bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-406: Identification of functional enhancer SNPs in breast cancer models though ChIP-sequencing screening
Authors: Westerling Thomas , Tavera-Mendoza Luz , Brown Myles
Published: August 2012

The American Cancer Society estimates there were 288,130 new breast cancer diagnoses, and 39,520 breast cancer deaths nationwide in 2011. A number of life-style factors can influence breast cancer risk, however, it is apparent that both previously identified and still unknown genetic risk factors are contributing to the disease. Recent estimates place the unknown genetic component at around 70% of the total familial risk. Knowing the underlying genetic risk factors in these cases could greatly influence prevention and treatment strategies and outcome. The role of polymorphism and breast cancer and disease risk in various populations, and multiple genome-wide association (GWAS) studies have identified variants that confer risk for developing cancer or for disease progression. Importantly, the majority of these variants confer small increases in risk. Recent developments in genomics is rapidly increasing the amount of known genetic variants further confounding the discovery of risk alleles due to the need for extremely large cohorts in GWAS studies. Thus there is a clear and growing need to refine the static data with functional screening. Much of the genetic variation maps to non-coding gene deserts, leading to the popular idea that they affect cis-regulatory regions (distal enhancers) that serve as binding sites for long-range transcription factor (TF) activity, as recently demonstrated for a common variant that lies 350 kb upstream of the MYC oncogene. In order to identify functional variants that reside in and affect distal enhancer function we are employing high depth ChIP-sequencing of nuclear hormone receptors and their pioneer factors combined with SNP-array and whole genome sequencing data. Through this strategy we are building a bank of known functionally relevant SNPs that have direct association to a known DNA binding factor and its biological outcome in breast cancer models.

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 LB-406. doi:1538-7445.AM2012-LB-406
Abstract LB-412: TargetRich™ cancer gene panels: targeted next generation sequencing in cancer samples
Authors: Spayd Katherine J. , Vasenkova Irina , Shvetsova Tatiana , Bachmeyer Randall C. , Myers Richard M. , Moore D. Troy , Varley Katherine E.
Published: August 2012

Crucial to the adoption of next-generation sequencing within clinical cancer research is the ability to deeply sequence hundreds to thousands of targeted genomic regions across a large number of patient samples. Several targeting (PCR) and capture (hybridization) methods have been developed for next-generation sequencing, however these methods have limited utility with cancer patient specimens due to drawbacks such as large input DNA quantity requirements, wasted off-target sequencing, high cost of reagents, low sample throughput, specialized equipment, and inflexible content design. We developed TargetRich cancer gene panels employing Nested PatchPCR, which enables the targeted sequencing of hundreds of genomic regions in large numbers of patient samples to fully and efficiently utilize next-generation sequencers. Nested PatchPCR required only 250 ng genomic DNA, and was compatible with the fragmented DNA obtained from formalin fixed paraffin embedded samples (FFPE). No special equipment was needed, only a standard PCR machine. Patient samples were processed in parallel in a single 96-well plate. For each patient sample, we simultaneously amplified hundreds of exons from genes that are frequently mutated in cancer. We utilized standard library construction and barcoding methods to sequence targeted genes from 96 patient samples on a single Illumina GAIIx flowcell. The TargetRich cancer gene panels were highly specific; 95% of sequencing reads aligned to the targeted regions. The high percentage of on-target sequence data and focused content, allowed us to achieve high coverage across the loci (average of 400X read depth) for the sensitive detection of cancer mutations. We have created two cancer panels: CR (157 regions covering exons from 10 genes) and CS (760 regions covering exons from 62 genes) for use on the Illumina MiSeq, GAIIx & HiSeq platforms. Additionally, a CR panel for the Ion Torrent PGM has been developed with platform-specific primers added during the Nested PatchPCR reaction, allowing direct sequencing of products without time-consuming library construction.

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 LB-412. doi:1538-7445.AM2012-LB-412
Abstract LB-418: A live-cell miRNA reporter library for identifying non-genetic drug resistance networks at single-cell resolution
Authors: Leya Gregory , Albeck John , Brugge Joan
Published: August 2012

The effectiveness of targeted cancer therapies is limited by cellular resistance. Emerging research has demonstrated that a major source of drug resistance is non-genetic: pre-existing heterogeneity in protein expression levels, or induction of adaptive feedback loops, can protect cells from the effects of kinase inhibitors and other drugs. Traditional genomic or proteomic techniques may fail to identify key resistance pathways because they do not stem from changes in genetic sequences, are often transient in nature, and may operate in only a subset of cells within a population. To address this challenge, we have developed a library of over 80 live-cell reporters that, in combination with high-throughput automated microscopy, enable the identification of transiently active resistance pathways in drug-treated cells. These reporters are based on miRNA regulatory sequences since numerous miRNAs have been implicated in drug resistance and because miRNAs can act as surrogate indicators for the activation of signaling pathways in which they participate. We have developed and validated a novel ratiometric reporter design for optimal detection of miRNA expression changes at single-cell resolution and have constructed retroviral reporters for miRNAs involved in apoptosis, cell proliferation, cancer stem cells, metabolism, and stress response. Live imaging of mammary epithelial cells treated with inhibitors targeting EGFR, PI3-K, mTOR, and Bcl-2 identified a set of 20-30 miRNA reporters with significant expression level alterations in surviving cells that are consistent with miRNA expression changes characteristic of cancer cells. Bioinformatic analyses of these miRNAs revealed commonly regulated pathways and downstream targets, including Bcl-2 and Cyclin-D. Thus, the reporter library is capable of identifying, in living cells, pathways involved in the cellular response to targeted cancer therapies. By identifying components of the signaling networks controlling inhibitor resistance, we hope to discover new drug targets that can be used to sensitize tumor cells to existing targeted therapies. The reporter library can be easily expressed in most cell lines of interest and should have broad utility for identifying transiently regulated pathways.

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 LB-418. doi:1538-7445.AM2012-LB-418
Abstract LB-74: The estrogen receptor regulates the transcription of p53 target genes in breast cancer cells
Authors: Bailey Shannon T. , Shin Hyunjin , Liu X. Shirley , Brown Myles
Published: August 2012

Breast Cancer is a disease that affects thousands of women every year. A large subset of breast cancer is attributed to estrogen receptor (ER) dysregulation. Previously, our lab and others have determined the estradiol-stimulated ER cistrome in the MCF7 mammary epithelial cell line. To determine the relationship between ER and the apoptotic response, we compared our ER cistrome to a published p53 dataset. The p53 transcription factor is a tumor suppressor protein that is responsible for cell-cycle control and apoptosis. Our lab generated a doxorubicin-stimulated p53 cistrome in MCF7 cells, and we employed an integrative analysis approach examining the p53 and ER cistromes and gene expression microarray data to determine the genes coordinately regulated by both transcription factors. We identified a number of genes that are involved in the cell cycle, apoptosis, and DNA damage repair. By treating MCF7 cells with both stimuli, we found that the ER could inhibit the expression of a p53 target gene subset, thus diminishing the efficacy of the p53 program. These genes correlate with poor breast cancer clinical outcome. Moreover, we found that treatment of breast cancer cells with a combination of the anti-estrogen fulvestrant with p53 stimuli (i.e., doxorubicin and nutlin-3) leads to the synergistic enhancement of pro-apoptotic genes. Together, these data point to a set of genes essential for breast cell survival in ER-mediated breast cancer and suggest an improved paradigm for ER-positive breast cancer treatment i.e., the addition of fulvestrant with a p53 stabilizing drug.

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 LB-74. doi:1538-7445.AM2012-LB-74
Abstract LB-79: Synergistic anticancer effects of the 9.2.27PE immunotoxin and ABT-737 in melanoma involves silencing of the anti-apoptotic protein Mcl-1
Authors: Risberg Karianne , Fodstad Øystein , Andersson Yvonne
Published: August 2012

In cancer, combinations of drugs targeting different cellular functions is well accepted to improve tumor control. We studied the effects of a Pseudomonas exotoxin A (PE)-based immunotoxin, the 9.2.27PE, and the Bcl-2 family inhibitor ABT-737 in a panel of melanoma cell lines. ABT-737 inhibits the Bcl-2, Bcl-xl and the Bcl-w, but not Mcl-1 and A1 of the Bcl-2 family. The 9.2.27PE + ABT-737 drug combination resulted in synergistic cytotoxicity in the melanoma cells independent of BRAF mutation status. The cell death observed was associated with apoptosis, as activation of caspase-3, inactivation of Poly (ADP-ribose) polymerase (PARP) and increased DNA fragmentation could be prevented by pre-treatment with caspase and cathepsin inhibitors. In addition, ABT-737 caused endoplasmic reticulum (ER) stress with increased GRP78, phosphorylated eIF2α protein levels and increased intracellular calcium levels. The increased intracellular calcium levels were enhanced by silencing of Mcl-1 by short hairpin RNA or by treatment with the 9.2.27PE immunotoxin. These results suggests that Mcl-1 has an inhibitory effect on calcium release from the ER, and that strongly decreased Mcl-1 protein levels after treatment with 9.2.27PE or shRNA may be responsible for the increased intracellular calcium levels in ABT-737 treated melanoma cells. Calcium release has been shown to take place through the inositol 1,4,5-triphosphate receptor in the ER membrane, and the Bcl-2 family proteins Bcl-2, Bcl-xl and Mcl-1 have been shown to interact with the inositol 1,4,5-triphosphate receptor, supporting our results.1 Notably, the combination of 9.2.27PE and ABT-737 caused growth delay in a human melanoma xenograft mice model. 1. Eckenrode EF et. Al., J Biol Chem. 2010 Apr 30;285(18):13678-84

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 LB-79. doi:1538-7445.AM2012-LB-79
Abstract LB-86: Metabolic presentation of bladder cancer in urine
Authors: McDunn Jonathan , Perichon Regis , Goodison Steve , Rosser Charles J.
Published: August 2012

Introduction and Objective Recently it has been shown that many oncogenes regulate metabolism, revitalizing interest in Warburg's observation of aerobic glycolysis by tumors. We and others have demonstrated the utility of metabolic signatures for the diagnosis of cancer in minimally invasive clinical samples and the differential diagnosis of cancer by stage and grade using biopsy samples. Here we apply state of the art metabolomic analysis to the diagnosis of bladder cancer from urine samples. Methods A case controlled study of ten transitional cell carcinoma (TCC) patients and matched non-TCC controls was performed. Briefly, clarified urine was extracted into aqueous methanol and characterized using three analytical platforms (gas chromatography mass spectrometry (MS) and ultrahigh performance liquid chromatography tandem MS). Spectral data were compared against an in-house library of over 2500 authentic standards and the relative abundance of each compound within the data set was calculated. Two-group statistics (R) and multivariate analysis (Array Studio, OmicSoft) were performed to identify differentially abundant metabolites. Results Three hundred and sixty-seven compounds were identified in this study and polypharmacy did not compromise the quality of the signal obtained for endogenous metabolites. Thirteen compounds, arising from diverse metabolic pathways, including: energetics, oxidative stress and amino acid catabolism, exhibited statistically significant differences between TCC and non-TCC cases. Principal component (PC) analysis demonstrated that the majority of the information in these metabolites (PC 1) separated TCC from non-TCC cases. Conclusions These data indicate the feasibility of a novel, non-invasive, urine-based diagnostic test to detect the presence of bladder tumors. Such a test could be positioned for use in conjunction with the current standard of care to improve patient management.

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 LB-86. doi:1538-7445.AM2012-LB-86
Abstract LB-90: Essential kinases for human metastatic cells pertaining to c-Met signaling
Authors: Ai Nanping , Harlow Ed , Li Wenliang
Published: August 2012

Kinases play key roles in the regulation of many cellular processes and are postulated to participate in the development of metastatic capability. To test the role of kinases in tumor progression, we compared pairs of non-metastatic and metastatic tumor cells, a commonly used model, to study the cellular changes that accompany metastasis. As such, we performed arrayed shRNA screens to determine how kinase requirements for survival and proliferation varied between the matched cell lines. These screens revealed patterns of kinase requirements among 4 pairs of cell lines. Of particular interest, we identified a set of kinases that were essential predominately for metastatic cells, including c-Met. In vivo metastasis experiments are underway to evaluate which kinases can promote metastasis when ectopically expressed in otherwise non-metastatic cells. Since inhibition of these kinases phenocopied c-Met inhibition, we also sought to test if any of these kinases are functionally linked to c-Met signaling. Indeed, several of the identified kinases, including PRKCZ, became essential when immortalized melanocytes were made tumorigenic and metastatic by introduction of activated c-Met. Biochemical and genetic rescue experiments are currently ongoing to further examine the links between these genes and c-Met. These studies offer new insights into the cellular signaling pathways operating in metastatic cancer cells and also suggest potential targets to treat metastatic cancers.

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 LB-90. doi:1538-7445.AM2012-LB-90
Abstract LB-94: Highly specific and sensitive detection of BRAF and KRAS mutations in tumor samples
Authors: Mishra Anjali , Chupreta Sergey , Beaubien Ron , Kurihara Laurie , Kelchner Vanessa , LaLiberte Julie , Mikheykin Andrey , Makarov Vladimir
Published: August 2012

The development of highly sensitive and specific mutation detection assays that are suitable for clinical and laboratory research opens up new opportunities in the fields of cancer diagnostics and therapeutics. Swift Biosciences has developed myT™ Primer technology which has unique structural and thermodynamic properties that enable highly sensitive mismatch discrimination. Real-time PCR assays using myT Primers are able to detect 1% mutant BRAF V600E/K or mutant KRAS (codons 12A, 12R, 12C, 12V, 12S, 12D and 13D) present in a background of 103 wild-type genomic DNA copies. Notably there is no non-specific amplification from wild-type. The extreme selectivity and reproducibility of such assays results in a definitive Yes/No answer and eliminates the need to use a delta Ct method to call positives. myT Primer specific reagents are well suited for genotyping and have been tested on FFPE samples derived from melanoma, colorectal and lung tumors and their corresponding normal adjacent samples, and are also effective on fresh frozen tissues. A separate ultrasensitive version of myT Primers has also been developed. The ultrasensitive myT Primers format enables the detection of a single mutant copy of BRAF or KRAS in > 104 wild-type genomic DNA copies, representing 0.01% detection; again, non-specific amplification from wild-type was not observed. The myT Primer ultrasensitive reagents are ideal for use when sample sizes are limiting such as in needle biopsies, CTCs, and serum. myT Primers are compatible with Roche LC480, ABI 7500 and Bio-Rad CFX96 real-time PCR instruments as well as different PCR master mixes. Thus the use of myT Primer reagents will allow for better detection, evaluation and monitoring of cancer.

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 LB-94. doi:1538-7445.AM2012-LB-94
Abstract PL04-03: Cell signaling by receptor tyrosine kinases: From basic principles to cancer therapy
Authors: Schlessinger Joseph
Published: August 2012

Receptor tyrosine kinases (RTKs) comprise a family of cell surface receptors that control many critical cellular processes. Various human diseases are caused by dysfunction in RTKs or in their intracellular signaling pathways. Stem Cell Factor (SCF) initiates its multiple cellular responses by binding to the extracellular region of the RTK KIT resulting in receptor dimerization and tyrosine kinase activation. We have determined the crystal structure of the entire extracellular region of KIT before and after SCF stimulation. The structures show that KIT dimerization is driven by SCF binding whose sole role is to bring two KIT molecules together. We have used X-ray crystallography, electron microscopy (EM) and biochemical experiments to determine the three dimensional structure of intact, SCF-stimulated KIT dimers. Several forms of dimeric KIT molecules with different asymmetric arrangements of the two tyrosine kinase domains were identified. These asymmetric contacts may represent specific interactions occurring between two KIT tyrosine kinase domains poised towards trans autophosphorylation. We propose that cooperative interactions mediated by multiple weak homotypic contacts between the extracellular, transmembrane and cytoplasmic regions of KIT are responsible for tyrosine kinase activation and cell signaling in normal and transformed cells. Sutent is a drug that blocks the tyrosine kinase activities of several RTKs including KIT and VEGFR2. Sutent has been approved by the FDA for the treatment of advanced kidney cancers, gastrointestinal tumors and for endocrine pancreatic cancers. A scaffold-based drug discovery approach was developed enabling the development of new families of inhibitors for protein kinases and other enzymes that play a role in cell signaling. V600E B-RAF mutant is an oncogenic mutation identified in approximately 50% of melanomas and in 4% of all solid tumors. By using a scaffold-based drug discovery approach, a potent inhibitor of V600E B-RAF mutant has been discovered designated PLX 4032 (Vemurafenib). Phase-I and-II clinical trials in multiple medical centers revealed 80% responses such as tumor shrinkage, delay in tumor progression and survival of melanoma patients harboring the B-RAF mutation. Primary endpoints of phase-III clinical trials in multiple medical centers were achieved to support Vemurafenib registration.

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 PL04-03. doi:1538-7445.AM2012-PL04-03
Abstract SY04-02: Reaching escape velocity: Using lineage tracing to study EMT and dissemination in pancreatic cancer
Authors: Stanger Ben Z.
Published: August 2012

Metastastic spread has been difficult to study because it involves a series of rare events that are difficult to observe in vivo. To capture such events, we have employed lineage tracing - a technique which allows cells to be tagged and tracked - and applied it to an autochthonous mouse model of pancreatic cancer. Using this approach, found that pancreas-derived cells entered the circulation at the PanIN-stage, prior to the presence of a histologically recognizable tumor. Moreover, invasive behavior was almost universally associated with epithelial-to-mesenchymal transition (EMT), and bloodstream entry was associated with a “cancer stem cell” phenotype. These observations demonstrate that cellular dissemination in pancreatic cancer can occur at a very early stage of tumor progression.

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 SY04-02. doi:1538-7445.AM2012-SY04-02
Abstract SY05-01: microRNAs: Micromanagers of human cancers
Authors: Calin George A.
Published: August 2012

The newly discovered differential expression in numerous tissues, key cellular processes and multiple diseases for several families of long and short non-codingRNAs (ncRNAs, RNAs that do not codify for proteins but for RNAs with regulatory functions), including the already famous class of microRNAs (miRNAs) strongly suggest that the scientific and medical communities have significantly underestimated the spectrum of ncRNAs whose altered expression has significant consequences in diseases. MicroRNA and other short or long non-codingRNAs alterations are involved in the initiation, progression and metastases of human cancer. The main molecular alterations are represented by variations in gene expression, usually mild and with consequences for a vast number of target protein coding genes. The causes of the widespread differential expression of non-codingRNAs in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the processing machinery. MicroRNA and other short or long non-codingRNAs expression profiling of human tumors has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify non-codingRNAs that may represent downstream targets of activated oncogenic pathways or that are targeting protein coding genes involved in cancer. Recent studies proved that miRNAs and non-coding ultraconserved genes are main candidates for the elusive class of cancer predisposing genes and that other types of non-codingRNAs participate in the genetic puzzle giving rise to the malignant phenotype. Last, but not least, the shown expression correlations of these new ncRNAs with cancer metastatic potential and overall survival rates suggest that at least some member of these novel classes of molecules could potentially find use as biomarkers or novel therapeutics in cancers and other diseases.

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 SY05-01. doi:1538-7445.AM2012-SY05-01
Abstract SY36-01: Mechanisms of autophagy addiction in cancer
Authors: White Eileen P.
Published: August 2012

Autophagy is a catabolic pathway utilized by cells to eat themselves and recycle cellular components to support metabolism and survival in response to starvation. Autophagy also functions to clear damaged proteins and organelles. Autophagy can thereby maintain tissue health and suppress tissue degeneration and cancer initiation in liver, and in this context autophagy is a tumor suppressor. Autophagy, however, is also a survival pathway used by both normal cells and established cancers to sustain metabolism and tolerate stress, and in this context autophagy is a tumor promoter. Activation of a powerful oncogene such as Ras, for example, up-regulates basal autophagy required for tumor cell survival in stress and in tumorigenesis. In Ras-driven cancer cells, defective autophagy causes accumulation of abnormal mitochondria, reduces oxygen consumption, and impairs metabolism causing energy depletion. Thus, without autophagy, tumor cells have impaired stress tolerance that reduces tumorigenesis. As cancers with Ras mutations have a poor prognosis, this “autophagy addiction” suggests that targeting autophagy is valuable new approaches to treat these aggressive cancers. Recent findings demonstrating roles for autophagy in genetically engineered mouse models for cancer and the regulation of nutrient sensing and autophagy regulation by mTOR will be presented. New developments in the approach to and effectiveness of autophagy modulation in cancer therapy and the mechanism of cancer cell death induction will be discussed.

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 SY36-01. doi:1538-7445.AM2012-SY36-01
Abstract SY36-02: Autophagy in cell death and cancer
Authors: Ryan Kevin
Published: August 2012

Macroautophagy (autophagy) is a catabolic membrane-trafficking process that serves to deliver cytoplasmic constituents to lysosomes for degradation. The process functions in the majority, if not all, cells as a means to turnover damaged proteins and organelles. Autophagy therefore functions as a cellular homeostatic mechanism which when perturbed leads to accumulation of misfolded proteins and non-functional organelles and loss of cellular integrity. The levels and cargoes of autophagy can respond to various extracellular and intracellular cues to bring about selective and sometimes contrasting effects. For example, in relation to cell death, autophagy has, depending on context, been reported to have both positive and negative effects on cell viability. Due the multiple roles of autophagy in regulating cellular homeostasis, it is not a surprise that changes in autophagy can have effects on tumour development. It is not yet clear, however, when autophagy is tumour-promoting or tumour-suppressive in any given context. We have therefore been addressing this issue by studying the role of autophagy at different stages of tumour development in vivo. Data from these studies will be presented alongside our in vitro studies to understand the role of autophagy in tumour suppression.

Work in our laboratory is supported by Cancer Research UK and The Association for International Cancer Research.

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 SY36-02. doi:1538-7445.AM2012-SY36-02
Ovarian-Protective Effects of Clotrimazole on Ovarian Ischemia/Reperfusion Injury in a Rat Ovarian-Torsion Model
Authors: Osmanağaoğlu Mehmet A. , Kesim Murat , Yuluğ Esin , Menteşe Ahmet , Karahan S. Caner
Published: August 2012

Background/Aims: To evaluate the ovarian-protective effects of clotrimazole on ovarian ischemia/reperfusion injury in a rat ovarian-torsion model. Methods: 32 Sprague-Dawley rats were randomly divided into four groups: (1) ischemia group (n = 8) in which only left adnexal torsion was performed for 2 h, but no treatment was given; (2) vehicle group (n = 8) in which left adnexal torsion was performed for 2 h and at the end of 2 h ischemia polyethylene glycol (3% PEG, 1 ml, i.p.) was administered and a 24-hour reperfusion was continued; (3) clotrimazole group (n = 8) in which left adnexal torsion was performed for 2 h and at the end of 2 h ischemia clotrimazole (30 mg/kg, i.p.) was administered and a 24-hour reperfusion was continued, and (4) control group (sham-operated, n = 6) in which no adnexal torsion and no treatment were given. The criteria for ovarian ischemia were follicular cell degeneration, vascular congestion, hemorrhage and infiltration by inflammatory cells. Each specimen was scored for each criterion (0, none; 1, mild; 2, moderate; 3, severe). Results: Clotrimazole significantly decreased plasma levels of serum malondialdehyde, ischemia-modified albumin, and total oxidant status. Conclusion: This study showed the ovarian-protective effects of clotrimazole on ovarian ischemia/reperfusion injury.
Comparative Study of Systemic Inflammatory Responses in Psoriasis Vulgaris and Mild to Moderate Allergic Contact Dermatitis
Authors: Kaur S. , Zilmer K. , Leping V. , Zilmer M.
Published: August 2012

Background: Psoriasis vulgaris (PV) is associated with low-grade systemic inflammation. Objective: Cytokines’ and growth factors’ serum patterns in patients with PV, allergic contact dermatitis (ACD) and healthy subjects were investigated to describe and compare systemic inflammatory responses in these diseases. Methods: A total of 12 inflammation-sensitive biomarkers were analyzed simultaneously by means of the Evidence Investigator™ biochip technology. Results: In PV, proinflammatory tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukins (IL)-1β, -2, -6, -8, and monocyte chemoattractant protein (MCP)-1 were elevated. In ACD, 2 markers, TNF-α and MCP-1, were increased, and regulatory cytokine IL-10 was decreased. Proinflammatory IL-2 had the strongest correlations with other pro- as well as anti-inflammatory cytokines in PV and ACD, whilst IL-6 correlated positively with the Psoriasis Area and Severity Index. Growth factors’ levels correlated with MCP-1, but only in PV. Conclusion: Although psoriasis induces a more variegated proinflammatory systemic response, ACD is likewise associated with a systemic increase in inflammatory mediators.
Natural and Orthogonal Interaction Framework for Modeling Gene-Environment Interactions with Application to Lung Cancer
Authors: Ma Jianzhong , Xiao Feifei , Xiong Momiao , Andrew Angeline S. , Brenner Hermann , Duell Eric J. , Haugen Aage , Hoggart Clive , Hung Rayjean J. , Lazarus Philip , Liu Changlu , Matsuo Keitaro , Mayordomo Jose Ignacio , Schwartz Ann G. , Staratschek-Jox Andrea , Wichmann Erich , Yang Ping , Amos Christopher I.
Published: August 2012

Objectives: We aimed at extending the Natural and Orthogonal Interaction (NOIA) framework, developed for modeling gene-gene interactions in the analysis of quantitative traits, to allow for reduced genetic models, dichotomous traits, and gene-environment interactions. We evaluate the performance of the NOIA statistical models using simulated data and lung cancer data. Methods: The NOIA statistical models are developed for additive, dominant, and recessive genetic models as well as for a binary environmental exposure. Using the Kronecker product rule, a NOIA statistical model is built to model gene-environment interactions. By treating the genotypic values as the logarithm of odds, the NOIA statistical models are extended to the analysis of case-control data. Results: Our simulations showed that power for testing associations while allowing for interaction using the NOIA statistical model is much higher than using functional models for most of the scenarios we simulated. When applied to lung cancer data, much smaller p values were obtained using the NOIA statistical model for either the main effects or the SNP-smoking interactions for some of the SNPs tested. Conclusion: The NOIA statistical models are usually more powerful than the functional models in detecting main effects and interaction effects for both quantitative traits and binary traits.
Selecting Representative Days for More Efficient Dynamical Climate Downscaling: Application to Wind Energy
Authors: Rife Daran L. , Vanvyve Emilie , Pinto James O. , Monaghan Andrew J. , Davis Christopher A. , Poulos Gregory S.
Published: August 2012

This paper describes a new computationally efficient and statistically robust sampling method for generating dynamically downscaled climatologies. It is based on a Monte Carlo method coupled with stratified sampling. A small yet representative set of “case days” is selected with guidance from a large-scale reanalysis. When downscaled, the sample closely approximates the long-term meteorological record at a location, in terms of the probability density function. The method is demonstrated for the creation of wind maps to help determine the suitability of potential sites for wind energy farms. Turbine hub-height measurements at five U.S. and European tall tower sites are used as a proxy for regional climate model (RCM) downscaled winds to validate the technique. The tower-measured winds provide an independent test of the technique, since RCM-based downscaled winds exhibit an inherent dependence upon the large-scale reanalysis fields from which the case days are sampled; these same reanalysis fields would provide the boundary conditions to the RCM. The new sampling method is compared with the current approach widely used within the wind energy industry for creating wind resource maps, which is to randomly select 365 case days for downscaling, with each day in the calendar year being represented. The new method provides a more accurate and repeatable estimate of the long-term record of winds at each tower location. Additionally, the new method can closely approximate the accuracy of the current (365 day) industry approach using only a 180-day sample, which may render climate downscaling more tractable for those with limited computing resources.
Large-Eddy Simulations of Air Flow and Turbulence within and around Low-Aspect-Ratio Cylindrical Open-Top Chambers
Authors: Cunningham Philip , Linn Rodman R. , Koo Eunmo , Wilson Cathy J.
Published: August 2012

The flow around cylindrical open-top chambers (OTCs) with aspect ratios (i.e., height-to-diameter ratios) much less than unity is investigated using a large-eddy simulation (LES) model. The solid structures are represented using the immersed boundary method, and the ambient flow in which the OTCs are embedded is representative of a turbulent atmospheric boundary layer. Results from the LES model show that the flow inside OTCs depends strongly on the height of the chamber wall. In particular, as chamber height increases the flow impinging on the upstream wall is deflected more in the vertical direction, a stronger recirculation flow develops inside the chamber, turbulence intensities are greater, and there is stronger vertical transport and mixing within the OTC, even at or near the ground. For low wall heights (i.e., very low aspect ratios), however, the flow impinging on the OTC is only diverted weakly in the vertical direction; aside from a small recirculation zone inside the OTC near the upstream wall and a small region near the downstream wall as the flow separates from the ground, there is minimal vertical mixing and the turbulence intensities are small. The results of these simulations, while general in nature, are particularly relevant to design considerations for manipulative field experiments in highly heterogeneous, low-stature ecosystems such as Arctic shrubs and grasses.
Quantifying the Non-Gaussianity of Wintertime Daily Maximum and Minimum Temperatures in the Southeast
Authors: Stefanova Lydia , Sura Philip , Griffin Melissa
Published: August 2012

In this paper the statistics of daily maximum and minimum surface air temperature at weather stations in the southeast United States are examined as a function of the El Niño–Southern Oscillation (ENSO) and Arctic Oscillation (AO) phase. A limited number of studies address how the ENSO and/or AO affect U.S. daily—as opposed to monthly or seasonal—temperature averages. The details of the effect of the ENSO or AO on the higher-order statistics for wintertime daily minimum and maximum temperatures have not been clearly documented.

Quality-controlled daily observations collected from 1960 to 2009 from 272 National Weather Service Cooperative Observing Network stations throughout Florida, Georgia, Alabama, and South and North Carolina are used to calculate the first four statistical moments of minimum and maximum daily temperature distributions. It is found that, over the U.S. Southeast, winter minimum temperatures have higher variability than maximum temperatures and La Niña winters have greater variability of both minimum and maximum temperatures. With the exception of the Florida peninsula, minimum temperatures are positively skewed, while maximum temperatures are negatively skewed. Stations in peninsular Florida exhibit negative skewness for both maximum and minimum temperatures. During the relatively warmer winters associated with either a La Niña or AO+, negative skewnesses are exacerbated and positive skewnesses are reduced. To a lesser extent, the converse is true of the El Niño and AO−. The ENSO and AO are also shown to have a statistically significant effect on the change in kurtosis of daily maximum and minimum temperatures throughout the domain.
Changes in the Tropical Pacific SST Trend from CMIP3 to CMIP5 and Its Implication of ENSO
Authors: Yeh Sang-Wook , Ham Yoo-Geun , Lee June-Yi
Published: August 2012

This study assesses the changes in the tropical Pacific Ocean sea surface temperature (SST) trend and ENSO amplitude by comparing a historical run of the World Climate Research Programme Coupled Model Intercomparison Project (CMIP) phase-5 multimodel ensemble dataset (CMIP5) and the CMIP phase-3 dataset (CMIP3). The results indicate that the magnitude of the SST trend in the tropical Pacific basin has been significantly reduced from CMIP3 to CMIP5, which may be associated with the overestimation of the response to natural forcing and aerosols by including Earth system models in CMIP5. Moreover, the patterns of tropical warming over the second half of the twentieth century have changed from a La Niña–like structure in CMIP3 to an El Niño–like structure in CMIP5. Further analysis indicates that such changes in the background state of the tropical Pacific and an increase in the sensitivity of the atmospheric response to the SST changes in the eastern tropical Pacific have influenced the ENSO properties. In particular, the ratio of the SST anomaly variance in the eastern and western tropical Pacific increased from CMIP3 to CMIP5, indicating that a center of action associated with the ENSO amplitude has shifted to the east.
The Source of Turnout Decline
Authors: Blais André , Rubenson Daniel
Published: August 2012

Voter turnout has consistently declined since the 1980s across a wide range of advanced democracies. Much of this decline appears to be the result of young people abstaining. In this article the authors test two arguments for this trend. The first rests on the claim that the character of elections has changed, specifically that elections have become less competitive and that young people’s propensities for voting are particularly negatively affected by this. The second maintains that recent generations have different values and that these value differences explain turnout declines. The authors test these two explanations using three different data sets: (a) individual-level and election-specific data from 83 elections in eight countries since the 1950s, (b) longitudinal individual-level and district-level data from British elections for the period 1974–2005, and (c) panel data from American presidential elections. The findings provide strong evidence for the generational value change argument, whereas the authors find scant support for the competition argument.
Reflections on research: Families affected by counter-terrorism in the UK
Authors: Guru Surinder
Published: August 2012

Following the terrorist attacks on New York and London, the counterterrorism legislation in the UK strengthened surveillance and national security and led to the incarceration of many Muslim men. Whilst the treatment of prisoners and detainees received considerable attention in public debate, the families that are left behind have been neglected by politicians, academics, the media and service providers alike. This article reflects on the experiences of conducting a small exploratory study amongst such families in the West Midlands and highlights some of the ways in which the heightened concerns about national security impinged upon the research process.
Mechanical properties of randomly oriented snake grass fiber with banana and coir fiber-reinforced hybrid composites
Authors: Sathishkumar TP , Navaneethakrishnan P , Shankar S , Kumar J
Published: August 2012

Composite materials are extensively used in the structural applications due to its enhanced load-bearing capabilities. Mostly, the mechanical properties of the natural fiber-reinforced hybrid composites are better than the single fiber-reinforced composites and almost equal to the synthetic fiber composites. This paper presents the extraction and preparation methodology of the isophtallic polyester composites using the naturally available fibers like snake grass, banana and coir fibers. The tensile and flexural properties of the snake grass fiber-reinforced composites are compared with the snake grass/banana and snake grass/coir fiber-reinforced hybrid composites. The stress–strain curves of the snake grass, snake grass/banana and snake grass/coir fiber composites and the fiber pull-outs in the fractured specimen are analyzed for the higher and lower mechanical properties. The result shows that the snake grass/banana and snake grass/coir fiber composites have the maximum tensile and flexural properties when compared with the snake grass fiber composites.
Digital Dimension of Cultural Capital
Authors: Paino Maria , Renzulli Linda A.
Published: August 2012

We update theories of teacher expectancy and cultural capital by linking them to discussions of technology. We argue for broadening the span of culturally important forms of capital by including the digital dimension of cultural capital. Based on data from the third-grade and fifth-grade waves of the Early Childhood Longitudinal Survey–Kindergarten cohort (ECLS-K), results suggest a comprehensive model where teachers play a prominent, mediating role in the effects of computer proficiency on academic achievement. These findings have practical applications within classrooms, which can lead to a reduction in stratification. Our findings modernize and renew theoretical tools for understanding teacher and student interactions and the effects on achievement outcomes
Risk Recognition and Sensation Seeking in Revictimization and Posttraumatic Stress Disorder
Authors: Volkert Jana , Randjbar Sarah , Moritz Steffen , Jelinek Lena
Published: August 2012

Impaired risk recognition has been suggested to be associated with the risk for revictimization and the development of posttraumatic stress disorder (PTSD). Moreover, risk behavior has been linked to high sensation seeking, which may also increase the probability of revictimization. A newly designed behavioral experiment with five audiotaped risk scenarios was used to investigate risk recognition in revictimized, single-victimized, and nontraumatized individuals with and without PTSD. Moreover, the potential role of sensation seeking in revictimization, and PTSD as well as its relation to risk recognition was explored. Revictimized, single-victimized, and nontraumatized individuals did not differ with regard to general risk recognition. However, delayed risk recognition was found for the revictimized group when arousal ratings were considered. No differences in sensation seeking were found between the three groups; only the nontraumatized group showed lower boredom susceptibility relative to the revictimized group. Delayed risk recognition was associated with high sensation seeking. Furthermore, PTSD symptoms significantly predicted exit levels of risk scenarios. Findings are discussed against the background of previous research.
The Role of Neighborhood Safety in Recovery From Mobility Limitations
Authors: Latham Kenzie , Clarke Philippa J.
Published: August 2012

Prior research has documented a link between perceived neighborhood safety and functional limitations including incident mobility limitation; yet, no research has explored the association between perceived neighborhood safety and recovery from functional limitations. This study investigates whether perceived neighborhood safety independently predicts recovery. Using longitudinal data from the Health and Retirement Study (HRS; 1996–2008), discrete-time event history models with multiple competing events were estimated using multinomial logistic regression. Robust standard errors were used to adjust for clustering. In the unadjusted model, the odds ratio for recovery from mobility limitations was 1.22 (Confidence interval [CI]: [1.17, 1.27]) for respondents reporting greater neighborhood safety, while, in the fully adjusted model, the odds ratio was 1.11 (CI: [1.05, 1.17]). Even after controlling for sociodemographic characteristics and numerous health risk factors, perceived neighborhood safety was a robust predictor of mobility limitation recovery. This research provides further evidence that environmental factors shape functional health outcomes including recovery.
Control and Dignity in Professional, Manual and Service-Sector Employment
Authors: Crowley Martha
Published: August 2012

This study investigates implications of complex control combinations applied in manual, service and professional occupations for expressive, behavioral and emotional aspects of workplace dignity. Qualitative comparative analyses of 154 content-coded workplace ethnographies suggest that professionals encounter persuasive ‘bundles’ of control that enhance expressive and behavioral manifestations of dignity as well as pride. However, these benefits come at the expense of high levels of stress associated with internal drives and externally driven normative orientations and behaviors. Workers in manual and service occupations confront a broader array of approaches, including coercive control combinations that erode pride and effort by dehumanizing workers and inviting abuse. Furthermore, the benefits of persuasive control combinations in these settings are mitigated by supplementary constraints, which promote maintenance of a protective distance from employers that may also help to limit stress. The paper concludes with organizational strategies for curbing abuse in coercive manual and service environments and a discussion of changes necessary to address the problem of stress in the professions.