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Nelson H.H.,Masonic Cancer Center | Nelson H.H.,University of Minnesota | Birnbaum A.E.,Brown University | McClean M.D.,Boston University | Kelsey K.T.,Brown University
Cancer Epidemiology Biomarkers and Prevention | Year: 2013

Background: Gastric reflux can reach into the upper airway, inducing cellular damage in the epithelial lining. This condition is believed to be a risk factor for development of laryngopharyngeal squamous cell carcinoma (LPSCC), although the literature is conflicting. Methods: To better clarify this relationship, we assessed the association of self-reported heartburn history and medication use among 631 patients with LPSCCs and 1234 control subjects (frequency-matched on age, gender, and town of residence) enrolled as part of a population-based case-control study of head and neck squamous cell carcinoma in the greater Boston area. Results: After adjusting for age, gender, race, smoking, alcohol consumption, HPV16 seropositivity, education, and body mass index, subjects reporting a history of frequent heartburn and who were neither a heavy smoker nor heavy drinker had a significantly elevated risk of LPSCCs [OR, 1.78; 95% confidence interval (CI), 1.00-3.16]. Among those with a history of heartburn, there was an inverse association between antacid use and LPSCCs relative to those never taking heartburn medication (OR, 0.59; 95% CI, 0.38-0.93) that remained consistent when analyzed by smoking/drinking status, HPV16 status, or by primary tumor site. Conclusions: Our data show that gastric reflux is an independent risk factor for squamous cancers of the pharynx and larynx. Further studies are needed to clarify the possible chemopreventive role of antacid use for patients with gastric reflux. Impact: Elucidation of additional risk factors for head and neck cancer can allow for risk stratification and inform surveillance of high-risk patients. © 2013 American Association for Cancer Research.

Elliott S.P.,Urologic | Elliott S.P.,Masonic Cancer Center | Wilt T.J.,University of Minnesota | Wilt T.J.,Center for Chronic Disease Outcomes Research | Virnig B.A.,Masonic Cancer Center
Journal of the National Cancer Institute | Year: 2010

Background:Use of androgen suppression therapy (AST) in prostate cancer increased more than threefold from 1991 to 1999. The 2003 Medicare Modernization Act reduced reimbursements for AST by 64% between 2004 and 2005, but the effect of this large reduction on use of AST is unknown. Methods A cohort of 72818 men diagnosed with prostate cancer in 1992-2005 was identified from the Surveillance, Epidemiology, and End Results database. From Medicare claims data, indicated AST was defined as 3 months or more of AST in the first year in men with metastatic disease (n = 8030). Non-indicated AST was defined as AST given without other therapies such as radical prostatectomy or radiation in men with low-risk disease (n = 64788). The unadjusted annual proportion of men receiving AST was plotted against the median Medicare AST reimbursement. A multivariable model was used to estimate the odds of AST use in men with low-risk and metastatic disease, with the predictor of interest being the calendar year of the payment change. Covariates in the model included age in 5-year categories, clinical tumor stage (T1-T4), World Health Organization grade (1-3, unknown), Charlson comorbidity (0, 1, 2, ≥3), race, education, income, and tumor registry site, all as categorical variables. The models included variations in the definition of AST use (≥1, ≥3, and ≥6 months of AST). All statistical tests were two-sided. Results AST use in the low-risk group peaked at 10.2% in 2003, then declined to 7.1% in 2004 and 6.1% in 2005. After adjusting for tumor and demographic covariates, the odds of receiving non-indicated primary AST decreased statistically significantly in 2004 (odds ratio [OR] = 0.70, 95% confidence interval = 0.61 to 0.80) and 2005 (OR = 0.61, 95% confidence interval = 0.53 to 0.71) compared with 2003. AST use in the metastatic disease group was stable at 60% during the payment change, and the adjusted odds ratio of receiving AST in this group was unchanged in 2004-2005. Conclusion sIn this example of hormone therapy for prostate cancer, decreased physician reimbursement was associated with a reduction in overtreatment without a reduction in needed services. © 2010 The Author.

Li Y.,Masonic Cancer Center | Chan S.C.,Masonic Cancer Center | Brand L.J.,Graduate Program in Microbiology | Brand L.J.,Masonic Cancer Center | And 5 more authors.
Cancer Research | Year: 2013

Persistent androgen receptor (AR) transcriptional activity underlies resistance to AR-targeted therapy and progression to lethal castration-resistant prostate cancer (CRPC). Recent success in retargeting persistent AR activity with next generation androgen/AR axis inhibitors such as enzalutamide (MDV3100) has validated AR as a master regulator during all stages of disease progression. However, resistance to next generation AR inhibitors limits therapeutic efficacy for many patients. One emerging mechanism of CRPC progression is AR gene rearrangement, promoting synthesis of constitutively active truncated AR splice variants (AR-V) that lack the AR ligand-binding domain. In this study, we show that cells with AR gene rearrangements expressing both full-length and AR-Vs are androgen independent and enzalutamide resistant. However, selective knock-down of AR-V expression inhibited androgen-independent growth and restored responsiveness to androgens and antiandrogens. In heterogeneous cell populations, AR gene rearrangements marked individual AR-V-dependent cells that were resistant to enzalutamide. Gene expression profiling following knock-down of full-length AR or AR-Vs showed that AR-Vs drive resistance to AR-targeted therapy by functioning as constitutive and independent effectors of the androgen/AR transcriptional program. Further, mitotic genes deemed previously to be unique ARV targets were found to be biphasic targets associated with a proliferative level of signaling output from either ARVs or androgen-stimulated AR. Overall, these studies highlight AR-Vs as key mediators of persistent AR signaling and resistance to the current arsenal of conventional and next generation AR-directed therapies, advancing the concept of AR-Vs as therapeutic targets in advanced disease. © 2012 AACR.

Peterson L.A.,Masonic Cancer Center
Journal of Nucleic Acids | Year: 2010

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N′ -nitrosonornicotine (NNN) are tobacco-specific nitrosamines present in tobacco products and smoke. Both compounds are carcinogenic in laboratory animals, generating tumors at sites comparable to those observed in smokers. These Group 1 human carcinogens are metabolized to reactive intermediates that alkylate DNA. This paper focuses on the DNA pyridyloxobutylation pathway which is common to both compounds. This DNA route generates 7-[4-(3-pyridyl)-4-oxobut-1-yl]- 2′ -deoxyguanosine, O2-[4-(3-pyridyl)-4-oxobut-1-yl]- 2′ -deoxycytosine, O2-[4-(3-pyridyl)-4-oxobut-1-yl]- 2′ -deoxythymidine, and O6-[4-(3-pyridyl)-4-oxobut-1-yl]- 2′ -deoxyguanosine as well as unstable adducts which dealkylate to release 4-hydroxy-1- {3-pyridyl) -1-butanone or depyriminidate/depurinate to generate abasic sites. There are multiple repair pathways responsible for protecting against the genotoxic effects of these adducts, including adduct reversal as well as base and nucleotide excision repair pathways. Data indicate that several DNA adducts contribute to the overall mutagenic properties of pyridyloxobutylating agents. Which adducts contribute to the carcinogenic properties of this pathway are likely to depend on the biochemistry of the target tissue. © 2010 Lisa A. Peterson.

Roger E.,University of Minnesota | Kalscheuer S.,University of Minnesota | Kirtane A.,University of Minnesota | Guru B.R.,University of Minnesota | And 4 more authors.
Molecular Pharmaceutics | Year: 2012

The oral absorption of drugs that have poor bioavailability can be enhanced by encapsulation in polymeric nanoparticles. Transcellular transport of nanoparticle-encapsulated drug, possibly through transcytosis, is likely the major mechanism through which nanoparticles improve drug absorption. We hypothesized that the cellular uptake and transport of nanoparticles can be further increased by targeting the folate receptors expressed on the intestinal epithelial cells. The objective of this research was to study the effect of folic acid functionalization on transcellular transport of nanoparticle- encapsulated paclitaxel, a chemotherapeutic with poor oral bioavailability. Surface-functionalized poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles loaded with paclitaxel were prepared by the interfacial activity assisted surface functionalization technique. Transport of paclitaxel-loaded nanoparticles was investigated using Caco-2 cell monolayers as an in vitro model. Caco-2 cells were found to express folate receptor and the drug efflux protein, p-glycoprotein, to high levels. Encapsulation of paclitaxel in PLGA nanoparticles resulted in a 5-fold increase in apparent permeability (P app) across Caco-2 cells. Functionalization of nanoparticles with folic acid further increased the transport (8-fold higher transport compared to free paclitaxel). Confocal microscopic studies showed that folic acid functionalized nanoparticles were internalized by the cells and that nanoparticles did not have any gross effects on tight junction integrity. In conclusion, our studies indicate that folic acid functionalized nanoparticles have the potential to enhance the oral absorption of drugs with poor oral bioavailability. © 2012 American Chemical Society.

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