Quantification of Hair Cortisol Concentration in Common Marmosets (\u3cem\u3eCallithrix jacchus\u3c/em\u3e) and Tufted Capuchins (\u3cem\u3eCebus apella\u3c/em\u3e)

Quantifying cortisol concentration in hair is a non-invasive biomarker of long-term hypothalamic-pituitary-adrenal (HPA) activation, and thus can provide important information on laboratory animal health. Marmosets (Callithrix jacchus) and capuchins (Cebus apella) are New World primates increasingly used in biomedical and neuroscience research, yet published hair cortisol concentrations for these species are limited. Review of the existing published hair cortisol values from marmosets reveals highly discrepant values and the use of variable techniques for hair collection, processing, and cortisol extraction. In this investigation we utilized a well-established, standardized protocol to extract and quantify cortisol from marmoset (n = 12) and capuchin (n = 4) hair. Shaved hair samples were collected from the upper thigh during scheduled exams and analyzed via methanol extraction and enzyme immunoassay. In marmosets, hair cortisol concentration ranged from 2710 – 6267 pg/mg and averaged 4070 ± 304 pg/mg. In capuchins, hair cortisol concentration ranged from 621 – 2089 pg/mg and averaged 1092 ± 338 pg/mg. Hair cortisol concentration was significantly different between marmosets and capuchins, with marmosets having higher concentrations than capuchins. The incorporation of hair cortisol analysis into research protocols provides a non-invasive measure of HPA axis activity over time, which offers insight into animal health. Utilization of standard protocols across laboratories is essential to obtaining valid measurements and allowing for valuable future cross-species comparisons

Effect of dietary omega-3 fatty acids on castrate-resistant prostate cancer and tumor-associated macrophages.

BackgroundM2-like macrophages are associated with the pathogenesis of castrate-resistant prostate cancer (CRPC). We sought to determine if dietary omega-3 fatty acids (ω-3 FAs) delay the development and progression of CRPC and inhibit tumor-associated M2-like macrophages.MethodsMycCap cells were grown subcutaneously in immunocompetent FVB mice. Mice were castrated when tumors reached 300 mm2. To study effects of dietary ω-3 FAs on development of CRPC, ω-3 or ω-6 diets were started 2 days after castration and mice sacrificed after early regrowth of tumors. To study ω-3 FA effects on progression of CRPC, tumors were allowed to regrow after castration before starting the diets. M2 (CD206+) macrophages were isolated from allografts to examine ω-3 FA effects on macrophage function. Omega-3 fatty acid effects on androgen-deprived RAW264.7 M2 macrophages were studied by RT-qPCR and a migration/ invasion assay.ResultsThe ω-3 diet combined with castration lead to greater MycCap tumor regression (tumor volume reduction: 182.2 ± 33.6 mm3) than the ω-6 diet (tumor volume reduction: 148.3 ± 35.2; p = 0.003) and significantly delayed the time to CRPC (p = 0.006). Likewise, the ω-3 diet significantly delayed progression of established castrate-resistant MycCaP tumors (p = 0.003). The ω-3 diet (as compared to the ω-6 diet) significantly reduced tumor-associated M2-like macrophage expression of CSF-1R in the CRPC development model, and matrix metallopeptidase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in the CRPC progression model. Migration of androgen-depleted RAW264.7 M2 macrophages towards MycCaP cells was reversed by addition of docosahexaenoic acid (ω-3).ConclusionsDietary omega-3 FAs (as compared to omega-6 FAs) decreased the development and progression of CRPC in an immunocompetent mouse model, and had inhibitory effects on M2-like macrophage function. Clinical trials are warranted evaluating if a fish oil-based diet can delay the time to castration resistance in men on androgen deprivation therapy, whereas further preclinical studies are warranted evaluating fish oil for more advanced CRPC

Intake of Lycopene and other Carotenoids and Incidence of Uterine Leiomyomata: A Prospective Ultrasound Study

BACKGROUND: Uterine leiomyomata (UL) are the leading indication for hysterectomy in the United States. Dietary supplementation with lycopene was associated with reduced size and incidence of oviduct leiomyoma in the Japanese quail. Two US prospective cohort studies of women reported little association between intake of lycopene, or other carotenoids, and UL incidence. However, these studies relied on self-reported physician-diagnosed UL, which is prone to misclassification. OBJECTIVE: This study examines the association between dietary intake of carotenoids and UL incidence. DESIGN: Data were derived from the Study of the Environment, Lifestyle, and Fibroids, a prospective cohort study. Women completed self-administered baseline questionnaires on demographic characteristics, reproductive history, and lifestyle, including a 110-item validated food frequency questionnaire, from which dietary intakes of carotenoids-including alpha carotene, beta carotene, cryptoxanthin, lutein-zeaxanthin, and lycopene-and vitamin A were estimated. PARTICIPANTS/SETTING: One thousand two hundred thirty Black women aged 23 to 35 years who did not have a previous diagnosis of UL, cancer, or autoimmune disease were eligible for enrollment (2010-2012). Participants were residents of the Detroit, MI, metropolitan area. MAIN OUTCOME MEASURES: Transvaginal ultrasound was used to assess UL at baseline and 20, 40, and 60 months of follow-up. STATISTICAL ANALYSES PERFORMED: Cox regression was used to estimate hazard ratios and 95% CIs, adjusted for energy intake, age at menarche, education, body mass index, parity, age at first birth, years since last birth, current use of oral contraceptives or progestin-only injectables, alcohol intake, and cigarette smoking. RESULTS: Among 1,230 women without prevalent UL at baseline, 301 incident UL cases during follow-up were identified. Intakes of lycopene, other carotenoids, and vitamin A were not appreciably associated with UL incidence. Hazard ratios comparing quartiles 2 (2,376 to 3,397 μg/day), 3 (3,398 to 4,817 μg/day), and 4 (≥4,818 μg/day) with quartile 1 (\u3c2,376 μg/day) of lycopene intake were 1.03 (95% CI 0.72 to 1.47), 1.22 (95% CI 0.86 to 1.72), and 0.95 (95% CI 0.67 to 1.36), respectively. CONCLUSIONS: Study findings do not support the hypothesis that greater carotenoid intake is associated with reduced UL incidence

Acute hepatitis A virus infection is associated with a limited type I interferon response and persistence of intrahepatic viral RNA

Hepatitis A virus (HAV) is an hepatotropic human picornavirus that is associated only with acute infection. Its pathogenesis is not well understood because there are few studies in animal models using modern methodologies. We characterized HAV infections in three chimpanzees, quantifying viral RNA by quantitative RT-PCR and examining critical aspects of the innate immune response including intrahepatic IFN-stimulated gene expression. We compared these infection profiles with similar studies of chimpanzees infected with hepatitis C virus (HCV), an hepatotropic flavivirus that frequently causes persistent infection. Surprisingly, HAV-infected animals exhibited very limited induction of type I IFN-stimulated genes in the liver compared with chimpanzees with acute resolving HCV infection, despite similar levels of viremia and 100-fold greater quantities of viral RNA in the liver. Minimal IFN-stimulated gene 15 and IFIT1 responses peaked 1–2 wk after HAV challenge and then subsided despite continuing high hepatic viral RNA. An acute inflammatory response at 3–4 wk correlated with the appearance of virus-specific antibodies and apoptosis and proliferation of hepatocytes. Despite this, HAV RNA persisted in the liver for months, remaining present long after clearance from serum and feces and revealing dramatic differences in the kinetics of clearance in the three compartments. Viral RNA was detected in the liver for significantly longer (35 to >48 wk) than HCV RNA in animals with acute resolving HCV infection (10–20 wk). Collectively, these findings indicate that HAV is far stealthier than HCV early in the course of acute resolving infection. HAV infections represent a distinctly different paradigm in virus–host interactions within the liver

Use of aspirin, other nonsteroidal anti-inflammatory drugs and acetaminophen and risk of endometrial cancer : the Epidemiology of Endometrial Cancer Consortium

Background: Regular use of aspirin has been associated with a reduced risk of cancer at several sites but the data for endometrial cancer are conflicting. Evidence regarding use of other analgesics is limited. Patients and methods: We pooled individual-level data from seven cohort and five case-control studies participating in the Epidemiology of Endometrial Cancer Consortium including 7120 women with endometrial cancer and 16 069 controls. For overall analyses, study-specific odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression and combined using random-effects meta-analysis; for stratified analyses, we used mixed-effects logistic regression with study as a random effect. Results: At least weekly use of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an approximately 15% reduced risk of endometrial cancer among both overweight and obese women (OR 1/4 0.86 [95% CI 0.760.98] and 0.86 [95% CI 0.76-0.97], respectively, for aspirin; 0.87 [95% CI 0.76-1.00] and 0.84 [0.74-0.96], respectively, for nonaspirin NSAIDs). There was no association among women of normal weight (body mass index<25 kg/ m2, Pheterogeneity 0.04 for aspirin, Pheterogeneity 1/4 0.003 for NSAIDs). Among overweight and obese women, the inverse association with aspirin was stronger for use 2-6 times/ week (OR 1/4 0.81, 95% CI 0.68-0.96) than for daily use (0.91, 0.80-1.03), possibly because a high proportion of daily users use low-dose formulations. There was no clear association with use of acetaminophen. Conclusion: Our pooled analysis provides further evidence that use of standard-dose aspirin or other NSAIDs may reduce risk of endometrial cancer among overweight and obese women.Peer reviewe

Topical Polyethylene Glycol as a Novel Chemopreventive Agent for Oral Cancer via Targeting of Epidermal Growth Factor Response

Head and neck squamous cell carcinoma (HNSCC) is a major cause of morbidity and mortality underscoring the need for safe and effective chemopreventive strategies. Targeting epidermal growth factor receptor (EGFR) is attractive in that it is an early critical event in HNSCC pathogenesis. However, current agents lack efficacy or have unacceptable toxicity. Several groups have demonstrated that the over-the-counter medication, polyethylene glycol (PEG) has remarkable chemopreventive efficacy against colon carcinogenesis. Importantly, we reported that this effect is mediated through EGFR internalization/degradation. In the current study, we investigated the chemopreventive efficacy of this agent against HNSCC, using both the well validated animal model 4-NQO (4-nitroquinoline 1-oxide) rat model and cell culture with the human HNSCC cell line SCC-25. We demonstrated that daily topical application of 10% PEG-8000 in the oral cavity (tongue and cavity wall) post 4NQO initiation resulted in a significant reduction in tumor burden (both, tumor size and tumors/tumor bearing rat) without any evidence of toxicity. Immunohistochemical studies depicted decreased proliferation (number of Ki67-positive cells) and reduced expression of EGFR and its downstream effectors cyclin D1 in the tongue mucosa of 4NQO-rats treated with PEG. We showed that EGFR was also markedly downregulated in SCC-25 cells by PEG-8000 with a concomitant induction of G1-S phase cell-cycle arrest, which was potentially mediated through upregulated p21cip1/waf1. In conclusion, we demonstrate, for the first time, that PEG has promising efficacy and safety as a chemopreventive efficacy against oral carcinogenesis

Analgesic Use and Ovarian Cancer Risk: An Analysis in the Ovarian Cancer Cohort Consortium.

BACKGROUND:Aspirin use is associated with reduced risk of several cancers. A pooled analysis of 12 case-control studies showed a 10% decrease in ovarian cancer risk with regular aspirin use, which was stronger for daily and low-dose users. To prospectively investigate associations of analgesic use with ovarian cancer, we analyzed data from 13 studies in the Ovarian Cancer Cohort Consortium (OC3). METHODS:The current study included 758 829 women who at study enrollment self-reported analgesic use, among whom 3514 developed ovarian cancer. Using Cox regression, we assessed associations between frequent medication use and risk of ovarian cancer. Dose and duration were also evaluated. All statistical tests were two-sided. RESULTS:Women who used aspirin almost daily (≥6 days/wk) vs infrequent/nonuse experienced a 10% reduction in ovarian cancer risk (rate ratio [RR] = 0.90, 95% confidence interval [CI] = 0.82 to 1.00, P = .05). Frequent use (≥4 days/wk) of aspirin (RR = 0.95, 95% CI = 0.88 to 1.03), nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs; RR = 1.00, 95% CI = 0.90 to 1.11), or acetaminophen (RR = 1.05, 95% CI = 0.88 to 1.24) was not associated with risk. Daily acetaminophen use (RR = 1.28, 95% CI = 1.00 to 1.65, P = .05) was associated with elevated ovarian cancer risk. Risk estimates for frequent, long-term (10+ years) use of aspirin (RR = 1.15, 95% CI = 0.98 to 1.34) or nonaspirin NSAIDs (RR = 1.19, 95% CI = 0.84 to 1.68) were modestly elevated, although not statistically significantly so. CONCLUSIONS:This large, prospective analysis suggests that women who use aspirin daily have a slightly lower risk of developing ovarian cancer (∼10% lower than infrequent/nonuse)-similar to the risk reduction observed in case-control analyses. The observed potential elevated risks for 10+ years of frequent aspirin and NSAID use require further study but could be due to confounding by medical indications for use or variation in drug dosing

Chronic Obstructive Pulmonary Disease and Lung Cancer: Underlying Pathophysiology and New Therapeutic Modalities

Chronic obstructive pulmonary disease (COPD) and lung cancer are major lung diseases affecting millions worldwide. Both diseases have links to cigarette smoking and exert a considerable societal burden. People suffering from COPD are at higher risk of developing lung cancer than those without, and are more susceptible to poor outcomes after diagnosis and treatment. Lung cancer and COPD are closely associated, possibly sharing common traits such as an underlying genetic predisposition, epithelial and endothelial cell plasticity, dysfunctional inflammatory mechanisms including the deposition of excessive extracellular matrix, angiogenesis, susceptibility to DNA damage and cellular mutagenesis. In fact, COPD could be the driving factor for lung cancer, providing a conducive environment that propagates its evolution. In the early stages of smoking, body defences provide a combative immune/oxidative response and DNA repair mechanisms are likely to subdue these changes to a certain extent; however, in patients with COPD with lung cancer the consequences could be devastating, potentially contributing to slower postoperative recovery after lung resection and increased resistance to radiotherapy and chemotherapy. Vital to the development of new-targeted therapies is an in-depth understanding of various molecular mechanisms that are associated with both pathologies. In this comprehensive review, we provide a detailed overview of possible underlying factors that link COPD and lung cancer, and current therapeutic advances from both human and preclinical animal models that can effectively mitigate this unholy relationship