Aims To evaluate the feasibility of using self-collected capillary blood samples for islet autoantibody testing to identify risk in relatives of people with Type 1 diabetes. Methods Participants were recruited via the observational TrialNet Pathway to Prevention study, which screens and monitors relatives of people with Type 1 diabetes for islet autoantibodies. Relatives were sent kits for capillary blood collection, with written instructions, an online instructional video link and a questionnaire. Sera from capillary blood samples were tested for autoantibodies to glutamic acid decarboxylase, islet antigen-2, insulin autoantibody and zinc transporter 8. ‘Successful’ collection was defined as obtaining sufficient volume and quality to provide definitive autoantibody results, including confirmation of positive results by repeat assay. Results In 240 relatives who returned samples, the median (range) age was 15.5 (1–49) years and 51% were male. Of these samples, 98% were sufficient for glutamic acid decarboxylase, islet antigen-2 and zinc transporter 8 autoantibody testing and 84% for insulin autoantibody testing and complete autoantibody screen. The upper 90% confidence bound for unsuccessful collection was 4.4% for glutamic acid decarboxylase, islet antigen-2 and/or zinc transporter 8 autoantibody assays, and 19.3% for insulin autoantibody. Despite 43% of 220 questionnaire respondents finding capillary blood collection uncomfortable or painful, 82% preferred home self-collection of capillary blood samples compared with outpatient venepuncture (90% of those aged <8 years, 83% of those aged 9–18 years and 73% of those aged >18 years). The perceived difficulty of collecting capillary blood samples did not affect success rate. Conclusions Self-collected capillary blood sampling offers a feasible alternative to venous sampling, with the potential to facilitate autoantibody screening for Type 1 diabetes risk.

While treatment with sulindac plus atorvastatin has been shown to be more efficacious than either agent alone in inhibiting chemically-induced colorectal tumors, the effectiveness of this same drug combination against sporadic colorectal cancer has not been evaluated. The goal of this study was to assess the chemopreventive activity of sulindac plus atorvastatin, in combination, in a unique strain of Apc+/Min-FCCC mice that spontaneously develops colorectal adenomas at a high multiplicity and incidence. Male Apc+/Min-FCCC mice (6-8 weeks of age) were subjected to colonoscopic examinations at baseline (prior to treatment) and randomized to receive either control chow or chow supplemented with sulindac (300 ppm), atorvastatin (100 ppm) or sulindac plus atorvastatin for 100 days. All drugs were well tolerated, with no significant change in body weight observed among the treatment groups. At the time of euthanasia, gross small intestinal (SI) and colonic tumors were identified and the height, width and length of the colonic tumors was measured using calipers. Only the colon was submitted for histopathological evaluation. The multiplicity of gross SI tumors was decreased in animals administered sulindac (54%) or sulindac plus atorvastatin (41%), as compared to those receiving either control diet or atorvastatin alone (P ≤ 0.00024). Based on the results of the colonoscopic evaluation, mice were categorized as being tumor-free or tumor-bearing at baseline. Treatment with atorvastatin, alone or in combination, lead to a 2.4-3.6-fold increase in the percentage of mice that were tumor-free both at baseline and at the time of euthanasia: control 12.5%; sulindac 9.1%; atorvastatin 44.4% and sulindac plus atorvastatin 30%. Interestingly, atorvastatin completely inhibited the formation of microadenomas in mice that were tumor-free at baseline (P = 0.002). In mice that were tumor-bearing at baseline, only the sulindac plus atorvastatin combination therapy reduced the multiplicity of colon adenomas significantly as compared to that of controls (Mean ± SEM, 3.7 ± 0.7 and 6.4 ± 1.2, respectively) (P = 0.049). The effect of drug exposure on tumor volume was evaluated at the time of euthanasia. Colon tumor volume was reduced 2-fold in mice treated with sulindac as compared to that of mice administered control diet or diet supplemented with atorvastatin or sulindac plus atorvastatin in combination (P &lt; 0.03). These data suggest that the chemopreventive activity of sulindac and/or atorvastatin against colorectal adenomas is dictated in part by the status of the animal (tumor-free or tumor-bearing) at the time treatment is initiated. Additional experimentation is required to establish the patient subgroup and drug schedule that will yield optimal therapeutic activity in a clinical setting. (Supported by NIH R21CA129467) Citation Format: Wen-Chi Chang, Christina Ferrara, Stacy Mosier, Harry Cooper, Karthik Devarajan, Harvey Hensley, Tianyu Li, Margie Clapper. Effect of sulindac and/or atorvastatin on colorectal adenomas in the Apc+/Min-FCCC mouse model varies depending on the presence or absence of adenomas at the time of drug initiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 195. doi:10.1158/1538-7445.AM2013-195

Recent efforts to improve the vascular and gastrointestinal safety of nonsteroidal anti-inflammatory drugs (NSAIDs) have included the addition of a nitric oxide-donating moiety. The ability of the common NSAID naproxen and nitric oxide (NO)-naproxen to inhibit azoxymethane-induced aberrant crypt foci in the rat colon has been demonstrated. However, the chemopreventive activity of these agents against spontaneous colorectal tumors has not been reported. The goal of the present study was to compare the ability of naproxen and NO-naproxen (low- and high-dose molar equivalents) to inhibit colorectal adenomas in a unique strain of mice (Apc+/Min-FCCC) that spontaneously develops multiple colorectal tumors. Male Apc+/Min-FCCC mice (50 days of age) were randomized (n = 17 per group) to receive control diet or diet supplemented with naproxen (132 or 400 ppm) or NO-naproxen (182 or 550 ppm) for 45 days. Body weights were recorded weekly and did not differ significantly among treatment groups. At sacrifice, small intestinal and colonic tissues were examined grossly and the entire colon was submitted for histopathologic analysis. Low-dose naproxen and low-dose NO-naproxen decreased the multiplicity of gross small intestinal adenomas by 70.3% (mean ± SEM – 9.9 ± 1.45, P = 0.04) and 64.0% (12.0 ± 1.9), respectively, as compared to that of control mice (33.3 ± 14.0). No additional benefit was obtained by administering a higher dose of either agent. Histopathologic analyses revealed that the incidence of colorectal adenomas in mice treated with naproxen (low dose – 70.6%; high dose – 64.7%) was significantly less than that of both control mice (100%) (P = 0.019 and 0.0076, respectively) and mice treated with NO-naproxen (low dose – 88.2% and high dose – 100%). Low-dose naproxen reduced the multiplicity of colorectal adenomas by 41.5% as compared to control (mean ± SEM, 1.8 ± 0.5, 3.1 ± 0.7, respectively), while the efficacy of all other treatments was less. Interestingly, treatment with high-dose naproxen caused a dramatic (89.3%) reduction in the multiplicity of microadenomas as compared to unsupplemented control diet. This study represents the first demonstration that naproxen can inhibit spontaneous colorectal adenomas in a controlled model system. The ability of naproxen to disrupt the formation of colorectal lesions early in the carcinogenesis process (microadenomas) provides strong support for its further development as a regimen for the chemoprevention of colorectal cancer in high-risk individuals. (Supported by NIH N01 CN-43309.) 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 LB-457. doi:10.1158/1538-7445.AM2011-LB-457

Results from recent clinical and epidemiological studies continue to suggest that non-steroidal anti-inflammatory drugs (NSAIDs) are promising chemopreventive agents with activity against colorectal cancer. Nitric oxide (NO)-donating NSAIDs represent a novel class of agents that have been reported to have greater safety and higher efficacy in inhibiting the growth of cancer cells than the parent compounds. However, the mechanism of chemopreventive action of NO-NSAIDs is not well elucidated. Dysregulation of the WNT/ β-catenin pathway is one of the earliest events during tumorigenesis in the colon and thus an attractive molecular target for chemopreventive intervention. The major goal of the current study was to compare the effect of naproxen, an NSAID commonly used to reduce pain, fever and inflammation, and NO-naproxen on β-catenin-mediated TCF4 signaling in colon cancer cells. Human SW480 colon carcinoma cells that express mutant APC were transfected with either pGL3 basic plasmid or a luciferase reporter construct under the control of 3 copies of either wild-type (pGL3-OT) or mutated (pGL3-OF) TCF4 regulatory element using LipofectAmine 2000. Cells were treated with 0.01 - 0.4 mM naproxen or NO-naproxen or vehicle (water or DMSO, respectively) and harvested 48 hrs later. Cell lysates were prepared and luciferase activity was measured using the Promega Luciferase Assay kit. The results demonstrate that NO-naproxen reduces β-catenin-mediated TCF4 transcriptional activity in SW480 cells in a dose dependent manner. At a given dose, the luciferase activity of cells exposed to NO-naproxen was approximately 50% of that of cells treated with the parent compound. In conclusion, these data suggest that the chemopreventive activity of NO-naproxen is attributed in part to its ability to inhibit the transcriptional activation of TCF4; a response that is greater than that of the conventional drug naproxen. The availability of a multiple intestinal neoplasia mouse model that, unlike the conventional strain, develops multiple colorectal adenomas provides a unique opportunity to compare the efficacy of these agents against colorectal tumor growth in vivo. Supported by NIH N01 CN43309. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5695.

No abstract