Selenium supplementation and insulin resistance in a randomized, clinical trial

Objective: While controversial, observational and randomized clinical trial data implicate the micronutrient selenium (Se) in the development of type 2 diabetes (T2D). The aim of this study was to test the hypothesis that Se supplementation adversely affects pancreatic beta-cell function and insulin sensitivity. Research design and methods: In a subset of 400 individuals participating in a randomized, placebocontrolled trial of Se at 200 mu g/day for colorectal adenomatous polyps, fasting plasma glucose and insulin were measured before randomization and within 6 months of completing intervention. Change in the homeostasis model assessment-beta cell function (HOMA2-%beta) and insulin sensitivity (HOMA2-%S) were compared between arms. A subgroup of 175 (79 Se and 96 placebo) participants underwent a modified oral glucose tolerance test (mOGTT) at the end of intervention and change in glucose values was assessed. Results: No statistically significant differences were observed for changes in HOMA2-%beta or HOMA2-%S between those who received Se compared with placebo. After a mean of 2.9 years on study, mean HOMA2-%beta values were 3.1 +/- 24.0 and 3.1 +/- 29.8 for the Se and placebo groups, respectively (p=0.99). For HOMA2-%S, the values were -0.5 +/- 223.2 and 80.9 +/- 1530.9 for the Se and placebo groups, respectively (p=1.00). Stratification by sex or age did not reveal any statistically significant effects on insulin sensitivity by treatment group. For mOGTT, mean baseline fasting blood glucose concentrations were significantly higher among participants in the placebo group compared with the Se group (96.6 +/- 14.6 and 92.3 +/- 12.0, respectively; p=0.04), a trend which remained through the 20 min assessment. Conclusions: These findings do not support a significant adverse effect of daily Se supplementation with 200 mu g/day of selenized yeast on beta-cell function or insulin sensitivity as an explanation for previously reported associations between Se and T2D. Further clarification of longer term effects of Se is needed.National Cancer Institute Cancer Center Support Grant [P30 CA023074]; NIH/NCI [R01CA151708, P01 CA041108]; NIH [R01DK047396]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Article on vitamin A suppressing skin cancer. Clinical Trials Safety and Efficacy of Dose-Intensive Oral Vitamin A in Subjects with Sun-Damaged Skin

ABSTRACT Purpose: Previously, we reported the results of a Phase III, placebo-controlled trial in 2,297 randomized participants with moderately severe actinic keratoses wherein 25,000 IU/day vitamin A caused a 32% risk reduction in squamous cell skin cancers. We hypothesized that dose escalation of vitamin A to 50,000 or 75,000 IU/day would be both safe and more efficacious in skin cancer chemoprevention. Experimental Design: One hundred and twenty-nine participants with severely sun-damaged skin on their lateral forearms were randomized to receive placebo or 25,000, 50,000, or 75,000 IU/day vitamin A for 12 months. The primary study end points were the clinical and laboratory safety of vitamin A, and the secondary end points included quantitative, karyometric image analysis and assessment of retinoid and rexinoid receptors in sun-damaged skin. Results: There were no significant differences in expected clinical and laboratory toxicities between the groups of participants randomized to placebo, 25,000 IU/day, 50,000 IU/day, and 75,000 IU/day. Karyometric features were computed from the basal cell layer of skin biopsies, and a total of 22,600 nuclei from 113 participants were examined, showing statistically significant, dose-response effects for vitamin A at the 25,000 and 50,000 IU/day doses. These karyometric changes correlated with increases in retinoic acid receptor , retinoic acid receptor ß, and retinoid X receptor at the 50,000 IU/day vitamin A dose. Conclusions: The vitamin A doses of 50,000 and 75,000 IU/day for 1 year proved safe and equally more efficacious than the 25,000 IU/day dose and can be recommended for future skin cancer chemoprevention studies

Inhibition of phosphatidylinositol-3-kinase and mitogen-activated protein kinase kinase 1/2 prevents melanoma development and promotes melanoma regression in the transgenic TPRas mouse model

A number of human melanomas show hyperactivation of the Ras pathway due to mutations of the molecule or alteration of upstream or downstream effectors. In this study, we evaluated the effect of blocking the two Ras downstream pathways phosphatidylinositol-3-kinase/Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase on melanoma development and regression in the TPRas mouse model. The inhibition of these two signaling cascades by topically applied Ly294002 and U0126 significantly delayed melanoma development and significantly decreased the tumor incidence, particularly when the drugs were applied in combination. Treatment with the inhibitors of established melanomas resulted in complete remission in 33% of mice and partial regression in 46% of mice when drugs were delivered in combination. These responses correlated with increased apoptosis and decreased proliferation both in vitro and in vivo and reduced tumor angiogenesis. In conclusion, this study strongly supports the role of the phosphatidylinositol-3-kinase/Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways in the development and maintenance of Ras-dependent melanomas and supports the notion that specific inhibition of these effectors may represent a very promising avenue for the treatment and prevention of the disease

Feasibility of a family-focused YMCA-based diabetes prevention program in youth: The E.P.I.C. Kids (Encourage, Practice, and Inspire Change) Study

Efficacious lifestyle modification programs for children at risk of type 2 diabetes (T2D) have not been well established outside of clinical settings. In this study, the feasibility of a family-focused, YMCA-based prevention program for children at risk of T2D was evaluated between September 2015 and July 2016 in Tucson, Arizona. A 12-week YMCA-led lifestyle intervention was adapted for 9–12-year-old children and their families to encourage healthy eating, physical activity, and supportive home environments. Two YMCA locations were randomized to offer either a face-to-face lifestyle coach-led intervention or an alternating face-to-face and digitally-delivered intervention. Program feasibility and preliminary effects on child anthropometric and behavioral outcomes were assessed at baseline and post-intervention. Changes were assessed using linear regression combining delivery formats, with adjustment for clustering of participants within site/format. Forty-eight children (10.9 ± 1.2 years old; 45% female; 40% Hispanic; 43% White; 87% obese) and their parents enrolled, and 36 (75%) completed 12-week measures. Weekly program attendance averaged 61%. Participants and coaches highly rated program content and engagement strategies. Statistically significant changes in child BMI-z score (−0.05, p = 0.03) and family food and physical activity environment (+5.5% family nutrition and physical activity score, p = 0.01) were observed. A YMCA-led family-focused T2D intervention was feasible for the YMCA and participants and effects on child weight, behavior, and the home environment warranted further investigation. Keywords: Pediatric obesity, Type 2 diabetes mellitus, Lifestyle intervention, YMCA, Diabetes preventio

Ciliated prostate cancer and stromal cells have decreased axoneme lengths.

<p>(A and B) Primary cilia (Ac-Tub; red), centrosomes (γ-Tub; green), nuclei (Hoechst; blue), and cytokeratin 5 (CK5; white), are shown to illustrate representative ciliary lengths. Images were selected to represent the median length for normal and the 25^th percentile for PIN and cancer cells (note that many PIN and cancer cells have cilia shorter than those shown). Cilia lengths are given. (A) Normal basal cell, normal luminal cell, CK5+ basal cell in PIN, CK5-cancer cell and (B) stromal cell in normal, PIN, and cancer tissue. Boxplots of cilia lengths for (C, top) all epithelial, (D, top) CK5+, (E, top) CK5-and (F, top) stromal cells per patient for normal, PIN, cancer (Ca), and perineural invasion (Peri). Q4, Q1 are as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0068521#pone-0068521-g001" target="_blank">Figure 1</a>. Statistics were performed using linear regression (* = p<0.05, *** = p<0.001) (C, D, E, and F, bottom). The percent of patients with abnormally long cilia (Q4; orange) or abnormally short cilia (Q1; blue).</p

Primary cilia loss correlates with greater nuclear β-catenin in normal.

<p>(A) Immunohistochemistry (IHC) images of β-catenin staining in normal prostate, demonstrate a lack of β-catenin localization in basal cells (blue nuclei, black arrows; left). Basal cells were identified based on position, morphology, and cytokeratin 5 (CK5) staining in the adjoining serial section (white arrows; right). The lumen (Lum) and stroma (Strm) are labeled. IHC images show different levels and spatial distributions of β-catenin staining in (B) PIN, (C) cancer, and (D) perineural invasion. (E) Graphs display percent ciliated cells versus β-catenin nuclear score. Scattergraphs were plotted per location for normal, PIN, cancer, and perineural invasion tissue. For normal, basal cells (green) and luminal cells (blue) are shown. For PIN, cancer and perineural invasion, all epithelial/cancer cells are plotted red. High nuclear β-catenin was defined as the 75^th percentile of normal, denoted by the dotted line, and was used to compare normal to PIN, cancer and perineural cells. Percentages represent the locations with high nuclear β-catenin. Statistical analysis was performed using linear regression and included all of the data points, and comparisons to normal basal cells are denoted with p, and comparisons to normal luminal cells are denoted with p*.</p

Primary cilia frequency is decreased on both CK5+ and CK5- cancer cells.

<p>Images of normal prostate and invasive prostate cancer. Nuclei (Hoechst; blue), cytokeratin 5 (CK5; white), primary cilia (Ac-Tub; red) and centrosomes (γ-Tub; green) are labeled. (A) CK5 marks the basal cell population in normal tissue. (A, left) A ciliated CK5+ normal cell and (A, right) an unciliated CK5+ cancer cell are shown at higher magnification. (B, left) A ciliated CK5- normal cell, and (B, right) an unciliated CK5- cancer cell. (C, top) Boxplots of the percent ciliated CK5+ and (D, top) CK5- epithelial and cancer cells per patient for each tissue type: normal, prostatic intraepithelial neoplasia (PIN), cancer (Ca), and perineural invasion (Peri). Q4, Q1 are as in Fig. 1. Statistics were performed using linear regression (*=p<0.05, ***= p<0.001). (C, bottom) Percent of CK5+ and (D, bottom) CK5- patients with an abnormally high percent cilia (Q4; orange), or an abnormally low percent cilia (Q1; blue).</p

Primary cilia expression is decreased in preinvasive and invasive prostate cancer.

<p>Images of (A) normal prostate and (B) invasive prostate cancer. Serially adjacent slides were stained with H&E to visualize tissue morphology or stained fluorescently for nuclei (Hoechst; blue), primary cilia (Ac-Tub; red) and centrosomes (γ-Tub; green). Labeled structures are lumen (Lum), cancer (Ca), and stroma (Strm). Inset shows magnification of (A) a primary cilium on a normal epithelial cell and (B) a centrosome without a cilium on a cancer cell. Asterisk denotes nonspecific staining (C, top). Box plot of the percent of ciliated epithelial and cancer cells per patient for each tissue type: normal, prostatic intraepithelial neoplasia (PIN), cancer (Ca), and perinerual invasion (Peri). Orange line and arrow correspond to Q4 (quartile 4; greater than the 75^th percentile for normal tissue) and blue line and arrow correspond to Q1 (quartile 1; less than or equal to the 25^th percentile for normal tissue). Statistics were performed using linear regression (*** = p<0.001) (C, bottom). The percent of patients with an abnormally high percent cilia (Q4; orange) or an abnormally low percent cilia (Q1; blue). (D) Percent of Ki67 positive invasive cancer cells and perineural invasion cancer cells per patient (x-axis) versus percent ciliated cancer cells for the same patient (y-axis). Statistical analysis was a non-parametric spearman correlation.</p