bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-93: The role of GSK-3 in mammary gland development and oncogenesis
Authors: Dembowy Joanna , Woodgett Jim 
Published: July 2012

Abstract
Glycogen synthase kinase 3, comprised of two isoforms: α and β, is a central regulator of several signaling pathways that play key roles in development and cancer. Chemical inhibition or genetic loss of GSK-3 in a normal mouse breast cell line cultured under conditions resembling the physiological breast environment resulted in morphological defects reminiscent of early stages of disease. A similar phenotype was also observed upon expression of an activated allele of β-catenin, a major GSK-3 target protein often mutated and elevated in human cancers. These findings implicate GSK-3 as a key regulator of normal ductal development, which may be disrupted early in cancer progression. Upon genetic deletion of GSK-3 (double knock-out of all four alleles, DKO) from breast tissues of mice, dams are unable to nurse their pups. These animals develop severe mammary intraepithelial neoplasia and squamous metaplasia frequently at first pregnancy. Following 4–6 months of continuous breeding, breast adenocarcinomas are observed with elevated levels of ß-catenin and Gli, along with increased expression of a putative mammary progenitor cell marker. Increased cell growth as well as expression of smooth muscle actin, a myoepithelial marker, are also features of these tumors. Similar developmental and functional defects are also observed in mice with breast glands lacking GSK-3 as well as ß-catenin (triple knock-out, TKO). The epithelium of TKO mammary glands undergoes various degrees of squamous differentiation and keratinization, although at a lower penetrance than the DKOs. Multiparious TKOs develop tumors, albeit with a longer latency (7–9 months). Preliminary flow cytometry analysis of mammary glands from DKO and TKO animals show the ratio of luminal to basal cell populations is increased in absence of GSK-3. We are currently investigating how GSK-3 may regulate mammary stem/progenitor cell commitment to these mammary cell lineages.
Previously reported expression of stabilized ß-catenin in the mammary epithelium induces squamous metaplasia, but no adenocarcinomas were observed at 6 months. In our hands, these animals do develop small tumors at ∼10 months of age. These data suggest the observed DKO and TKO phenotypes are not solely mediated via aberrant ß-catenin signaling and that GSK-3 has ß-catenin-independent functions in mammary gland disease. Other pathways regulated by GSK-3 including Notch, Hedgehog and PI3K are being interrogated in DKO and TKO tumor-initiating cells to gain a molecular understanding of tumor development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-93. doi:10.1158/1538-7445.AM2011-LB-93
Abstract LB-95: Inhibition of CXCR4/Stat3 signaling by AMD3465 exerts major tumor- and metastasis-suppressive effects in syngenic 4T1 breast cancer model
Authors: Ling Xiaoyang , Spaeth Erika L. , Shi Yue-xi , Konopleva Marina 
Published: July 2012

Abstract
Stromal-derived factor-1 α (SDF-1α, also termed CXCL12) and its receptor CXCR4 have been shown to play important roles in hematopoietic stem cell homing, and high expression of CXCR4 has been associated with poor prognosis in hematologic malignancies. The CXCR4/SDF-1α axis is also functional in solid tumors, including breast cancer. It has been postulated that Stat3 may promote metastases in breast cancer through direct interaction with CXCR4, promoting tumor growth and survival. Phosphorylated Stat3 was found to trigger overexpression or activation of several potent oncoproteins. In order to evaluate the role of CXCR4 in metastases, we used the specific CXCR4 inhibitor, AMD3465, to block CXCR4 in the syngeneic 4T1 breast cancer model. Stat3, Akt, Erk1/2, Jak2 and MMP9 activity was found to be almost completely inhibited and expression levels of GSK-3β and cMyc were greatly reduced. Growth of 4T1 cells orthotopically implanted into the mammary fat pad as well as pulmonary and liver metastases were significantly (&gt;95%) reduced in vivo when AMD3465 was given as continuous infusion at a dose of 428.57μg/mouse/day over 14 days. Furthermore, we observed that CXCR4 inhibition by AMD3465 significantly reduced lung metastases in three immunocompetent syngeneic mouse models after surgical resection of the primary breast tumors. This experimental design mimics current clinical treatment strategies. Kozin et al. (Cancer Research 70: 5679–85; 2010) recently suggested that CD11b+ myeloid/monocytic cells (a cell type implicated in supporting angiogenesis) may play a role in tumor re-growth in response to SDF-1 α. In support of this observation, we observed significantly reduced CD11b+ cells in lungs, livers and spleens (P&lt;0.01 for all 3 organs) following treatment with AMD3465, as compared to PBS controls. Hence, our data suggest that pharmacological CXCR4 inhibition in breast cancer-bearing mice following primary tumor resection is well tolerated and potently controls the development of distant metastatic lesions. In conclusion, interruption of the SDF-1/CXCR4/Stat3 signaling axis by the CXCR4-specific inhibitor, AMD3465, effectively inhibits pulmonary and hepatic breast cancer metastasis via disruption of intracellular microenvironment mediated signaling in breast cancer cells and through effects on CD11b+ tumor infiltrating myeloid cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-95. doi:10.1158/1538-7445.AM2011-LB-95
Abstract PL04-02: Synthetic lethality: Targeting DNA repair mechanisms in clinical trials
Authors: Tutt Andrew 
Published: July 2012

Abstract
Epithelial carcinomas are in general diseases occurring as a result of the acquisition of and selection for multiple mutations in a parental somatic cell clone in the tissues of the primary site. In the last two decades the role of genome caretakers, which function in key areas of the DNA damage response, have been recognized as important tumor suppressor genes. Inactivating mutations in these genes occur as germline and /or as somatic mutations. In either event, loss of function in a tumor cell precursor clone leads to accelerated mutation acquisition and underpins the etiology of the tumor. As an understanding of the complex network that is the DNA damage response matures additional roles for signaling pathways, already recognized to be central to the establishment of the cancer phenotype, as controllers of DNA repair are being discovered. This has relevance to identification of wider populations of patients with tumors susceptible to approaches that target DNA repair deficiency. These have claissically been with DNA damaging chemotherapy but recently the development of small molecule inhibitors of DNA repair enzymes such as Poly-ADP polymerases PARP-1 and PARP-2 have been shown to target deficiencies in DNA repair as well as sensitize to DNA damaging therapeutics such as radiation and chemotherapy. Early-phase trials with efficacy endpoints have been presented for the PARP inhibitors AG014699, Olaparib, Veliparib, Iniparib and MK4827 have all been presented. The results of the first phase II trials that explore monotherapy PARP inhibitor strategies, based on revisiting the concept of synthetic lethality, have emerged and will be reviewed. PARP inhibitors are also being explored as sensitizers to DNA damaging therapies. The phase II and III trials that have or are exploring combinations with DNA damaging therapy in these contexts will be discussed. I will then discuss biomarkers that have been proposed and are being investigated to develop optimum drug schedule and optimize patient selection for PARP inhibitor therapy approaches.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr PL04-02. doi:10.1158/1538-7445.AM2011-PL04-02
Abstract SY01-02: Mapping the landscape of conditional vulnerabilities in non-small cell lung cancer
Authors: Kim Hyunseok , Gao Hua , Minna John , Posner Bruce , White Michael A. 
Published: July 2012

Abstract
Recognition that cancer is a diverse disease, driven by discordant patient-specific aberrations of cell function, has launched intense efforts to identify drugs matched to the needs of individual patients. However, selection of appropriate treatment is dramatically limited by the paucity of available drugs and by the difficulty of linking treatment options to the appropriate patients. We are employing an extensive panel of non-small cell lung cancer-derived cell lines and clinically pathologically annotated tumor samples to model the diversity of molecular etiologies driving lung cancer initiation and progression. By using quantitative measures of molecular correlates together with concordant responses to whole-genome genetic perturbations and 200,000 small molecule perturbations, we have parsed this heterogeneous panel into a limited number of clades defined by shared liabilities coupled to robust molecular biomarkers. Many of these liabilities represent new intervention targets together with chemical matter that intersects those targets.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY01-02. doi:10.1158/1538-7445.AM2011-SY01-02
Abstract SY13-01: Noncoding RNAs: From bench to bedside
Authors: Calin George A. 
Published: July 2012

Abstract
The newly discovered differential expression in numerous tissues, key cellular processes and multiple diseases for several families of long and short noncoding RNAs (ncRNAs, genes 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 noncoding RNAs 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 noncoding RNAs 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 noncoding RNAs 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 noncoding RNAs 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 noncoding RNAs 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 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY13-01. doi:10.1158/1538-7445.AM2011-SY13-01
Omega-3 Fatty Acids Ameliorate Atherosclerosis by Favorably Altering Monocyte Subsets and Limiting Monocyte Recruitment to Aortic Lesions
Authors: Brown Amanda L. , Zhu Xuewei , Rong Shunxing , Shewale Swapnil , Seo Jeongmin , Boudyguina Elena , Gebre Abraham K. , Alexander-Miller Martha A. , Parks John S. 
Published: July 2012

Objective—
Fish oil, containing omega-3 fatty acids, attenuates atherosclerosis. We hypothesized that omega-3 fatty acid–enriched oils are atheroprotective through alteration of monocyte subsets and their trafficking into atherosclerotic lesions.

Methods and Results—

Low–density lipoprotein receptor knockout and apolipoprotein E
−/−
mice were fed diets containing 10% (calories) palm oil and 0.2% cholesterol, supplemented with an additional 10% palm oil, echium oil (containing 18:4 n-3), or fish oil. Compared with palm oil–fed low–density lipoprotein receptor knockout mice, echium oil and fish oil significantly reduced plasma cholesterol, splenic Ly6C
hi
monocytosis by ≈50%, atherosclerosis by 40% to 70%, monocyte trafficking into the aortic root by ≈50%, and atherosclerotic lesion macrophage content by 30% to 44%. In contrast, atherosclerosis and monocyte trafficking into the artery wall was not altered by omega-3 fatty acids in apolipoprotein E
−/−
mice; however, Ly6C
hi
splenic monocytes positively correlated with aortic root intimal area across all diet groups. In apolipoprotein E
−/−
mice, fish oil reduced the percentage of blood Ly6C
hi
monocytes, despite an average 2-fold higher plasma cholesterol relative to palm oil.

Conclusion—

The presence of splenic Ly6C
hi
monocytes parallels the appearance of atherosclerotic disease in both low–density lipoprotein receptor knockout and apolipoprotein E
−/−
mice. Furthermore, omega-3 fatty acids favorably alter monocyte subsets independently from effects on plasma cholesterol and reduce monocyte recruitment into atherosclerotic lesions.
Cholesterol-Induced Membrane Microvesicles As Novel Carriers of Damage–Associated Molecular Patterns
Authors: Liu Ming-Lin , Scalia Rosario , Mehta Jawahar L. , Williams Kevin Jon 
Published: July 2012

Objective—
Cholesterol enrichment occurs in vivo when phagocytes ingest retained and aggregated lipoproteins, damaged or senescent cells, and related debris. We previously reported that enrichment of human monocyte/macrophages with unesterified cholesterol (UC) triggers the release of highly procoagulant microvesicles ([MVs], also called microparticles) through induction of apoptosis. We determined whether UC-induced MVs (UCMVs) might transmit endogenous danger signals and, if so, what molecular processes might be responsible for their production, recognition, and detoxification.

Methods and Results—

Injection of UCMVs into rats provoked extensive leukocyte rolling and adherence to postcapillary venules in vivo. Likewise, exposure of mouse aortic explants or cultured human endothelial cells to UCMVs augmented the adhesion of human monocytes by several fold and increased endothelial cell intercellular adhesion molecule-1 via nuclear factor-κB activation. To explore molecular mechanisms, we found that UC enrichment of human monocytes, in the absence of other stimuli, induced mitochondrial complex II–dependent accumulation of superoxide and peroxides. A subset of these moieties was exported on UCMVs and mediated endothelial activation. Strikingly, aortic explants from mice lacking lectin–like oxidized low–density lipoprotein receptor-1, a pattern-recognition receptor, were essentially unable to respond to UCMVs, whereas simultaneously treated explants from wild-type mice responded robustly by increasing monocyte recruitment.
Moreover, high-density lipoprotein
and its associated enzyme paraoxonase-1 exerted unexpected roles in the
detoxification of UCMVs.

Conclusion—
Overall, our study implicates MVs from cholesterol–loaded human cells as novel carriers of danger signals. By promoting maladaptive immunologic and thrombotic responses, these particles may contribute to atherothrombosis and other conditions in vivo.
Brain transcriptome variation among behaviorally distinct strains of zebrafish (Danio rerio)
Authors: Drew Robert E , Settles Matthew L , Churchill Erin J , Williams Shayna M , Balli Soniya , Robison Barrie D 
Published: July 2012

AbstractBackgroundDomesticated animal populations often show profound reductions in predator avoidance and fear-related behavior compared to wild populations. These reductions are remarkably consistent and have been observed in a diverse array of taxa including fish, birds, and mammals. Experiments conducted in common environments indicate that these behavioral differences have a genetic basis. In this study, we quantified differences in fear-related behavior between wild and domesticated zebrafish strains and used microarray analysis to identify genes that may be associated with this variation.ResultsCompared to wild zebrafish, domesticated zebrafish spent more time near the water surface and were more likely to occupy the front of the aquarium nearest a human observer. Microarray analysis of the brain transcriptome identified high levels of population variation in gene expression, with 1,749 genes significantly differentially expressed among populations. Genes that varied among populations belonged to functional categories that included DNA repair, DNA photolyase activity, response to light stimulus, neuron development and axon guidance, cell death, iron-binding, chromatin reorganization, and homeobox genes. Comparatively fewer genes (112) differed between domesticated and wild strains with notable genes includinggpr177(wntless), selenoprotein P1a, synaptophysin and synaptoporin, and acyl-CoA binding domain containing proteins (acbd3andacbd4).ConclusionsMicroarray analysis identified a large number of genes that differed among zebrafish populations and may underlie behavioral domestication. Comparisons with similar microarray studies of domestication in rainbow trout and canids identified sixteen evolutionarily or functionally related genes that may represent components of shared molecular mechanisms underlying convergent behavioral evolution during vertebrate domestication. However, this conclusion must be tempered by limitations associated with comparisons among microarray studies and the low level of population-level replication inherent to these studies.
Genetic polymorphisms located in genes related to immune and inflammatory processes are associated with end-stage renal disease: a preliminary study
Authors: Jimenez-Sousa Ma Angeles , López Elisabeth , Fernandez-Rodríguez Amanda , Tamayo Eduardo , Fernández-Navarro Pablo , Segura-Roda Laura , Heredia María , Gómez-Herreras José I , Bustamante Jesús , García-Gómez Juan Miguel , Bermejo-Martin Jesús F , Resino Salvador 
Published: July 2012

Abstract

Background
Chronic kidney disease progression has been linked to pro-inflammatory cytokines and markers of inflammation. These markers are also elevated in end-stage renal disease (ESRD), which constitutes a serious public health problem.

Objective
To investigate whether single nucleotide polymorphisms (SNPs) located in genes related to immune and inflammatory processes, could be associated with ESRD development.

Design and methods
A retrospective case-control study was carried out on 276 patients with ESRD and 288 control subjects. Forty-eight SNPs were genotyped via SNPlex platform. Logistic regression was used to assess the relationship between each sigle polymorphism and the development of ESRD.

Results
Four polymorphisms showed association with ESRD: rs1801275 in the interleukin 4 receptor (IL4R) gene (OR: 0.66 (95%CI = 0.46-0.95); p = 0.025; overdominant model), rs4586 in chemokine (C-C motif) ligand 2 (CCL2) gene (OR: 0.70 (95%CI = 0.54-0.90); p = 0.005; additive model), rs301640 located in an intergenic binding site for signal transducer and activator of transcription 4 (STAT4) (OR: 1.82 (95%CI = 1.17-2.83); p = 0.006; additive model) and rs7830 in the nitric oxide synthase 3 (NOS3) gene (OR: 1.31 (95%CI = 1.01-1.71); p = 0.043; additive model). After adjusting for multiple testing, results lost significance.

Conclusion
Our preliminary data suggest that four genetic polymorphisms located in genes related to inflammation and immune processes could help to predict the risk of developing ESRD.
Incidence and risk factors for infection in oral cancer patients undergoing different treatments protocols
Authors: Panghal Manju , Kaushal Vivek , Kadayan Sangeeta , Yadav Jaya Parkash 
Published: July 2012

AbstractBackgroundOver the past decade, advances in cancer treatments have been counterbalanced by a rising number of immunosuppressed patients with a multitude of new risk factors for infection. Hence, the aim of this study was to determine risk factors, infectious pathogens in blood and oral cavity of oral cancer patients undergoing different treatment procedures.MethodsThe present prospective cohort analysis was conducted on the patients undergoing treatment in the radiotherapy unit of Regional Cancer Institute, Pt. B.D. Sharma University of Health Sciences, Rohtak, Haryana, during the period of January 2007 to October 2009. Total 186 patients with squamous cell carcinoma of oral cavity were analyzed in the study. Based on treatment procedures patients were divided into three groups, group I were under radiotherapy, group II under chemotherapy and group III were of radio chemotherapy together. Clinical isolates from blood and oral cavity were identified by following general microbiological, staining and biochemical methods. The absolute neutrophile counts were done by following the standard methods.ResultsPrevalent bacterial pathogens isolated wereStaphylococcus aureus,Escherichia coli,Staphylococcus epidermidis,Pseudomonas aeruginosa,Klebsiella pneumonia,Proteus mirabilis,Proteus vulgarisand the fungal pathogens wereCandida albicans,Aspergillus fumigatus. The predominant gram negative bacteria,Pseudomonas aeruginosaandKlebsiella pneumoniawere isolated from blood of radiotherapy and oral cavity of chemotherapy treated cases respectively. The predominance of gram positive bacteria (Staphylococcus aureusandStaphylococcus epidermidis) were observed in blood of chemotherapy, radio chemotherapy cases and oral cavity of radiotherapy, radio chemotherapy treated cases. Our study also revealed the presence ofC. albicansfungi as most significant oral cavity pathogens in radiotherapy and radio chemotherapy cases.ConclusionGram positive bacteria and Gram negative were reported from the blood of all the three groups of patients. Oral mucositis played a significant role in oral cavity infection and make patients more prone toC. albicansinfection.