bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-365: Regulation of VEGFR-2 by leptin-Notch signaling crosstalk in mammary cancer cells
Authors: Guo Shanchun , Fuller Miles , Gonzalez-Perez Ruben R. 
Published: February 2011

Abstract
VEGFR-2 (Flk-1 or KDR) is generally recognized as the major form that mediates VEGF-induced response and the earliest marker for endothelial cell development. More importantly, VEGFR-2 directly regulates tumor angiogenesis and cancer cell survival through autocrine/paracrine mechanisms. We have previously reported that leptin signaling induced the growth of breast cancer mainly through the up-regulation of pro-angiogenic and pro-proliferative molecules, i.e., VEGF/VEGFR-2. Disruption of leptin signaling markedly reduced the growth of tumors and the expression of VEGFR-2 in mouse models of syngeneic and human breast cancer xenografts (ER+ and ER-). On the other hand, Notch signaling is essential for tumor angiogenesis. We hypothesized that a crosstalk between Notch and leptin signaling could impact the expression of VEGFR-2 in breast cancer. To test this hypothesis, the 5′-end transcription region of mouse VEGFR-2 gene was cloned and used to establish VEGFR2-Luc assays in mouse mammary tumor (MT) cells. Leptin induced VEGFR-2-Luc activity through JAK2, JNK, p38 MAP kinase, as well as PKC signaling pathways and up-regulated several members of Notch family (Notch 1∼4) in MT. Interestingly, leptin-induced VEGFR-2 transcriptional activity was significantly inhibited by a gamma-secretase inhibitor which blocks Notch pathway activation. These results suggest that leptin and Notch signaling crosstalk could impact on angiogenesis and growth of MT. Furthermore, VEGFR-2 transcription and expression was heavily depending on VEGFR-2 gene methylation and histone acetylation that could be linked to leptin's effects. Our results provide novel evidence on how VEGFR-2 could be regulated in breast cancer. Present data reinforce the idea that disruption of leptin signaling could reduce tumor angiogenesis/growth by inhibiting leptin-mediated up-regulation of VEGFR-2 and/or by negatively impacting on signals from some key members of Notch family. This might help to design new pharmacological strategies aimed at controlling breast cancer growth and angiogenesis. [This work was supported in part by NIH/NCI 1SC1CA138658-02; NIH/ARRA/3SC1CA138658-02S1; NIH/UAB Breast SPORE Career Development Award and the Georgia Cancer Coalition Distinguished Cancer Scholar Award (to RRGP)].
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-365.
Abstract LB-369: Sphingosine-1-phosphate (S1P) as a novel target in renal cancer (RCC)
Authors: Bhatt Rupal S. , Zhang Liang , Bullock Andrea , Wang Xiaoen , Moreno Kelli , Signoretti Sabina , Atkins Michael B. , Sabbadini Roger , Mier James W. 
Published: February 2011

Abstract
Although treatment of patients (pts) with metastatic RCC with VEGFR2 inhibitors induces disease regression, these responses tend to be short-lived. Mouse models of VEGFR TKI treatment of RCC were used to study the mechanisms of resistance and identify novel targets. Drug-induced growth arrest was associated with enhanced expression of sphingosine kinase (sphk) whose only product is the bioactive signaling lipid, S1P.
To explore the role of this pathway in mice bearing 786-O RCC were treated with a neutralizing antibody against S1P. Vehicle treated tumors increased by 2mm after 5.8 ± 4.1 days (n=6) and treatment with 10mg/kg or 50mg/kg anti-S1P led to growth after 15.3 ± 3.5 days (n=7) and 20.5 ± 3.9 days (n=6) respectively (P&lt;0.01 for PBS vs. 10mg/kg or 50mg/kg), demonstrating that anti-S1P exhibits single agent activity in treatment naïve tumors.
To assess the activity of S1P ab in the setting of sunitinib resistance, mice whose tumors developed resistance to sunitinib, were switched to either an anti-isotype negative control antibody, or anti-S1P. Treatment with anti-S1P produced relative tumor stabilization: 23.0 ± 16.5 days (n=10) vs. isotype control 6.9 ± 2.1 days for switch to isotype (n=7, P=0.01). In an A498 RCC tumor xenograft model, vehicle and isotype treated tumors increased by 2mm after 5.0 ± 1.17 days (n=7) compared to15.3 ± 5.8 days (n=6) for mice treated with 50mg/kg anti-S1P (P&lt;0.01) and time to reach sacrifice size of 20mm was 30.7 ± 3.8 days (n=7) in vehicle and isotype treated tumors and 45.0 ± 8.6 days (n=6) with 50mg/kg anti-S1P (P=0.01).
S1P levels in pts with RCC were found to be significantly higher than control pts (2.7 ± 0.032uM (n=23) vs 0.588 ± 0.057 M (n=20, P&lt;0.0001). Thus, the S1P pathway is a novel target for the treatment of both treatment naïve and VEFGR TKI refractory RCC and anti-S1P therapy is an attractive new option for clinical investigation in RCC patients. The humanized anti-S1P mAb, ASONEPTM, has recently completed Phase I clinical trials in cancer and planning for Phase II efficacy trials is underway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-369.
Abstract LB-375: Development of new compounds specifically targeting prostate cancer bone metastases
Authors: Levine Alice C. , Weinstein Barrie , Liu XinHua , Regan Steven , Janout Vasek , Kirschenbaum Alexander 
Published: February 2011

Abstract
Introduction: Bone metastases are a major cause of morbidity for men with prostate cancer (PCa). Although PCa cells produce osteoblastic metastases, there is an initial and ongoing osteoclast (OC)-mediated osteolytic phase that is essential for PCa bone metastases. OC-mediated bone resorption is dependent upon OC secretion of bone acid phosphatase. PCa cells in bone secrete high levels of prostatic acid phosphatase (PAP) which differs from BAP in that PAP enzymatic activity is inhibited by tartrate and glyceric acid, whereas BAP is tartrate-resistant.
Hypothesis: PAP secreted by human PCa cells in bone acts similarly to OC-derived bone acid phosphatase to degrade bone matrix and enhance PCa bone-targeting and growth in bone. We developed new compounds consisting of glyceric acid or tartrate (known PAP inhibitors) conjugated to a bisphosphonate to inhibit PCa bone metastases.
Methods: PCa bone metastases derived from 7 patients were immunostained for androgen receptor (AR), prostate specific antigen (PSA) and PAP expression. The VCaP human PCa cell line derived from a vertebral metastases was inoculated intratibially into SCID mice (n=8) and bone lesions immunostained for AR, PSA, and PAP. Co-cultures of MC3T3 osteoblasts and VCaP cells were treated with tartrate and the effects on cell number, PAP and bone alkaline phosphatase (ALP) secretion measured by ELISA. Glyceric Acid and Tartaric acid were then conjugated with alendronate and the effects of these new conjugates on PAP enzymatic activity were compared to alendronate alone and tartrate alone.
Results: Human PCa bone lesions (7/7) had strongly positive expression of PAP, with little AR or PSA expression. 8/8 SCID mice inoculated with VCaP cells intratibially developed osteoblastic VCaP lesions and these similarly had high PAP expression and no PSA expression. Tartrate addition to co-cultures of VCaP and MC3T3 osteoblasts reduced MC3T3 cell numbers and ALP secretion. In vitro testing of the conjugates revealed that the glyceric acid-alendronate conjugate inhibited PAP enzymatic activity but the tartrate-alendronate conjugate and alendronate alone had no significant inhibitory activity.
Discussion: We have evidence that PAP secretion by PCa cells enhances their bone metastatic ability. We have developed new bone-targeting agents that consist of alendronate conjugated to PAP-inhibitory small molecules for further development as oral agents to prevent and treat PCa bone metastases.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-375.
Abstract LB-403: Levels of nitric oxide and prostate cancer development in healthy US men enrolled in the Health Professionals Follow-up Study
Authors: Wu Tianying , Wang Yushan , Ho Shuk-Mei , Giovannucci Edward 
Published: February 2011

Abstract
Nitric oxide (NO) has a strong impact on cancer development. Experimental studies have reported that, depending on levels, NO has either tumoricidal or tumor-promoting effects. In addition, NO is strongly associated with oxidative and inflammatory pathways, which have been implicated in prostate cancer. In general, maintaining normal-range levels of NO is important for physiological function and may actually have tumoricidal effects. Furthermore, extremely high levels of NO have been found to stimulate prostate tumor growth in rats. However, the relationship between plasma NO level and risk of prostate cancer (PCa) development has not been assessed.
NO is difficult to measure directly in large epidemiologic studies. This barrier has hampered the identification of NO-related pathways in cancer development. We have found that plasma levels of nitrite/nitrate, measured as a surrogate marker of NO, are both stable and reproducible within individuals over time. Using a prospective nested case-control design, we identified 600 PCa cases and 600 matched controls from 2000-2004 among men who provided a blood sample in 1993-1995. This study is nested within a blood cohort in the Health Professionals Follow-up Study. We have already measured baseline plasma levels of nitrite/nitrate in 170 cases and 170 controls. The multivariate-adjusted odds ratio of nitrite/nitrate from quintile 2-quintile 4 as compared to quintile 1 are 0.71 (95%CI, 0.24-2.75), 0.20 (95%CI, 0.05-0.75), 0.81 (95%CI, 0.30-2.91), and 1.12 (95%CI, 0.65-2.78), respectively. Our preliminary data suggest that medium levels of nitrite/nitrate maximally reduce the risk of prostate cancer, and that men with high or low levels of nitrite/nitrate may be at elevated risk of prostate cancer. Confirming our results in our remaining samples and other populations may have important implications for prevention of prostate cancer.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-403.
Abstract LB-406: A genetic variant near the PMAIP1/Noxa gene is associated with increased bleomycin sensitivity and cancer risk
Authors: Gu Jian , Ye Yuanqing , Spitz Margaret , Lin Jie , Kiemeney Lambertus A. , Xing Jingliang , Hildebrandt Michelle AT , Hong Waun Ki , Amos Christopher I. , Wu Xfeng 
Published: February 2011

Abstract
Background: Mutagen sensitivity, a measurement of chromatid breaks induced by various mutagens in short-term cultures of peripheral blood lymphocytes, is an established risk factor for a number of cancers and is highly heritable. The purpose of this study is to identify genetic predictors of mutagen sensitivity.
Methods: We conducted a multi-stage genome wide association study (GWAS). The primary scan analyzed 539,437 autosomal SNPs in 673 healthy individuals, followed by validations in two independent sets of 575 and 259 healthy individuals, respectively.
Results: One SNP, rs8093763, on chromosome 18q21showed consistent association with bleomycin sensitivity (combined P = 2.64×10-8). We observed consistently lower bleomycin-induced chromotid breaks for genotypes containing wild type allele compared with the homozygous variant genotype in the discovery set (0.71 vs. 0.90, P=3.77×10-5), in replication phase one (0.61 vs. 0.84, P=7.00×10-5), and in replication phase two (0.65 vs. 0.68, P=0.44). This SNP is approximately 64 kb from the PMAIP1/Noxa gene, which is a radiation- and bleomycin-inducible gene and exhibits significantly higher expression in bleomycin-sensitive lymphoblastoid cell lines than insensitive cell lines upon bleomycin treatment. This SNP also appeared to increase the risk of lung cancer and bladder cancer in two large case control studies.
Conclusions: We identified a biologically plausible genetic variation on 18q21 near PMAIP1/Noxa gene that is associated with bleomycin sensitivity. The homozygous variant genotype exhibited higher bleomycin sensitivity and increased risks of lung cancer and bladder cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-406.
Abstract LB-409: Opposing effect of CHEK2 mutations for lung and kidney cancer: a meta analysis
Authors: Maria Timofeeva N. , McKay James , Scelo Ghislaine , Zaridze David , Brennan Paul ,   on behalf of the IARC Central European Lung CancerStudy.
Published: February 2011

Abstract
Rare variants in CHEK2, checkpoint kinase 2, cell cycle control gene have been associated with various cancer sites including breast, prostate and colon cancer. Previously, two independent studies indicated a strong protective effect of CHEK2 mutations on the risk of lung and aero-digestive cancer but not kidney cancers (Brennan et al., 2007; Cybulski et al., 2008). We have conducted an independent case-control study to replicate these observed effects. 1202 cancer free controls, 481 individuals with primary lung cancer and 252 primary kidney cancer cases, all of Russian origin, were included in the study. All individuals were genotyped for the I157T variant (rs17879961) using Taqman. We also genotyped samples from the study published by Brennan et al. (2007) for three additional rare mutations found to be present in the central and eastern European population (1100delC, IVS2+1G&gt;A and the deletion of 5Kb (across exons 12 and 14)). We used logistic regression techniques to calculate odds ratios (ORs) and 95% confidence interval (95%CIs), adjusted for age, gender and pack-years of tobacco smoking. We additionally performed a meta-analysis of central and eastern European studies investigating lung and kidney cancer and CHEK2 mutations.
Based on new data, the I157T rare variant showed a similar trend as in previous studies (OR = 0.78, 95%CI 0.43-1.40 for lung cancer and OR= 1.30, 95%CI 0.75-2.26 for kidney cancer). The combined OR for all three studies based on a fixed effects model indicated a strong protective effect of the CHEK2 I157T rare variant on the risk of lung cancer with OR of 0.43 (95%CI 0.35-0.53). The effect was stronger for squamous cell carcinoma (OR=0.21, 95%CI 0.12-0.37) and non significant for adenocarcinoma (OR=0.90, 95%CI 0.61-1.34). Results of meta-analysis on kidney cancer confirmed the previously observed increased risk effect of the CHEK2 I157T mutation with an OR of 1.38 (95%CI 1.04-1.82). Similar effects were observed for the combination of all mutations. Furthermore, haplotype analysis indicates that each mutation is characterized by unique extended haplotype consistent with the notion of a founder effect. The present study and performed meta-analysis confirmed previous opposing results for the effects of CHEK2 mutations on the risk of lung and kidney cancer. The mechanism for these inverse effects is unknown.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-409.
Abstract LB-416: Genetic variants in the 53BP1 gene and risk of skin cancer
Authors: He Chunyan 
Published: February 2011

Abstract
TP53-binding protein 1 (53BP1) is a central mediator of the DNA damage checkpoint and plays an important role in DNA double-strand break repair. Genetic variation of the 53BP1 gene may interfere the proper repair that would result in genomic instability, leading to cell death or tumorigenesis. We conducted a skin cancer case-control study of Caucasians nested within the Nurses’ Health Study to evaluate whether common genetic variants of the 53BP1 gene are associated with skin cancer risk. We selected and genotyped 8 single nucleotide polymorphisms (SNPs) including potentially functional SNPs and tagging SNPs in the 53BP1 gene region in 218 incident melanoma, 285 incident squamous cell carcinoma (SCC) cases, 300 incident basal cell carcinoma (BCC) cases, and 870 age-matched controls. We found that three tagging SNPs (rs999047, rs2242069, and rs689647) were associated with a significantly decreased risk of BCC (additive multivariate ORs (95% CIs): 0.65(0.46-0.91), 0.67(0.49-0.90), and 0.68(0.48-0.96), respectively). The heterozygous variant of a putatively functional SNP, rs2602141, was significantly associated with an increased risk of melanoma (OR, 1.39; 95% CI, 1.01-1.90). The other two SNPs (rs1869258 and rs560191) highly correlated with rs260214 showed similar associations with melanoma risk. These SNPs (rs2602141, rs1869258 and rs560191) were also associated with lighter hair color and more moles among controls (p for trend, 0.003-0.07). The results suggest that the common genetic variants of 53BP1 are associated with pigmentary phenotypes and different types of skin cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-416.
Abstract LB-417: Polymorphisms and haplotypes in XRCC1 and risk of advanced non-small cell lung cancer
Authors: Kim In-Suk , Lee Gyeong-Won 
Published: February 2011

Abstract
Background: Base excision repair (BER) is the primary DNA damage repair mechanism for repairing small base lesions resulting from oxidation and alkylation damage. Genetic variants in XRCC1, one of the BER genes, may be associated with smoking-related cancers. We tested the hypothesis that single nucleotide polymorphisms (SNPs) and/or hyplotypes in XRCC1 are related with the risk of non-small-cell lung cancer (NSCLC).
Methods: We genotyped 3 known coding SNPs (Arg280His (rs25489), Arg399Gln (rs25487), and Gln632Gln (rs3547)) and 6 haplotype-tagging SNPs (htSNP) by Sequenom's (San Diego, CA, USA) high-throughput matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in 140 NSCLC patients and 217 controls from Korea. Analyses of individual SNPs and hyplotypes were performed using unconditional logistic regression adjusted for age, sex, and smoking status. Haplotypes were reconstructed according to the genotyping data and linkage disequilibrium status of these 9 SNPs using the Haploview version 4.1 software (Broad Institute of MIT and Harvard, Cambridge, MA, USA).
Results: Minor allele heterozygotes of htSNP rs1799778 was increased risk of advanced NSCLC (adjusted OR, 2.118, 95% CI, 1.175-3.818, P= 0.013) and minor allele homozygote of htSNP rs2293036 was decreased risk of advanced NSCLC (adjusted OR, 0.363, 95% CI, 0.254-0.854, P = 0.020). Seven possible haplotypes were demonstrated in this study (Haplotype frequency &gt;1%). The frequency of GGGGGGGGG haplotype composed of major alleles among selected all SNPs, was 0.109 and this haplotype showed protective effect of NSCLC risk (OR, 0.433; 95% CI, 0.246-0.740; P = 0.002). The association between the GGGGGGGGG haplotype and decreased risk of NSCLC was stable on permutation testing (P = 0.021). According to the smoking status, statistically significant associations between the rs1001581 polymorphisms and increased risk of NSCLC and the GGGGGGGGG haplotype and decreased risk of NSCLC risk were observed among never smokers (Adjusted P for trend = 0.005, P = 0.016), however, no association was noted among ever smokers.
Conclusions: These findings suggest that the GGGGGGGGG haplotype composed of major alleles in all selected SNPs showed protective role against development of NSCLC and the rs1001581 polymorphisms showed increased risk of NSCLC in Koreans, especially nonsmokers, and smoking status modifies the associations between the XRCC1 genetic variants and NSCLC risk. Thus, this study presents several novel aspects on genetic susceptibility to NSCLC and larger studies of the role of the rs1001581 and haplotypes for NSCLC risk would be needed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-417.
Abstract LB-433: A new method of colorectal cancer screening using microRNA expression profiles of colonocytes isolated from feces
Authors: Koga Yoshikatsu , Yasunaga Masahiro , Takahashi Amane , Kuroda Junichiro , Baba Hideo , Matsumura Yasuhiro 
Published: February 2011

Abstract
Background and Aims: Early detection of colorectal cancer (CRC) is desirable because this cancer can be cured surgically if it is diagnosed at an early stage. To reduce the mortality rate of CRC, the development of a screening test by which the cancer can be diagnosed early is needed. To date, we have reported several CRC screening methods using colonocytes isolated from feces. Recently, expression analysis of oncogenic microRNA (miRNA) in serum was reported for CRC detection. Here, we conducted miRNA expression analysis in exfoliated colonocytes isolated from feces for CRC screening.
Methods: First, oncogenic miRNA expression profiles were analyzed in CRC tissue and normal tissue. Next, 206 patients with CRC and 134 healthy volunteers were enrolled in the study, and oncogenic miRNA expression in colonocytes isolated from feces was analyzed by quantitative real-time PCR.
Results: In the CRC tissue, oncogenic miRNA expression was significantly higher than in normal tissue. There was sufficient miRNA to analyze the exfoliated colonocytes of 197 CRC patients and 119 healthy volunteers. The overall sensitivity of miRNA expression analysis was 74.1% (146/197, 95% CI; 67.4-80.1) and the specificity was 79.0% (94/119, 95% CI; 70.6-85.9). The sensitivity was significantly higher for cancers in the left side of the colon (P= 0.0001).
Conclusions: miRNA was well conserved in exfoliated colonocytes. miRNA expression analysis of colonocytes isolated from feces may be useful for CRC screening. Further investigation of oncogenic miRNA highly expressed in CRC is needed for future CRC screening test.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-433.