[Show abstract][Hide abstract] ABSTRACT: Dietary lipids have been shown to increase bioavailability of provitamin A carotenoids from a single meal, but the effects of dietary lipids on conversion to vitamin A during absorption are essentially unknown. Based on previous animal studies, we hypothesized that the consumption of provitamin A carotenoids with dietary lipid would enhance conversion to vitamin A during absorption compared with the consumption of provitamin A carotenoids alone. Two separate sets of 12 healthy men and women were recruited for 2 randomized, 2-way crossover studies. One meal was served with fresh avocado (Persea americana Mill), cultivated variety Hass (delivering 23 g of lipid), and a second meal was served without avocado. In study 1, the source of provitamin A carotenoids was a tomato sauce made from a novel, high-β-carotene variety of tomatoes (delivering 33.7 mg of β-carotene). In study 2, the source of provitamin A carotenoids was raw carrots (delivering 27.3 mg of β-carotene and 18.7 mg of α-carotene). Postprandial blood samples were taken over 12 h, and provitamin A carotenoids and vitamin A were quantified in triglyceride-rich lipoprotein fractions to determine baseline-corrected area under the concentration-vs.-time curve. Consumption of lipid-rich avocado enhanced the absorption of β-carotene from study 1 by 2.4-fold (P < 0.0001). In study 2, the absorption of β-carotene and α-carotene increased by 6.6- and 4.8-fold, respectively (P < 0.0001 for both). Most notably, consumption of avocado enhanced the efficiency of conversion to vitamin A (as measured by retinyl esters) by 4.6-fold in study 1 (P < 0.0001) and 12.6-fold in study 2 (P = 0.0013). These observations highlight the importance of provitamin A carotenoid consumption with a lipid-rich food such as avocado for maximum absorption and conversion to vitamin A, especially in populations in which vitamin A deficiency is prevalent. This trial was registered at clinicaltrials.gov as NCT01432210.
[Show abstract][Hide abstract] ABSTRACT: Limited data are available on the association between colorectal cancer (CRC) worry and CRC screening uptake, particularly in rural and underserved populations where there is an excess burden of CRC.
Journal of public health (Oxford, England). 05/2014;
[Show abstract][Hide abstract] ABSTRACT: Background and Purpose
Individuals with Huntington's disease (HD) experience balance and gait problems that lead to falls. Clinicians currently have very little information about the reliability and validity of outcome measures to determine the efficacy of interventions that aim to reduce balance and gait impairments in HD. This study examined the reliability and concurrent validity of spatiotemporal gait measures, the Tinetti Mobility Test (TMT), Four Square Step Test (FSST), and Activities-Specific Balance Confidence (ABC) Scale in individuals with HD.
Participants with HD [n = 20; mean age± SD =50.9 ± 13.7; 7 male] were tested on spatiotemporal gait measures and the TMT, FSST, and ABC Scale before and after a six week period to determine test-retest reliability and minimal detectable change (MDC) values. Linear relationships between gait and clinical measures were estimated using Pearson's correlation coefficients.
Spatiotemporal gait measures, the TMT total and the FSST showed good to excellent test-retest reliability (ICC > 0.75). MDC values were 0.30 m/s and 0.17 m/s for velocity in forward and backward walking respectively, four points for the TMT, and three seconds for the FSST. The TMT and FSST were highly correlated with most spatiotemporal measures. The ABC Scale demonstrated lower reliability and less concurrent validity than other measures.
The high test-retest reliability over a six week period and concurrent validity between the TMT, FSST, and spatiotemporal gait measures suggests that the TMT and FSST may be useful outcome measures for future intervention studies in ambulatory individuals with HD.
[Show abstract][Hide abstract] ABSTRACT: Patient navigation (PN) is a system-level strategy to decrease cancer mortality rates by reducing barriers to cancer care. Barriers to resolution among participants in the PN intervention arm with a breast or cervical abnormality in the Patient Navigation Research Program and navigators' actions to address those barriers were examined.
Data from seven institutions (2005-2010) included 1,995 breast and 1,194 cervical patients. A stratified Cox proportional hazards regression model was used to examine the effects of barriers on time to resolution of an abnormal screening test or clinical finding.
The range of unique barriers was 0 to 12 and 0 to 7 among participants with breast and cervical abnormalities, respectively. About two thirds of breast and one half of cervical participants had at least one barrier resulting in longer time to diagnostic resolution among breast (adjusted hazard ratio [HR], 0.744; p < .001) and cervical (adjusted HR, 0.792; p < .001) participants. Patient- and system-level barriers were most common. Frequent navigator actions were making arrangements, scheduling appointments, referrals, and education.
Having a barrier resulted in a delay in diagnostic resolution of an abnormal screening test or clinical finding. Health care systems can use these findings to improve existing PN programs or when developing new programs.
Women s Health Issues 01/2014; 24(1):e155-e162. · 1.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: XPO1/CRM1 is a key nuclear exporter protein that mediates translocation of numerous cellular regulatory proteins. We investigated whether XPO1 is a potential therapeutic target in melanoma using novel selective inhibitors of nuclear export (SINE). In vitro effects of SINE on cell growth and apoptosis were measured by MTS assay and flow cytometry [Annexin V/propidium iodide (PI)], respectively in human metastatic melanoma cell lines. Immunoblot analysis was used to measure nuclear localization of key cellular proteins. The in vivo activity of oral SINE was evaluated in NOD/SCID mice bearing A375 or CHL-1 human melanoma xenografts. SINE compounds induced cytostatic and pro-apoptotic effects in both BRAF wild type and mutant (V600E) cell lines at nanomolar concentrations. The cytostatic and pro-apoptotic effects of XPO1 inhibition were associated with nuclear accumulation of TP53, and CDKN1A induction in the A375 cell line with wild type TP53, while pMAPK accumulated in the nucleus regardless of TP53 status. The orally bioavailable KPT-276 and KPT-330 compounds significantly inhibited growth of A375 (p<0.0001) and CHL-1 (p = 0.0087) human melanoma cell lines in vivo at well tolerated doses. Inhibition of XPO1 using SINE represents a potential therapeutic approach for melanoma across cells with diverse molecular phenotypes by promoting growth inhibition and apoptosis.
PLoS ONE 01/2014; 9(7):e102983. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: While tamoxifen activity is mainly due to endoxifen and the concentration of this active metabolite is, in part, controlled by CYP2D6 metabolic status, clinical correlative studies have produced mixed results.
In an exploratory study, we determined the CYP2D6 metabolic status and plasma concentrations of endoxifen among 224 Filipino and Vietnamese women participating in a clinical trial of adjuvant hormonal therapy for operable breast cancer. We further conducted a nested-case-control study among 48 women (half with recurrent disease, half without) investigating the relationship of endoxifen concentrations and recurrence of disease. We found a significant association of reduced endoxifen plasma concentrations with functionally important CYP2D6 genotypes. High endoxifen concentrations were associated with higher risk of recurrence; with a quadratic trend fitted to a stratified Cox proportional hazards regression model, the likelihood ratio p-value was 0.002. The trend also showed that in 8 out of 9 pairs with low endoxifen concentrations, the recurrent case had lower endoxifen levels than the matched control.
This exploratory analysis suggests that there is an optimal range for endoxifen concentrations to achieve favorable effects as adjuvant therapy. In particular, at higher concentrations (>70 ng.ml), endoxifen may promote recurrence.
[Show abstract][Hide abstract] ABSTRACT: We determined the validity of self-reported colorectal cancer (CRC) screening data provided by Appalachian Ohio residents and identified correlates of providing accurate data.
We conducted cross-sectional telephone interviews between September 2009 and April 2010. Our study included Appalachian Ohio residents (n = 721) ages 51-75 years.
We compared self-reported CRC screening data to medical records to determine validity. Multivariable logistic regression was used to identify correlates of providing accurate self-reported screening data.
About 68% of participants self-reported having any CRC screening test within recommended guidelines, whereas medical records indicated that only 49% were within guidelines (concordance = 0.76). Concordance was higher for flexible sigmoidoscopy and fecal occult blood test compared with colonoscopy, although sensitivity and positive predictive value were much higher for colonoscopy. Participants overreported CRC screening behaviors for all tests. Participants who had a regular checkup in the last 2 years (OR = 2.78, 95% CI: 1.15-6.73), or who self-rated their health as good or better (OR = 1.88, 95% CI: 1.12-3.16) were more likely to provide accurate screening data.
Many participants failed to provide accurate CRC screening data, and validity varied greatly across individual CRC screening tests. Future CRC screening studies among Appalachian residents should use medical records, if possible, to determine screening histories.
Public Health Nursing 07/2013; 30(4):312-22. · 0.78 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:To investigate the feasibility, acceptability, and safety of a supervised video game exercise program administered via Dance Dance Revolution in individuals with Huntington's disease.Design:A cross-over, controlled, single-blinded, six-week trial.Setting:Home-based.Participants:Eighteen ambulatory individuals with Huntington's disease (seven male, mean age 50.7 SD 14.7).Interventions:Participants played the Dance Dance Revolution game with supervision and the handheld game without supervision for 45 minutes, two days per week for six weeks.Outcome measures:Game play performance and adherence, participant perceptions of the game, safety (vital signs, adverse health changes), spatiotemporal gait measures, Four-Square Step Test, Tinetti Mobility Test, Activities-Specific Balance Confidence Scale, and World Health Organization Quality of Life - Bref, before and after each intervention.Results:Most participants improved on game play, enjoyed playing the game, and wanted to continue playing after study completion. After playing Dance Dance Revolution, participants showed significant reductions in double support percentage (adjusted mean difference (95% confidence intervals): -2.54% (-4.75, -0.34) for forward walking and -4.18 (-6.89, -0.48) for backward walking) and those with less severe motor symptoms had reductions in heel-to-heel base of support during forward walking. The remaining measures were not significantly impacted by the intervention.Conclusion:Dance Dance Revolution appears to be a feasible, motivating, and safe exercise intervention for individuals with Huntington's disease.
[Show abstract][Hide abstract] ABSTRACT: Introduction
A sufficient dietary supply of vitamin A is a prerequisite for human health, ensuring a functional immune system as well as normal growth and development. Furthermore, vitamin A deficiency leads to severe ocular changes (xerophthalmia), which ultimately result in blindness. To date, a high prevalence of vitamin A deficiency is observed among children and pregnant women, especially in many developing countries. Preformed vitamin A is only found in animal products like eggs and dairy1. However, these foods are often expensive or simply unavailable to poorer populations, thus highlighting the dietary importance of fruits and vegetables rich in provitamin A carotenoids (i.e. mainly β-carotene, β-cryptoxanthin, α-carotene). Although humans can convert these carotenoids to vitamin A2, 3, their absorption and conversion is generally found to be low from plant foods. In fact, the US Institute of Medicine1 estimates that 12 µg of dietary β-carotene from fruits & vegetables is only equivalent to 1 µg of retinol activity equivalents (RAE, a measure of vitamin A).
This estimation of RAEs is based on the poor bioavailability of β-carotene from raw dark green vegetables and raw carrots1. Carrots contain large crystalline aggregates of β-carotene within their chromoplasts, and its low bioavailability is associated with the poor dissolution rate of these crystals during digestion. Poor dissolution results in an inefficient micellization in the duodenum, which is a prerequisite for the efficient absorption of carotenoids4-6. Although the plant matrix represents an important modifier for estimating RAEs1, direct comparisons of carotenoid bioavailability between carotenoid-rich fruits and vegetables are limited.
In this presentation, we discuss an often overlooked storage form of carotenoids - their liquid-crystalline deposition in nano-scale tubular elements, which we recently reported in the chromoplasts of papaya and mango5,7. In papaya, we also observed solid-crystalline lycopene crystals of a significantly smaller size than those found in tomato, suggesting that lycopene may be more bioavailable from papaya than tomato. We sought to investigate the impact of chromoplast morphology on carotenoid bioavailability. Therefore, we compared carotenoid liberation and absorption from papaya, mango, tomato, and carrots by in vitro studies and an in vivo human trial.
Besides the genuine plant matrix, further factors like heat treatment or addition of lipid have been previously demonstrated to enhance carotenoid bioavailability8,9. Thus, we also examined whether the observed differences in chromoplast morphology on bioavailability of β-carotene may be overcome by incorporating lipid into the diet or by commercial heat treatment. The poorly-bioavailable, large solid-crystalline accumulations of β-carotene found in carrot are also observed in a novel β-carotene-rich tomato variety. For these studies in healthy humans, the carrots were fed raw, while the high β-carotene tomatoes were commercially processed into tomato sauce. In order to investigate the effects of dietary lipid, carotenoid absorption with and without fresh avocado fruit was compared.
The studies presented herein compare three different strategies for efficiently providing dietary provitamin A, by the selection of adequate sources with naturally highly bioavailable carotenoids, by co-consumption with dietary lipid, and by commercial processing.
Methods & Results - in vitro digestion to determine bioaccessibility of carotenoids from various plant matrices
After discovering the liquid-crystalline deposition form of β-carotene and β-cryptoxanthin in tubular elements of papaya and mango fruit chromoplasts, carotenoid bioaccessibility was hypothesized to be superior from these fruits as compared to carrot and tomato, which contain large solid-crystalline β-carotene aggregates5,7. First, in vitro digestion experiments of raw carrot, tomato, papaya, and mango were carried out as described elsewhere4. β-carotene bioaccessibility from papaya and mango was significantly higher than from carrot and tomato (5.3% and 10.1% versus 0.5% and 3.1% of the dose fed, respectively). Lycopene liberation from the food matrix to the duodenal fluids was significantly enhanced from papaya when compared to tomatoes (2.4% and 0.4% of the dose fed, respectively). These results support the hypothesis that differences in chromoplast morphology may result in differences in carotenoid liberation and micellization. These significant differences in bioaccessibility provided strong preliminary evidence to support further investigation of bioavailability in human clinical trials.
Methods & Results - in vivo bioavailability of carotenoids from different plant matrices and the effect of dietary lipid and commercial processing
In study 1, a three-way randomized cross-over clinical trial was designed, and 16 healthy adult participants (21-44 years) were recruited. After dose-matching the respective carotenoids from fresh papaya, tomato, and carrot (13.0 mg lycopene and ~1.6 mg β-carotene), the test foods were fed with a breakfast meal containing 10 g of dietary lipid from a yoghurt enriched with soy oil. The triglyceride-rich lipoprotein fractions (TRLs) of blood plasma were analysed by HPLC-PDA-MS/MS over 9.5 h after test meal consumption to determine the baseline-corrected area under the concentration-versus-time curve (AUC) of the carotenoids as a measure of bioavailability.
Lycopene from papaya was shown to be 2.6 times more bioavailable in humans as compared to lycopene from tomato (P<0.001), confirming the trends observed in the in vitro experiments. Likewise, bioavailability of β-carotene from papaya was approximately 3.0 times higher than from both carrot and tomato (P<0.001). Differences in β-carotene absorption from carrot and tomato were insignificant (P>0.863). Additionally, papaya contained the provitamin A carotenoid β-cryptoxanthin, which was found to be 2.9 and 2.3-fold more bioavailable than β-carotene and lycopene from papaya, respectively (P<0.001). Furthermore, a 2.0-fold and 2.6-fold higher AUC of retinyl esters (i.e. vitamin A) was observed in the TRLs after the consumption of the papaya test meal as compared to the tomato and carrot test meals (P<0.001), respectively.
In the second human clinical study, the effects of lipid on the absorption of solid-crystalline β-carotene from raw carrots was explored. 12 healthy men and women were recruited for a randomized crossover study feeding raw carrots (27 mg β-carotene, 19 mg α-carotene). The carrots were fed with fresh avocado (delivering 23 g lipid) and without avocado (without lipid). Post-prandial blood samples were taken over 12 hours, and provitamin A carotenoids and vitamin A (as retinyl esters) were quantitated in TRLs to determine the AUC. Although study 2 fed a significantly higher dose of β-carotene from carrots (27 mg β-carotene), carotenoid absorption without avocado lipid was extremely poor, analogous to the results observed in study 1 where only 1.6 mg of β-carotene were fed from raw carrots. However, the addition of avocado lipid to the meal led to a striking 6.6-fold increase in the absorption of β-carotene from carrots (P<0.001). Furthermore, a 12.6-fold increase in retinyl esters appeared in the TRLs when carrots were co-consumed with avocado (P<0.001).
The third human clinical study was identical to study 2, except for the source of β-carotene which was a unique variety of tomatoes commercially processed into tomato sauce (delivering 34 mg of β-carotene per serving). We hypothesized that tomato processing would disrupt the cell structure including chromoplastidal carotenoid crystals. Dissolution of carotenoids in concomitant plant lipids should be enhanced by thermal treatment, thus providing a more bioavailable form of β-carotene, as has been demonstrated for lycopene in processed tomatoes10. Absorption of the β-carotene from the sauce meal alone was quite high, relative to the absorption of the β-carotene from raw carrots alone in study 2. In addition, consuming the tomato sauce with avocado lipid led to a 2.4 fold increase in AUC β-carotene. Likewise, a 4.6 fold increase in the AUC of retinyl esters was observed when the sauce was co-consumed with avocado as compared to no avocado. These results indicate that processing alone may have a significant impact on β-carotene bioavailability from this unique tomato variety, and meal lipid may further enhance provitamin A bioavailability and bioconversion from this product.
Discussion and conclusions – Which factors enhanced carotenoid bioavailability?
In this presentation, we hypothesize that the exceptional morphology of papaya chromoplasts is the crucial factor for the high carotenoid bioavailability observed in the in vitro studies and in the first human clinical study. Papaya was previously shown to contain β-carotene in a liquid-crystalline form, while β-carotene in carrots and tomatoes occurs in a solid-crystalline form. In contrast to physically different forms of β-carotene, lycopene in both papaya and tomato fruits was found to be deposited in a solid-crystalline form, although the crystals were significantly smaller in papaya7. Since the dissolution of carotenoids in dietary lipid is considered a prerequisite for efficient carotenoid absorption13,14, liquid-crystalline β-carotene and small-sized lycopene crystals from papaya might dissolve more readily and, hence, provide a more bioavailable form as compared to the large, solid-crystalline carotenoid crystals from tomato and carrot. Besides significantly increased absorption of lycopene and β-carotene from papaya, this hypothesis also accounts for the insignificant differences of β-carotene absorption from tomato and carrot. Irrespective of the factor ultimately responsible for our observations, papaya fruits represent an excellent dietary source for highly bioavailable lycopene, β-carotene, and β-cryptoxanthin, generating significant amounts of vitamin A post-prandially.
However, other factors may have also influenced carotenoid bioavailability from study 1. The firmer texture of the carrot test meal as compared to the softer papaya tissue might have impaired the mechanical breakdown of the carrot samples during mastication and digestion, possibly decreasing carotenoid bioavailability. However, carotenoid bioavailability from papaya and tomatoes was also significantly different, although the texture of both test foods was similar. Therefore, factors other than food texture must have caused the high bioavailability of papaya carotenoids. Dietary fibres, such as pectin, have also been demonstrated to affect carotenoid bioavailability11, 12. The estimated total amount of dietary fibre in the test meal was 6.8-8.6 g (papaya), 3.1-4.8 g (tomato), and 0.7-1.0 g (carrot). Although the papaya test meal contained substantially more dietary fibre, carotenoids were more bioavailable from papaya than from tomato and carrot. Thus, other factors which enhanced carotenoid bioavailability from papaya must have surpassed any negative impact caused by concomitant higher levels of dietary fibre.
In summary, differences in the deposition forms of carotenoids in papaya, carrot, and tomato chromoplasts most comprehensively explain the findings of our in vitro studies and human clinical study 1. The co-consumption of dietary lipid was previously shown to enhance the absorption of carotenoids, particularly when ingesting sources with disadvantageous solid-crystalline deposition forms of β-carotene (e.g. carrots and tomatoes). In studies 2 and 3, co-consumption of dietary lipid was shown to partially overcome this disadvantage, leading to the absorption of substantial amounts of β-carotene and resulting in an efficient post-prandial conversion to vitamin A. As expected, the absorption of a high dose of β-carotene from raw carrots was extremely poor, while the absorption from heat-treated β-carotene-rich tomato sauce was enhanced in comparison. After adding dietary lipid in form of fresh avocado, β-carotene absorption from both raw carrots and tomato sauce significantly increased. Interestingly, the relative increase in absorption was more pronounced when intact, raw carrots were consumed (6.6-fold increase) as compared to processed tomato sauce (2.4-fold increase).
In conclusion, efficient carotenoid absorption was achieved by three different strategies. First, the consumption of the highly bioavailable liquid-crystalline form from papaya was shown to provide significantly higher levels of carotenoid than the consumption of raw carrots and tomatoes. Secondly, the addition of dietary lipid resulted in an increase of the initially poor carotenoid absorption of crystalline β-carotene from carrots. Third, commercial processing of a novel tomato containing crystalline β-carotene delivered a surprisingly high level of β-carotene, an effect which was further enhanced with dietary lipid.
For diminishing vitamin A deficiencies worldwide, the World Health Organization of the United Nations recommended the education of affected populations to consume more dietary provitamin A from plants sources2. Co-consumption of dietary lipid should be heavily considered, particularly when carrots or other fruits and vegetables with solid-crystalline provitamin A carotenoids are consumed. Furthermore, nutritional education programs in vitamin A deficient countries, particularly in the tropics and subtropics, should highlight provitamin A carotenoid sources with highest bioavailability, like papaya fruits, in order to help diminishing this most prevalent but avoidable deficiency.
Pigments in Food VII Congress, Novara, Italy; 06/2013
[Show abstract][Hide abstract] ABSTRACT: There is an excess burden of colorectal cancer (CRC) in the Appalachian region of the United States, which could be reduced by increased uptake of CRC screening tests. Thus, we examined correlates of screening among Appalachian residents at average-risk for CRC. Using a population-based sample, we conducted interviews with and obtained medical records of Appalachian Ohio residents 51-75 years between September 2009 and April 2010. Using multivariable logistic regression, we identified correlates of being within CRC screening guidelines by medical records. About half of participants were within CRC screening guidelines. Participants who were older (OR = 1.04, 95 % CI 1.01, 1.07), had higher income ($30,000-$60,000, OR = 1.92, 95 % CI 1.29, 2.86; ≥$60,000, OR = 1.80, 95 % CI 1.19, 2.72), a primary care provider (OR = 4.22, 95 % CI 1.33, 13.39), a recent check-up (OR = 2.37, 95 % CI 1.12, 4.99), had been encouraged to be screened (OR = 1.57, 95 % CI 1.11, 2.22), had been recommended by their doctor to be screened (OR = 6.68, 95 % CI 3.87, 11.52), or asked their doctor to order a screening test (OR = 2.24, 95 % CI 1.36, 3.69) had higher odds of being screened within guidelines in multivariable analysis. Findings suggest that access to and utilization of healthcare services, social influence, and patient-provider communication were the major factors associated with CRC screening. Researchers and healthcare providers should develop and implement strategies targeting these barriers/facilitators to improve CRC screening rates and reduce the CRC burden among residents of Appalachia.
Journal of Community Health 03/2013; · 1.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pancreatic stellate cells (PSC) are a subset of pancreatic cancer-associated fibroblasts. These cells provide pro-survival signals to tumors, however little is known regarding their interactions with immune cells within the tumor microenvironment. We hypothesized that factors produced by human PSC could enhance myeloid-derived suppressor cell (MDSC) differentiation and function, which promotes an immunosuppressive microenvironment. Primary PSC cell lines (n=7) were generated from human specimens and phenotypically confirmed via expression of vimentin, alpha-smooth muscle actin (α-SMA), and glial fibrillary acidic protein (GFAP). Luminex analysis indicated that PSC but not human fetal primary pancreatic fibroblast cells (HPF; negative controls) produced MDSC-promoting cytokines (IL-6, VEGF, M-CSF) and chemokines (SDF-1, MCP-1). Culture of peripheral blood mononuclear cells (PBMC, n=3 donors) with PSC supernatants or IL-6/GM-CSF (positive control) for 7 days promoted PBMC differentiation into an MDSC (CD11b+CD33+) phenotype and a sub-population of polymorphonuclear CD11b+CD33+CD15+ cells. The resulting CD11b+CD33+ cells functionally suppressed autologous T lymphocyte proliferation. In contrast, supernatants from HPF did not induce an MDSC phenotype in PBMCs. Culture of normal PBMCs with PSC supernatants led to STAT3 but not STAT1 or STAT5 phosphorylation. IL-6 was an important mediator as its neutralization inhibited PSC supernatant-mediated STAT3 phosphorylation and MDSC differentiation. Finally, the FLLL32 STAT3 inhibitor abrogated PSC supernatant-mediated MDSC differentiation, PSC viability, and reduced autocrine IL-6 production indicating these processes are STAT3 dependent. These results identify a novel role for PSC in driving immune escape in pancreatic cancer and extend the evidence that STAT3 acts as a driver of stromal immunosuppression to enhance its interest as a therapeutic target.
[Show abstract][Hide abstract] ABSTRACT: Colorectal cancer (CRC) is the third leading type of cancer and the third leading cause of cancer death in the United States. National policy-making organizations recognize and support a variety of CRC screening strategies among average-risk adults aged 50 and older based on strong evidence showing that screening decreases mortality from CRC and can also reduce the incidence of the disease. The goal of this study was to test a multi-level stepped intervention to increase CRC screening rates. We used a group-randomized trial design where the units of assignment were clinics and the units of observation were eligible patients receiving care at those clinics, with stratified random assignment of clinics to study conditions. The primary analysis was planned as a mixed-model logistic regression to account for the expected positive intraclass correlation associated with clinics. Our recruitment experience reflected the difficulties of conducting research in the real world where changes in economic conditions, staff turnover/layoff, inadequate medical records, and poor acceptance of research can significantly impact study plans. It demonstrated the problems that can emerge when procedures used in the study depart from those used in the pilot work to generate parameter estimates for power analysis. It also demonstrated the importance of allowing for attrition at the group and patient levels so that if recruitment falls short, it is possible to maintain adequate power with only a slight increase in the detectable difference. This experience should assist others planning group-randomized trials, whether in cancer screening or in other areas.
[Show abstract][Hide abstract] ABSTRACT: Protein arginine methyltransferase-5 (PRMT5) is a Type II arginine methyltransferase that regulates various cellular functions. We hypothesized that PRMT5 plays a role in regulating the growth of human melanoma cells. Immunohistochemical analysis indicated significant upregulation of PRMT5 in human melanocytic nevi, malignant melanomas and metastatic melanomas as compared to normal epidermis. Furthermore, nuclear PRMT5 was significantly decreased in metastatic melanomas as compared to primary cutaneous melanomas. In human metastatic melanoma cell lines, PRMT5 was predominantly cytoplasmic, and associated with its enzymatic cofactor Mep50, but not STAT3 or cyclin D1. However, histologic examination of tumor xenografts from athymic mice revealed heterogeneous nuclear and cytoplasmic PRMT5 expression. Depletion of PRMT5 via siRNA inhibited proliferation in a subset of melanoma cell lines, while it accelerated growth of others. Loss of PRMT5 also led to reduced expression of MITF (microphthalmia-associated transcription factor), a melanocyte-lineage specific oncogene, and increased expression of the cell cycle regulator p27(Kip1). These results are the first to report elevated PRMT5 expression in human melanoma specimens and indicate this protein may regulate MITF and p27(Kip1) expression in human melanoma cells.
PLoS ONE 01/2013; 8(9):e74710. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epidemiological studies support a link between cumulative sun exposure and cutaneous squamous cell carcinoma (SCC) development. However, the presumed effects of extended ultraviolet light B (UVB) exposure on tumorigenesis in the sexes have not been formally investigated. We examined differences in ultimate tumorigenesis at 25 weeks in mice exposed to UVB for either 10 or 25 weeks. Additionally, we investigated the effect of continued UVB exposure on the efficacy of topical treatment with anti-inflammatory (diclofenac) or antioxidant (C E Ferulic or vitamin E) compounds on modulating tumorigenesis. Vehicle-treated mice in the 25-week UVB exposure model exhibited an increased tumor burden and a higher percentage of malignant tumors compared to mice in the 10-week exposure model, which correlated with increases in total and mutant p53-positive epidermal cells. Only topical diclofenac decreased tumor number and burden in both sexes regardless of UVB exposure length. These data support the commonly assumed but not previously demonstrated fact that increased cumulative UVB exposure increases the risk of UVB-induced SCC development and can also affect therapeutic efficacies. Our study suggests that cessation of UVB exposure by at-risk patients may decrease tumor development and that topical NSAIDs such as diclofenac may be chemopreventive.
[Show abstract][Hide abstract] ABSTRACT: Because of the ever-increasing incidence of ultraviolet light B (UVB)-induced skin cancer, considerable attention is being paid to prevention through the use of both sunscreens and after sun treatments, many of which contain antioxidants. Vitamin E is included as an antioxidant in many sunscreens and lotions currently on the market. Studies examining the efficacy of vitamin E as a topical preventative agent for UVB-induced skin cancer have yielded conflicting results. A likely contributor to differences in study outcome is the stability of vitamin E in the particular formulation being tested. In the current study we examined the effects of topical vitamin E alone as well as vitamin E combined with vitamin C and ferulic acid in a more stable topical formula (C E Ferulic®). Mice were exposed to UVB for 10 weeks in order to induce skin damage. Then, before the appearance of any cutaneous lesions, mice were treated for 15 weeks with a topical antioxidant, without any further UVB exposure. We found that topical C E Ferulic decreased tumor number and tumor burden and prevented the development of malignant skin tumors in female mice with chronically UVB-damaged skin. In contrast, female mice chronically exposed to UVB and treated topically with vitamin E alone showed a trend towards increased tumor growth rate and exhibited increased levels of overall DNA damage, cutaneous proliferation, and angiogenesis compared to vehicle-treated mice. Thus, we have demonstrated that topical 5% alpha tocopherol may actually promote carcinogenesis when applied on chronically UVB-damaged skin while treating with a more stable antioxidant compound may offer therapeutic benefits.
PLoS ONE 01/2013; 8(5):e63809. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ultraviolet B (UVB) light is the major environmental carcinogen contributing to nonmelanoma skin cancer (NMSC) development. There are over 3.5 million NMSC diagnoses in two million patients annually, with men having a three fold greater incidence of squamous cell carcinoma (SCC) compared to women. Chronic inflammation has been linked to tumorigenesis, with a key role for the cyclooxygenase-2 (COX-2) enzyme. Diclofenac, a COX-2 inhibitor and NSAID, currently is prescribed to patients as a short-term therapeutic agent to induce SCC precursor lesion regression. However, its efficacy as a preventative agent in patients without evidence of precursor lesions but with significant UVB-induced cutaneous damage has not been explored. We previously demonstrated in a murine model of UVB-induced skin carcinogenesis, that when exposed to equivalent UVB doses, male mice had lower levels of inflammation but developed increased tumor multiplicity, burden, and grade compared to female mice. Because of the discrepancy in inflammation levels between male and female skin, we set out to determine if topical treatment of previously damaged skin with an anti-inflammatory, COX-2 inhibitor agent would decrease tumor burden and if it would be equally effective in the sexes. Our results demonstrated that despite observed sex differences in the inflammatory response, prolonged topical diclofenac treatment of chronically UVB-damaged skin effectively reduced tumor multiplicity in both sexes. Unexpectedly, tumor burden was significantly decreased only in male mice. Our data suggest a new therapeutic use for currently available topical diclofenac as a preventative intervention for patients predisposed to cutaneous SCC development before lesions appear.