Citations

Abstract Background: Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) show indisputable promise as cancer chemoprevention agents. While aspirin and NSAID use have been suggested to lower risk of developing pancreatic cancer, the results of several epidemiological studies are not in consensus. Methods: Using a case-control design, we examined the association between aspirin, NSAID and acetaminophen use and the risk of pancreatic cancer. We enrolled 904 histological or clinically documented pancreatic ductal adenocarcinoma cases, and 1,223 age and gender matched healthy clinic-based controls evaluated at Mayo Clinic from April 2004 and September 2010. All subjects were ≥ 55 years old and self-reported by questionnaire their use of aspirin, NSAIDs, and acetaminophen at ages 41-60, along with extensive epidemiologic and demographic information. Multivariate logistic regression analysis was used to estimate risk of pancreatic cancer after adjusting for potential confounders. Results: The use of aspirin was associated with a decreased risk of pancreatic cancer. The unadjusted odds ratio (OR) associated with aspirin use ≥ 1 day/month, compared with never or < 1 day/month, was 0.79 [95% confidence interval (CI) 0.65. 0.96, p = 0.015]. This effect remained significant [OR 0.71, 95% CI 0.58,0.87, p = 0.0008], after adjusting for the potential confounders of body mass index and smoking status (never, former, current). The inverse relationship was stronger among former smokers (OR 0.61, 95% CI 0.46, 0.82, p =0.0008) than never and current smokers, although there was not a statistically significant interaction (Pintereaction = 0.333). NSAID and acetaminophen use was not associated with the risk of pancreatic cancer. Conclusions: Results from this large case-control study suggest that aspirin use, but not non-aspirin NSAID use, was associated with lower risk of developing pancreatic cancer and was more pronounced among former smokers than never and current smokers. 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 1902. doi:10.1158/1538-7445.AM2011-1902

Abstract Some studies show that childbearing at older age is associated with lower risk of endometrial cancer, but whether the association is independent of number of children or other factors still requires clarification. We pooled individual-level data from epidemiologic studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Data on age at last birth and/or last pregnancy were available from 14 studies: 11 case-control studies and 3 cohort studies; the latter were analyzed using a nested case-control design. A total of 9,613 endometrial cancer cases and 17,112 controls were included in the analysis. The majority of women were White (82%) and older than 55 years (69%). We estimated the effects of age at last birth using data from 12 studies and age at last pregnancy using data from 10 studies on the risk of endometrial cancer by calculating odds ratios (OR) and 95% confidence intervals (95% CI) using logistic regression models. Potential confounders included in the analysis were race, body mass index, parity, age at menarche, age at first birth, oral contraceptive use, postmenopausal hormone use, smoking status, and report of diabetes. After adjusting for potential confounders, a reduction in endometrial cancer risk was observed in women with increasing age at last birth (P trend <0.0001) and age at last pregnancy (P trend <0.0001). The OR per five-year increase in age at last birth and age at last pregnancy was 0.90 (95%CI: 0.86, 0.94) and 0.91 (95% CI: 0.87, 0.95), respectively. Women who had their last child at an age >40 years were at a 34% decreased risk compared with women who had their last child at an age <25 years (95% CI: 0.52, 0.82). Compared to women with age at last pregnancy <25 years, those with age at last pregnancy >40 years had a 30% decreased risk of endometrial cancer (95%CI: 0.57, 0.86). Inverse associations were observed for Whites and Asians in race-specific analysis and also in analysis restricted to women with at least 2 births. In this large pooled analysis, we show that late age at last birth or last pregnancy is a strong and independent protective factor for endometrial cancer. 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 1900. doi:10.1158/1538-7445.AM2011-1900

Abstract Background: Candidate gene and candidate pathway-based pharmacogenomic studies have been used to investigate the inherited variability of prognosis of lung cancer treated with platinum-based chemoptherapy. In order to make it possible to conduct an ‘unbiased’ query across the entire genome, a genome-wide association study (GWAS) in 283 lymphoblastoid cell lines (LCLs) was carried out to help identify candidate SNPs associated with variation in cisplatin cytotoxicity. Furthermore, we set out to test the hypothesis that genetic variation resulting in differences in cisplatin cytotoxicity might influence the overall survival of patients with lung cancer treated with platinum-based antineoplastic agents. Material and Methods: We applied ethnically diverse Coriell “Human Variation Panel” LCLs for GWAS. Then, we picked 168 top significant SNPs selected from GWAS in 283 LCLs and genotyped these SNPs in 1183 lung cancer patients (222 SCLC and 961 NSCLC) who received platinum-based chemotherapy. Genotyping was performed using the Illumina Golden Gate platform. The association of SNPs with lung cancer overall survival was analyzed by Cox regression model after adjusting for disease stage. Functional validation of candidate genes was performed by siRNA screening in NSCLC cell lines CRL5872, H1299 and SCLC cell line CRL5823. Results: A total of 157 SNPs were successfully genotyped for 1183 lung cancer patient samples. The Cox regression analysis indicated that 9 and 10 different SNPs were associated with overall survival for NSCLC and SCLC patients, respectively (p value <0.05). Fifteen genes including 7 genes located in the region of 200kb up or downstream of 4 SNPs (rs11169748, rs2440915, rs5952066 and rs7620841) and 8 genes for which the expression was correlated with three SNPs (rs11169748, rs2440915 and rs5952066) were selected for siRNA screening. Knockdown of DAPK3 and METTL6, for which the expression levels were correlated with the SNPs rs11169748 and rs2440915, significantly decreased cisplatin sensitivity in lung cancer cell lines CRL5872, H1299 and CRL5823. Conclusions: This series of clinical and complementary laboratory-based functional studies identified several candidate genes and SNPs that might help predict treatment outcomes of platinum-based therapy in lung cancer. 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 1285. doi:10.1158/1538-7445.AM2011-1285

New vibration pulses are proposed to increase the power of shear waves induced by ultrasound radiation force in a tissue region with a preferred spectral distribution. The new pulses are sparsely sampled from an orthogonal frequency wave composed of several sinusoidal signals. Those sinusoidal signals have different frequencies and are orthogonal to each other. The phase and amplitude of each sinusoidal signal are adjusted to control the shape of the orthogonal frequency wave. Amplitude of the sinusoidal signal is increased as its frequency increases to compensate for higher loss at higher frequency in the tissue region. The new vibration pulses and detection pulses can be interleaved for array transducer applications. The experimental results show that the new vibration pulses significantly increases induced tissue vibration with the same peak ultrasound intensity, compared with the binary vibration pulses.

Renal artery stenosis (RAS) promotes microvascular rarefaction and fibrogenesis, which may eventuate in irreversible kidney injury. We have shown that percutaneous transluminal renal angioplasty (PTRA) or endothelial progenitor cells (EPC) improve renal cortical hemodynamics and function in the poststenotic kidney. The renal medulla is particularly sensitive to hypoxia, yet little is known about reversibility of medullary injury on restoration of renal blood flow. This study was designed to test the hypothesis that PTRA, with or without adjunct EPC delivery to the stenotic kidney, may improve medullary remodeling and tubular function. RAS was induced in 21 pigs using implantation of irritant coils, while another group served as normal controls ( n = 7 each). Two RAS groups were then treated 6 wk later with PTRA or both PTRA and EPC. Four weeks later, medullary hemodynamics, microvascular architecture, and oxygen-dependent tubular function of the stenotic kidneys were examined using multidetector computed tomography, microcomputed tomography, and blood oxygenation level-dependent MRI, respectively. Medullary protein expression of vascular endothelial growth factor, endothelial nitric oxide synthase, hypoxia-inducible factor-1α, and NAD(P)H oxidase p47 were determined. All RAS groups showed decreased medullary vascular density and blood flow. However, in RAS+PTRA+EPC animals, EPC were engrafted in tubular structures, oxygen-dependent tubular function was normalized, and fibrosis attenuated, despite elevated expression of hypoxia-inducible factor-1α and sustained downregulation of vascular endothelial growth factor. In conclusion, EPC delivery, in addition to PTRA, restores medullary oxygen-dependent tubular function, despite impaired medullary blood and oxygen supply. These results support further development of cell-based therapy as an adjunct to revascularization of RAS.

Renal function and blood flow decline during aging in association with a decrease in the number of intrarenal vessels, but if loss of estrogen contributes to this microvascular, rarefaction remains unclear. We tested the hypothesis that the decreased renal microvascular density with age is aggravated by loss of estrogen. Six-month-old female C57/BL6 mice underwent ovariectomy (Ovx) or sham operation and then were allowed to age to 18–22 mo. Another comparable group was replenished with estrogen after Ovx (Ovx+E), while a 6-mo-old group served as young controls. Kidneys were then dissected for evaluation of microvascular density (by micro-computed tomography) and angiogenic and fibrogenic factors. Cortical density of small microvessels (20–200 μm) was decreased in all aged groups compared with young controls (30.3 ± 5.8 vessels/mm2, P < 0.05), but tended to be lower in sham compared with Ovx and Ovx+E (9.9 ± 1.7 vs. 17.2 ± 4.2 and 18 ± 3.0 vessels/mm2, P = 0.08 and P = 0.02, respectively). Cortical density of larger microvessels (200–500 μm) decreased only in aged sham ( P = 0.04 vs. young control), and proangiogenic signaling was attenuated. On the other hand, renal fibrogenic mechanisms were aggravated in aged Ovx compared with aged sham, but blunted in Ovx+E, in association with downregulated transforming growth factor-β signaling and decreased oxidative stress in the kidney. Therefore, aging induced in female mice renal cortical microvascular loss, which was likely not mediated by loss of endogenous estrogen. However, estrogen may play a role in protecting the kidney by decreasing oxidative stress and attenuating mechanisms linked to renal interstitial fibrosis.

ABSTRACT To characterize the importance of infection of epithelial cells for morbillivirus pathogenesis, we took advantage of the severe disease caused by canine distemper virus (CDV) in ferrets. To obtain a CDV that was unable to enter epithelial cells but retained the ability to enter immune cells, we transferred to its attachment (H) protein two mutations shown to interfere with the interaction of measles virus H with its epithelial receptor, human nectin-4. As expected for an epithelial receptor (EpR)-blind CDV, this virus infected dog and ferret epithelial cells inefficiently and did not cause cell fusion or syncytium formation. On the other hand, the EpR-blind CDV replicated in cells expressing canine signaling lymphocyte activation molecule (SLAM), the morbillivirus immune cell receptor, with similar kinetics to those of wild-type CDV. While ferrets infected with wild-type CDV died within 12 days after infection, after developing severe rash and fever, animals infected with the EpR-blind virus showed no clinical signs of disease. Nevertheless, both viruses spread rapidly and efficiently in immune cells, causing similar levels of leukopenia and inhibition of lymphocyte proliferation activity, two indicators of morbillivirus immunosuppression. Infection was documented for airway epithelia of ferrets infected with wild-type CDV but not for those of animals infected with the EpR-blind virus, and only animals infected with wild-type CDV shed virus. Thus, epithelial cell infection is necessary for clinical disease and efficient virus shedding but not for immunosuppression.

Abstract Many phytochemicals possess antioxidant and cancer-preventive properties, some putatively through antioxidant response element–mediated phase II metabolism, entailing mutagen/oxidant quenching. In our recent studies, however, most candidate phytochemical agents were not potent in inducing phase II genes in normal human lung cells. In this study, we applied a messenger RNA (mRNA)–specific gene expression–based high throughput in vitro screening approach to discover new, potent plant-derived phase II inducing chemopreventive agents. Primary normal human bronchial epithelial (NHBE) cells and immortalized human bronchial epithelial cells (HBECs) were exposed to 800 individual compounds in the MicroSource Natural Products Library. At a level achievable in humans by diet (1.0 μM), 2,3-dihydroxy-4-methoxy-4′-ethoxybenzophenone (DMEBP), triacetylresveratrol (TRES), ivermectin, sanguinarine sulfate, and daunorubicin induced reduced nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 (NQO1) mRNA and protein expression in NHBE cells. DMEBP and TRES were the most attractive agents as coupling potency and low toxicity for induction of NQO1 (mRNA level, ≥3- to 10.8-fold that of control; protein level, ≥ two- to fourfold that of control). Induction of glutathione S-transferase pi mRNA expression was modest, and none was apparent for glutathione S-transferase pi protein expression. Measurements of reactive oxygen species and glutathione/oxidized glutathione ratio showed an antioxidant effect for DMEBP, but no definite effect was found for TRES in NHBE cells. Exposure of NHBE cells to H2O2 induced nuclear translocation of nuclear factor erythroid 2–related factor 2, but this translocation was not significantly inhibited by TRES and DMEBP. These studies show that potency and low toxicity may align for two potential NQO1-inducing agents, DMEBP and TRES.

AbstractAspirin and other nonsteroidal anti-inflammatory drugs (NSAID) show indisputable promise as cancer chemoprevention agents. However, studies have been inconsistent as to whether aspirin has a protective effect in development of pancreatic cancer. To further evaluate the association between aspirin, NSAID, and acetaminophen use with pancreatic cancer risk, we used a clinic-based case–control study of 904 rapidly ascertained histologically or clinically documented pancreatic ductal adenocarcinoma cases, and 1,224 age- and sex-matched healthy controls evaluated at Mayo Clinic from April 2004 to September 2010. Overall, there is no relationship between non-aspirin NSAID or acetaminophen use and risk of pancreatic cancer. Aspirin use for 1 d/mo or greater was associated with a significantly decreased risk of pancreatic cancer (OR = 0.74, 95% CI: 0.60–0.91, P = 0.005) compared with never or less than 1 d/mo. Analysis by frequency and frequency-dosage of use categories showed reduced risk (P = 0.007 and 0.022, respectively). This inverse association was also found for those who took low-dose aspirin for heart disease prevention (OR = 0.67, 95% CI: 0.49–0.92, P = 0.013). In subgroup analyses, the association between aspirin use and pancreatic cancer was not significantly affected by pancreatic cancer stage, smoking status, or body mass index. Our data suggest that aspirin use, but not non-aspirin NSAID use, is associated with lowered risk of developing pancreatic cancer. Cancer Prev Res; 4(11); 1835–41. ©2011 AACR.

Abstract Purpose: Inherited variability in the prognosis of lung cancer patients treated with platinum-based chemotherapy has been widely investigated. However, the overall contribution of genetic variation to platinum response is not well established. To identify novel candidate single nucleotide polymorphisms (SNP)/genes, we carried out a genome-wide association study (GWAS) for cisplatin cytotoxicity by using lymphoblastoid cell lines (LCL), followed by an association study of selected SNPs from the GWAS with overall survival (OS) in lung cancer patients. Experimental Design: A GWAS for cisplatin was conducted with 283 ethnically diverse LCLs. A total of 168 top SNPs were genotyped in 222 small cell lung cancer (SCLC) and 961 non-SCLC (NSCLC) patients treated with platinum-based therapy. Association of the SNPs with OS was determined by using the Cox regression model. Selected candidate genes were functionally validated by siRNA knockdown in human lung cancer cells. Results: Among 157 successfully genotyped SNPs, 9 and 10 SNPs were top SNPs associated with OS for patients with NSCLC and SCLC, respectively, although they were not significant after adjusting for multiple testing. Fifteen genes, including 7 located within 200 kb up or downstream of the 4 top SNPs and 8 genes for which expression was correlated with 3 SNPs in LCLs were selected for siRNA screening. Knockdown of DAPK3 and METTL6, for which expression levels were correlated with the rs11169748 and rs2440915 SNPs, significantly decreased cisplatin sensitivity in lung cancer cells. Conclusions: This series of clinical and complementary laboratory-based functional studies identified several candidate genes/SNPs that might help predict treatment outcomes for platinum-based therapy of lung cancer. Clin Cancer Res; 17(17); 5801–11. ©2011 AACR.