PUFA to n-3 PUFA endogenously, to determine the impact of n-3 PUFAs on pancreatic intraepithelial neoplasms (PanINs) and their progression to PDAC. LSL-KrasG12D/+ and p48Cre/+ mice were bred with Fat-1 mice and offspring of activated p48Cre/+-LSL-KrasG12D/+ and Fat-1-p48Cre/+-LSL-KrasG12D/+ were generated. Six-week old transgenic mice p48Cre/+-LSL-KrasG12D/+ (12/group), Fat-1-p48Cre/+-LSL-KrasG12D/+ (12/group), and wild-type (12/group) mice were fed (AIN-76A) a diet containing 10% safflower oil for 35 weeks. Pancreata were collected, weighed, and evaluated histopathologically for PanINs and PDAC. To understand the mechanisms, we analyzed levels of fatty acids and assessed the proliferation, apoptosis, and cell cycle markers by GC, IHC, IHF, Western blotting, Real time and/or RT-PCR. Results show a dramatic reduction in incidence of PDAC (85.8% p&lt;0.02) in Fat-1-p48Cre/+-LSL-KrasG12D/+ mice compared to p48Cre/+-LSL-KrasG12D/+ mice. Importantly, significant reduction of pancreatic ducts with carcinoma (90%, p&lt; 0.0001) and a significant suppression of PanIN 3 (∼50%; p&lt;0.001) were observed in Fat-1-p48Cre/+-LSL-KrasG12D/+ transgenic mice. The levels of n-3 PUFA, -Linoleic acid, DPA and DHA were much higher (∼90%) in pancreatic tissues of Fat-1-p48Cre/+-LSL-KrasG12D/+ mice than that of p48Cre/+-LSL-KrasG12D/+ and WT animals. Importantly, molecular analysis of pancreas showed a significant down-regulation of fatty acid synthase, insulin receptor, insulin receptor substrate-1, PCNA, COX-2, 5-LOX, FLAP, Bcl-2, and cyclin D1 expression levels in Fat-1-p48Cre/+-LSL-KrasG12D/+ mice compared to p48Cre/+-LSL-KrasG12D/+. These data highlight the potential for use of n-3 fatty acids for chemoprevention of pancreatic cancer and represent an important strategy to delay/prevent pancreatic cancer in high-risk individuals. {Supported by Kerley-Cade Chair Endowment for Cancer Research}
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A111.
Abstract A19: Label-free analysis of tissue polarity in live three-dimensional culture of breast epithelium by Raman imaging of lipid phase
Authors: Yue Shuhua , Cárdenas-Mora Juan Manuel , Chaboub Lesley S. , Lelièvre Sophie A. , Cheng Ji-Xin 
Published: June 2012

Abstract
The formation of the basoapical polarity axis in epithelia is critical for maintaining the homeostasis of differentiated tissues. Factors that influence cancer development notoriously affect tissue organization. Apical polarity appears as a specific tissue feature that, once disrupted, would facilitate the onset of mammary tumors. Thus, developing means to rapidly measure apical polarity alterations would greatly favor screening for factors that endanger or protect the breast epithelium. A Raman scattering based platform was used for label-free determination of apical polarity in live breast epithelial structures (acini) produced in three-dimensional cell culture. The coherent anti-Stokes Raman scattering signal permitted the visualization of the apical and basal surfaces in the equatorial plane of an acinus. Raman microspectroscopy subsequently revealed that in polarized acini lipids were more ordered at the apical membranes compared to basal membranes, and that an inverse situation occurred in acini that lost apical polarity upon treatment with Ca2+-chelator EGTA. This method overcame variation between different cultures by tracking the status of apical polarity longitudinally for the same acini. Therefore the disruption of apical polarity by dietary breast cancer risk factor, 6 fatty acid, could be observed significantly with this method, even when the effect was too moderate to permit a conclusive assessment by visually scoring the acinus population for apical location of tight junction marker ZO-1. Analysis of apical polarity markers and cytoskeleton by fluorescence microcopy revealed that the change of lipid ordering upon apical polarity loss corresponded to actual disruption of the apical polarity complex. Our label-free platform will enable rapid identification of environmental factors that either initiate or prevent the very early stage of breast neoplasia. Identifying risk and protective factors will facilitate the design of primary prevention strategies to reduce breast cancer incidence. Furthermore, the use of the membrane lipid phase as readout to assess tissue polarity should be applicable to other types of epithelia where over 90% of cancers originate.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A19.
Abstract A28: DCIS disease-free survival in the population-based Wisconsin In Situ Cohort
Authors: Sprague Brian , McLaughlin Vicki , Hampton John , Newcomb Polly , Trentham-Dietz Amy 
Published: June 2012

Abstract
Ductal carcinoma in situ (DCIS) now makes up 20% of new breast cancer diagnoses. Women diagnosed with DCIS face an increased risk of developing invasive breast cancer. A number of randomized trials have demonstrated the effectiveness of radiation and tamoxifen in reducing the risk of invasive cancer after a DCIS diagnosis. However, few population-based studies have examined disease-free survival according to treatment in community practice. We examined disease-free survival in the Wisconsin In Situ Cohort (WISC) Study, a longitudinal study of health outcomes among a large population-based cohort including 1959 DCIS cases enrolled between 1995 and 2006. Data on the initial DCIS diagnosis, treatments, second breast cancer events, and prognostic factors were collected from the statewide cancer registry, patient interviews, and pathology reports. Multivariate Cox proportional hazards regression was used to evaluate disease-free survival in relation to treatment while adjusting for prognostic patient and tumor characteristics. After an average of 7.0 years of follow-up, 133 second breast cancer events occurred. The overall five-year disease-free survival rate was 94.6% (95% CI: 93.3–95.6%). Use of mastectomy declined over time, from 46% of DCIS cases in 1995–1997 to 30% of cases in 2004–2006. Tamoxifen use increased from 14% in 1995–1997 to 47% in 2004–2006. Overall five-year disease-free survival rates were 100% for women undergoing a bilateral mastectomy, 94.7% for women undergoing ipsilateral mastectomy, 95.4% for women treated with breast conserving surgery (BCS) and radiation, 89.9% for women treated with BCS only, and 86.5% for women receiving no further treatment beyond biopsy. These differences were driven mainly by variation in rates of ipsilateral events, whereas five-year disease survival for contralateral events was above 96% regardless of treatment type. No statistically significant differences were observed for any type of second event according to tamoxifen use. These results of this study provide population-based data that can be used to guide treatment choice for DCIS.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A28.
Abstract A32: Genomic and epigenomic alterations in arsenic-related lung squamous cell carcinomas
Authors: Becker-Santos Daiana D. , Vucic Emily A. , Lam Stephen , Lam Wan L. , Martinez Victor D. 
Published: June 2012

Abstract
Background: Arsenic is a potent human carcinogen. It is estimated that over 100 million people worldwide are exposed to toxic levels of arsenic, mainly through drinking water. Skin, bladder, and lung are key target organs for arsenic-induced carcinogenesis. Lung cancer is the main cause of deaths due to arsenic toxicity, with this metalloid acting as the major etiological agent in cancers that occur in never smokers. Lung squamous cell carcinomas (SqCCs) occur at higher rates than other subtypes following arsenic exposure. The mechanisms for arsenic carcinogenesis are not fully understood, but it has been proposed that neoplastic effects as a result of arsenic biotransformation can occur at both the genetic and epigenetic levels. In this study, a rare panel of lung tumors from a population with chronic arsenic exposure, including SqCC tumors from patients with no smoking history, was analyzed to identify arsenic-associated copy-number alterations (CNAs) and DNA methylation changes.
Methods: 52 lung SqCCs were analyzed by whole-genome tiling path comparative genomic hybridization. Twenty-two were derived from arsenic-exposed patients from Northern Chile (10 never smokers and 12 smokers), and 30 additional cases were obtained for comparison from smokers without arsenic exposure from North America. In addition, 22 blood samples from healthy individuals from Northern Chile were examined to identify naturally occurring germline DNA copy-number variations that could be excluded from analysis. DNA methylation analysis was performed using Illumina's Infinium Human Methylation 450K array.
Results: We identified several DNA copy number alterations and DNA methylation changes associated with chronic arsenic exposure. These alterations were not accountable to either natural copy-number variations or smoking status. The most recurrent events were represented by DNA losses at chromosomes 1q21.1, 7p22.3, 9q12, and 19q13.31. The only arsenic-associated DNA gain occurred at 19q13.33, which contains genes previously recognized as oncogenes.
Conclusions: Our study has provided insights into the molecular mechanisms of arsenic-induced lung neoplasia. The unique and recurrent arsenic-associated genetic and epigenetic alterations suggest that this group of tumors may be considered as a distinct disease subclass.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A32.
Abstract A36: Identification of chromatin-based patterns across lung cancer grades
Authors: Druliner Brooke R. , Dennis Jonathan H. 
Published: June 2012

Abstract
A hallmark of the transformed phenotype is altered chromosomal structure. The development and progression of lung cancer, one of the most common cancers, is driven by the interplay of genetic and epigenetic changes. Although there have been numerous studies on chromosomal aberrations in lung cancer, and cancer in general, broad assessment of chromatin structure information has been understudied, and its role in malignant transformation remains poorly characterized. Cancer progression is classified by tumor grade, which is determined by examining morphological changes that cells undergo as they de-differentiate. Given that chromosomal aberrations are well-documented in nearly all cancers, it is surprising that there is currently no information on the role of chromatin structure in the progression of cancer. We have identified chromatin-based patterns across different lung adenocarcinoma cancer grades.
To address the role of chromatin structure in the progression of cancer, we compared the chromatin structure from primary lung adenocarcinomas of grades one, two and three to their normal adjacent tissue, from multiple individuals, using an innovative microarray strategy. We measured chromatin structure across cancer grades between normal and tumor samples at three levels of resolution: nucleosome distribution, chromatin accessibility and three-dimensional molecular cytology. We used micrococcal nuclease (MNase) as a surrogate for highly diffusible molecules such as transcription factors, mobile elements, replication and repair machinery, and small RNAs. Our work indicates that grade one lung adenocarcinomas have greatly altered nucleosome distributions compared to the adjacent normal tissue, but nearly identical chromatin accessibility. Conversely, the grade three samples show massive disruptions in chromosomal accessibility, but only modest changes in nucleosome distribution when tumor and normal samples are compared. This data has allowed us to develop a model in which we propose that early grade lung adenocarcinomas are linked to changes in nucleosome distributions, while later grade cancers are linked to large-scale chromosomal changes. These results indicate that we should be able to use these chromatin structural changes to identify grade sub-type specific cancer biomarkers.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A36.
Abstract A58: Green tea and silybin for breast cancer: A pilot presurgical study
Authors: Lazzeroni Matteo , Gonzaga Aliana Guerrieri , DeCensi Andrea , Bonanni Bernardo , Serrano Davide , Johansson Harriet , Gandini Sara , Bassi Fabio , Pruneri Giancarlo , Aristarco Valentina , Riva Antonella , Petrangolini Giovanna 
Published: June 2012

Abstract
The importance of new effective agents for breast cancer chemoprevention is highlighted by the fact that to date tamoxifen and raloxifene administration has not been completely accepted to reduce breast cancer risk, mostly because they are both associated with rare but serious toxic effects. Moreover, while SERMs and aromatase inhibitors do prevent the development of many ER-positive breast cancers, these drugs do not reduce the risk of ER-negative breast cancer. These results show that new approaches are needed also for the prevention of the latter.
Phytochemicals present in fruits, vegetables, wine, and some medical herbs, especially botanical polyphenolic antioxidants, have received increasing attention in the last decade as potential chemopreventive agents for different human cancers. However, so far there is a limited knowledge of the processes regulating the absorption of phytochemicals (and/or their metabolites) into the body, and how they reach their biological target. In spite of epidemiological studies and scientific evidences supporting the beneficial role of phytochemicals in blocking cancer initiation and progression, the trials have though failed to yield predicted results in randomized intervention studies.
Treatment in a window of opportunity (WOP) before surgery may improve clinical benefits and represents a very useful tool in selecting new chemopreventive agents against breast cancer. With this approach we will be able to study the kinetics of phytochemicals on the target organ as well as the effect on cell proliferation and other biomarkers by comparing the difference between pre- and post-treatment specimens.
In the present pilot pre-surgical trial, we will study the bioavailability of two natural products formulated in a phosphatydilcholine complex, Greenselect® Phytosome® (a standardized caffeine-free green tea extract) and Siliphos® (the polyphenolic flavonoid silybin isolated from milk thistle) in breast cancer tissue. Ten histologically confirmed primary breast cancer patients will receive Greenselect® Phytosome® 300 mg / day and ten patients will receive Siliphos® 2.8 g / day for four weeks before surgery. The primary endpoint is to assess the concentration of the active ingredients and their metabolites by high performance liquid chromatography (HPLC) in plasma, tumor and surrounding non-neoplastic tissues.
The study may provide important information for the development of future phase II clinical trials, specifically designed to explore the possible role of these two natural products in breast carcinogenesis. Moreover, the study will help to understand the biology and mechanisms of action of these potential chemopreventive agents.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A58.