bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2710: KSHV-induced PDGF signaling dyregulation drives a Rac1 and ROS-mediated paracrine tumorigenic mechanism necessary for Kaposi's sarcoma
Authors: Cavallin Lucas E. , Ma Qi , Goldschmidt-Clermont Pascal J. , Mesri Enrique A. 
Published: June 2012

Abstract
Kaposi's sarcoma (KS), caused by the Kaposi's sarcoma-associated herpesvirus (KSHV), is a major AIDS-associated malignancy characterized by angiogenesis and proliferation of spindle cells. KSHV-infected KS lesions are composed of latently-infected cells and a minority of cells expressing lytic genes such as vGPCR, which are implicated the development of KS angioproliferative phenotype via a paracrine mechanism. A key unsolved question is how this minor population of lytically-infected cells expressing vGPCR transduce an angio-proliferative phenotype to latently-infected cells. Here, we describe a Rac1 and ROS driven mechanism of paracrine amplification of viral oncogenesis in the KSHV-induced tumor model mECK36. It is triggered by vGPCR-induced PDGF secretion, which in the presence of high expression of PDGF receptors and NADPH oxidase family members caused by latent KSHV infection, leads to STAT3-mediated transcriptional activation of c-Myc, VEGF and KSHV latent genes. This paracrine loop, driven by PDGF signaling and regulated by Rac1 and ROS, amplifies vGPCR oncogenesis by driving proliferation and angiogenesis in latently-infected cells. Inhibtion of this molecular pathway by either the antioxidant N-acetylcysteine (NAC) or PDGF receptor tyrosine kinase inhibitors impair KSHV-induced tumorigenesis, angiogenesis and lymphangiogenesis, further validating this paracrine oncogenesis mechanism and its components as anti-KS tumor 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 2710. doi:10.1158/1538-7445.AM2011-2710
Abstract 2728: Clonal nature of benign and malignant salivary gland neoplasms
Authors: Gomes Carolina Cavalieri , Pereira Claudia Maria , Brito Joao Artur R , Amaral Fabricio Rezende , Barbosa Alvimar Afonso , de Marco Luiz , Gomez Ricardo Santiago 
Published: June 2012

Abstract
The pathogenesis of salivary gland neoplasms (SGN) has not been established. There is a real debate on clonality issues and all the definitive evidence is on the side of polyclonal tumor origin. Evidence that many tumor types may be polyclonal in origin has been published. Despite all this body of evidence, scientists have incorporated the clonal theory proposed by Knudson (1985) and only strengthen these results (and do not discuss contrary findings), because they think it is expected. There are few clonality studies on benign salivary neoplasms and almost no data on malignant neoplasms. The HUMARA assay was used in the present study to investigate the clonality of 27 samples of SGN (17 benign and ten malignant). Briefly, samples were digested with HhaI and HpaII methylation-sensitive enzymes and a PCR carried out. Eighteen out of 27 cases revealed monotypy, while three were non-informative and six showed heterotypy, indicating a true polyclonality. In summary, our results show evidence that a subset of SGN might be clonal in origin, while some samples are polyclonal.
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 2728. doi:10.1158/1538-7445.AM2011-2728
Abstract 2745: Genetic determinants of telomere length – a genome wide association study
Authors: Chen Meng , Gu Jian , Ye Yuanqing , Lin Jie , Chang David , Wu Xifeng 
Published: June 2012

Abstract
Telomere plays a critical role in maintaining genome integrity. Telomere shortening is associated with the risk of many age-related diseases. Classical twin studies have shown that genetic components may contribute up to 80% of the heritability of telomere length. Previous association studies have reported several genetic loci in regulating telomere length, but the results have been inconsistent. In this study, we adopted a three-stage genome-wide association study (GWAS) design to identify the genetic determinants of telomere length. The mean telomere length was measured by quantitative real-time PCR. Genotyping were done by illumin's whole-genome SNP array in stage I and II, and by TaqMan assay in stage III. Multivariate linear regression analysis was applied to assess the association between genetic variants and telomere length adjusting for age and gender. In stage I, we analyzed 300K SNPs in 459 healthy controls and found 15,351 SNPs that were associated with telomere length at P&lt;0.05. In phase II, we analyzed these 15,351 SNPs in two independent populations with GWAS data with 952 control subjects and 272 control subjects, respectively, and identified 18 SNPs, each with a combined P value &lt; 10−4. Among them, two loci located at chromosome 20q11.22 and 14q21 were associated with telomere length with a significant P value &lt; 10−7. We are in the process of genotyping these 18 SNPs and measuring telomere lengths in approximately 1,200 independent control subjects for stage III validation.
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 2745. doi:10.1158/1538-7445.AM2011-2745
Abstract 275: Burkitt lymphoma cells express GLI1 but are not responsive to Hedgehog signaling
Authors: Yoon Joon Won , Gallant Marisa , Lamm Marilynn , Leong King-Fu , Iannaccone Philip , Walterhouse David O. 
Published: June 2012

Abstract
Activation of the Hedgehog (HH) signaling pathway has been associated with a wide variety of human cancers. Some B-cell lymphomas express components of the HH signaling pathway, including patched (PTCH), smoothened (SMO), and GLI1. There is also evidence that HH ligands function as survival factors in these malignancies. However, specific roles for HH signaling in Burkitt lymphoma have not been characterized. Previously we showed that constitutive expression of c-MYC in Burkitt lymphoma cells up-regulates GLI1 and that GLI1 functions as an anti-apoptotic factor in this setting. Similar to other B-cell malignancies, we have shown expression of PTCH, SMO, and GLI1 in five Burkitt lymphoma cells lines. To test the role of HH signaling in Burkitt lymphoma, we exposed the cells to Sonic Hedgehog peptide or to SHH-containing conditioned media and measured the level of PTCH and GLI1 mRNA expression by quantitative RT PCR; cell viability by MTT assay; cell proliferation by BrdU incorporation; and apoptosis by caspase 3/7 assay. Although control cells (MC3T3) showed dramatic up-regulation of GLI1 and PTCH expression, the Burkitt lymphoma cell lines did not show changes in any of the assays. To inhibit HH signaling, we treated the Burkitt lymphoma cells with the SMO inhibitor, cyclopamine. Cyclopamine treatment did not affect GLI1 expression measured by quantitative RT PCR. Cyclopamine reduced viability of Burkitt lymphoma cells measured by MTT assays only when used at high concentrations (&gt;5 µm), possibly representing a non-specific cytotoxic effect. Collectively, the results suggest that Burkitt lymphoma cells are not HH responsive and that constitutive c-MYC expression plays an important role in regulating GLI1 expression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 275. doi:10.1158/1538-7445.AM2011-275
Abstract 2754: Maternal use of antidepressants in pregnancy is associated with hypermethylation at the IGF2 imprinted control regions in the offspring in a race-dependent fashion
Authors: Soubry Adelheid , Murphy Susan K. , Huang Zhiqing , Murtha Amy , Schildkraut Joellen M. , Jirtle Randy L. , Wang Frances , Kurtzberg Joanne , Demark-Wahnefried Wendy , Forman Michele , Hoyo Catherine 
Published: June 2012

Abstract
In utero exposures to environmental factors may result in persistent epigenetic modifications affecting normal development and susceptibility to chronic diseases in later life. We determined whether exposure of the growing fetus to maternal depression or antidepressants is associated with aberrant DNA methylation at two differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene, namely the DMRs upstream of the imprinted IGF2 promoters (IGF2 DMR) and the DMRs upstream of H19 (H19 DMR). Aberrant DNA methylation at these DMRs has been associated with deregulated IGF2 expression, childhood cancers and several chronic diseases during adulthood. Our study population comprises pregnant mothers and their newborns (n=436), recruited between 2005 and 2008 in Durham, NC. A standardized questionnaire was completed and medical record data were abstracted to ascertain prenatal and periconceptional depression and antidepressive drug use. DMR methylation percentages in umbilical cord blood leukocytes were quantified using pyrosequencing. While an association between depression and methylation profiles was not found, we discovered significant hypermethylation of the H19 DMRs in newborns of African American -but not Caucasian- mothers who were taking antidepressive drugs during pregnancy (β=+6.89, p=0.01). Our findings suggest that changes in the IGF2/H19-domain methylation in response to maternal exposure to antidepressants are race-dependent.
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 2754. doi:10.1158/1538-7445.AM2011-2754
Abstract 2766: DNA methylation status of MLH1, p16 and SOCS1 in Puerto Rican patients with acute myeloid leukemia
Authors: Tirado-Gomez Maribel , Munoz Cristina , Cordero Paul R. , Bernabe Raul , Lacourt Mercedes , Rivera Noridza , Cotto Maribel 
Published: June 2012

Abstract
Background: DNA methylation of gene promoters have been show to play a role in the pathogenesis of acute myeloid leukemia. We present in this study a preliminary report of the methylation status of MLH1, p16 and SOCS1 in Puertorrican patients with acute myeloid leukemia
Methods: Peripheral blood was obtained from 24 patients with diagnosis of acute myeloid leukemia before their induction treatments. DNA was isolated and further modified with sodium bisulfite. Methylation-specific polymerase (MSP) chain reaction was performed to detect aberrant promoter methylation of MLH1, p16 and SOCS1.
Results: A total of 24 samples were analyzed. The mean age was 49 years (range 22-71) with 17/24 patients younger than 60 years (71%). Most of the patients were female (13/24, 54%). Six patients had diploid cytogenetics (25%), 6 had low risk cytogenetics (25%) and 12 had high risk cytogenetics (50%). Fifteen patients were de Novo AML (63%). Nine patients (38%) presented with WBC counts higher than 10 × 109/L. Thirteen patients (54%) achieved a complete response at the end of the induction therapy. Methylation of MLH1 was detected in 3/24 patients (13%). Methylation of p16 was detected in 5/24 patients (21%). Methylation of SOCS1 was detected in 2/24 patients (8%).
Conclusions: A tendency toward an association of methylated p16 with treatment resistance was noted. Also, methylation of SOCS1 was more common among relapsed AML patients. No correlation between methylated MLH1 gene and clinicopathological characteristics was noted. Collection of more patient's samples and correlation with clinical data and patient's ultimate outcome is ongoing.
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 2766. doi:10.1158/1538-7445.AM2011-2766
Abstract 2771: Genetic variation in interleukin, TLR, TNF and TRAF genes of NF-κB activation pathway and risk of prostate cancer
Authors: Liu-Mares Wen , Hu Jennifer J. , Konidari Ioanna , Allen Glenn O. , Clark Peter E. , Hall M. Craig , Dong Chuanhui , Rao J. Sunil , Scott William K. 
Published: June 2012

Abstract
It has been suggested that NF-κB triggers both the onset and resolution of inflammation by governing the expression of genes essential in activating malignancy-promoting signaling pathways. Members of the NF-κB activation pathway include tumor necrosis factor (TNF), several interleukins (IL), TNF receptor associated factors (TRAFs), and toll-like receptors (TLR). These molecules are involved in cell proliferation, differentiation, apoptosis and response to proinflammatory cytokines and mediating the production of cytokines necessary for the development of effective immunity. Common single nucleotide polymorphisms (SNP) in TNF, IL, TRAF, TLR and the main units of NF-κB genes were assessed for the association with prostate cancer (PrCA) risk in a clinic-based study of Caucasian and African-American cases and controls. A total of 709 tagSNPs (with minor allele frequency &gt; = 5% and r2&gt;=0.8) in 54 genes were genotyped in 903 Caucasians (552 cases and 351 controls) and 174 African-Americans (74 cases and 100 controls) using a custom Illumina Infinium II ® assay. Logistic regression models were used to examine each tagSNP with PrCA (adjusting for age and family history of prostate cancer and using an additive model for the SNP). Empirical p-values were generated by permutation (using 10,000 replicates) to correct for multiple comparisons. Statistically significant associations were observed in Caucasians at the NFkBIL1 and IL1R1 genes. The strongest evidence for association came at a polymorphism in the promoter region of the NFkBIL1 gene (rs3219184) (OR = 0.51 [95% CI 0.35-0.74], p = 0.0005), and a polymorphism in the 3’ flanking region of the IL1R1 gene (rs3917332) (OR = 1.60 [95% CI 1.23-2.09], p = 0.0005). We conclude that common variations in NFkBIL1 and IL1R1 might play important roles in PrCA susceptibility.
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 2771. doi:10.1158/1538-7445.AM2011-2771
Abstract 2782: Genetic susceptibility to prostate cancer progression and relationship with PSA level: Case-case study
Authors: Pashayan Nora , Neal David , Hamdy Freddie , Donovan Jenny , Martin Richard , Duffy Stephen , Pharoah Paul 
Published: June 2012

Abstract
Purpose: Prostate cancer is a mixture of progressive and non-progressive cancers. To date, genome-wide association studies have identified more than 30 common susceptibility variants associated with the risk of prostate cancer. However, case-control study designs have failed to identify variants consistently associated with aggressive cancer. The aim of this study is to investigate whether prostate cancer susceptibility variants distinguish between progressive and non-progressive cancers, using case-case study design.
Methods: We genotyped 85 prostate cancer susceptibility variants in 4,856 men with prostate cancer identified from the Prostate Testing for Cancer and Treatment (ProtecT), Prostate Cancer Mechanisms of Progression and Treatment (ProMPT), and Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) studies. Men with advanced stage (T3-T4) (n=624), or Gleason score ≥ 7 (n=1,792) prostate cancer were compared to those with localised stage (T1-T2) (n=3,805), or Gleason score &lt;7 (n=2,090) cancer, respectively, using logistic regression to estimate the odds ratio (OR) associated with risk allele and genotype, after controlling for age at diagnosis, PSA level at diagnosis, stage and / or Gleason score.
Results: On univariate analysis, three variants (rs16901979, rs10896449, rs2735839) were associated with stage, and six (rs1447295, rs16901979, rs10896449, rs2735839 rs17181356 rs3760511) with Gleason score. In multivariate analysis, the variant rs2735839 at 19q13 in KLK2/3 region was associated with 42% increase in the odds for advanced stage cancer (adjusted OR per allele =1.42; 95% CI 1.08-1.87; ptrend =0.01). However, there was evidence of interaction with PSA level (p&lt;0.001). The adjusted OR for rs2735839 for advanced compared to localised cancers among those with PSA ≥10ng/ml was 1.79 (95% CI 1.26-2.54; p=0.001), whereas among those with PSA&lt;10ng/ml, the OR was 0.96 (95% CI 0.60-1.56; p=0.88). Whereas the variant rs3760511 at 17q12 was associated with reduced risk for high Gleason score cancer (adjusted OR per allele=0.85 95% CI 0.75-0.96; ptrend =0.01).
Conclusion: The interaction between PSA level and stage may inform the underlying biological mechanism for cancer progression in stage. These findings may also have clinical utility in identifying tumours with and without the potential for progression to advanced stage or higher Gleason score. Further validation in larger studies would be needed.
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 2782. doi:10.1158/1538-7445.AM2011-2782
Abstract 2784: Association between polymorphisms in angiogenesis-related genes and risk of urothelial carcinoma in Taiwan
Authors: Wang Yuan-Hung , Liu Chi-Tung , Yeh Shauh-Der , Wu Meei-Maan , Shen Kun-Hung , Shen Cheng-Hung , Chiou Hung-Yi 
Published: June 2012

Abstract
Introduction: Urothelial carcinoma (UC) including cancers of bladder, renal pelvis and ureter. Tumor staging and grading are considered to be useful indices for cancer prognosis. Recently, more and more studies indicated that angiogenesis is a necessary step in tumor growth and metastasis. This study aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) of four angiogenesis-related genes including FIH-1, VHL, HIF-1 and VEGF and clinico-pathological characteristics, recurrence, and survival rate of UC.
Materials and Methods: In this case-control study, a total of 850 pathologically- confirmed UC cases and 850 cancer-free controls, frequency-matched on age, were recruited from those who admitted to the same hospitals for a health examination. Genotyping is determined using PCR-RFLP and Real-time PCR. Written informed consent was obtained from each of participants. This protocol was approved by the institutional review boards of the collaborated hospitals.
Results: We found that study subjects with cigarette smoking, alcohol consumption, occupational exposure, arsenic exposure, and high-salt diet have a significantly higher UC risk of 2.0, 1.6, 1.8, 1.9 and 1.5. Study subjects carrying C/G and G/G genotypes of FIH-1 gene had a 1.3-fold risk of developing to stage II or worse status. Cigarette smokers with the C/C genotype of VHL gene had a higher UC risk of 2.4. In addition, cigarette smokers with the T/T genotype of VEGF-460 C/T polymorphism had 1.6- fold UC risk of developing to stage II or worse status. In the combined analysis, study subjects who carried 2 or more risk genotypes of angiogenesis-related genes had a significantly higher UC risk of 1.6 for developing to T2 and stage II or more serious.
Conclusions: Our results suggested a significant association between polymorphisms in angiogenesis-related genes and morbidity and tumor stage of UC, however, without a significant association between these SNPs and tumor grade.
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 2784. doi:10.1158/1538-7445.AM2011-2784
Abstract 2788: Design, optimization, and biological evaluation of potent irreversible inhibitors of BTK kinase
Authors: Bearss David J. , Venkataswamy Sorna , Warner Steven L. , Vankayalapati Hariprasad , Bearss Jared J. , Sharma Sunil 
Published: June 2012

Abstract
Bruton's tyrosine kinase (BTK) is a cytoplasmic nonreceptor tyrosine kinase belonging to the Tec family of kinases. Critical for its function, BTK contains a pleckstrin homology (PH) domain and Src homology SH3 and SH2 domains. It signals downstream of the B-cell receptor (BCR) and is centrally involved in B-cell development. Activation of B-cells by various ligands is accompanied by the translocation of BTK to the cell membrane where it binds phosphatidylinositol-3,4,5-trisphosphate through its PH domain. Activation of BTK results in downstream signaling through the PI3K/AKT, PLCγ, NFκB, and other signaling pathways important for B-cell development and function. Recent reports have shown the aberrant expression and function of BTK in some cancers, including B-cell malignancies. We describe here the design, synthesis, molecular modeling, and biological evaluation of a series of small molecule, inhibitors of BTK kinase. Our initial lead compounds were identified via cross-docking experiments utilizing the crystal structure of BTK kinase and screening a previously in-house explored kinase inhibitor scaffold. We subsequently carried out structure-activity relationship studies and optimized the lead structures, which have IC50 activities in the range of 1 to 10μM against BTK. A critical step in the optimization of this chemical series against BTK was to explore the possibility of adding a Michael's acceptor group to react with Cys481 in the ATP-binding pocket of BTK. Optimization efforts yielded the currently best leads, HCI-1684 and HCI-1685, which inhibit BTK with IC50 values of 12 and 45 nM, respectively. Modeling data suggest these compounds irrepressibly bind in the ATP-binding pocket of BTK. HCI-1684, HCI-1685 and other lead compounds were further evaluated in cell-based assays and were demonstrated to inhibit BTK function downstream of BCR activation. This series of BTK inhibitors were shown to decrease phospho-PLCγ1/2 levels and other downstream phosphorylation events in malignant B-cell cell lines, such as Ramos B. Compound optimization and biological evaluation of this chemical series and evaluation in animal pharmacodynamic endpoint studies will be presented. Taken together, these results suggest BTK is a potential therapeutic target in cancer and that HCI-1684 is an exciting agent to potentially treat B-cell malignancies
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 2788. doi:10.1158/1538-7445.AM2011-2788