Gender- and site-specific differences of colorectal neoplasia relate to vitamin D.

BACKGROUND: The effect of vitamin D on colorectal adenomas may vary with regard to gender, localisation and histological type of the lesion. AIM: To define the role of vitamin D and gender in a Caucasian cohort of subjects undergoing screening colonoscopy after consideration of established risk factors. METHODS: One thousand five hundred and thirty-two subjects (813 males, 58.8 ± 9.7 years; 719 females, 59.7 ± 10.7 years) were allocated to tertiles of 25-hydroxyvitamin D3 [25(OH)D3 ] serum concentrations. The number, localisation, size and histology of the detected colonic lesions were recorded. RESULTS: Among men, no association was found between vitamin D and the total number, size and histological stage of adenomas at any site. In female subjects, less women with adenomas were found in the highest vitamin D tertile (N = 42/239; 17.2%) as compared to the low vitamin D group (N = 60/240; 25.0%; P = 0.035). In particular, the number of women with adenomas in the proximal colon was significantly lower in the highest tertile (N = 21/239, 8.8%) compared to the low vitamin D group (N = 41/240; 17.1%; P = 0.007). The rates at other sites were not different. The inverse association of vitamin D serum concentrations with the presence of adenomas in the proximal colon was maintained after adjustment for potential confounders. In 80 women on vitamin D supplementation, the rate of adenomas was lower compared to those not on supplementation (3/80; 3.8%; vs. 90/719; 12.5%; P = 0.016). CONCLUSIONS: A potential preventive effect of vitamin D on colorectal adenomas was found in the proximal colon in women. This observation is supported by further decrease of lesions in the proximal colon of women on vitamin D supplementation.

Combination of GHRH antagonists and docetaxel shows experimental effectiveness for the treatment of triple-negative breast cancers.

In preclinical studies, antagonists of growth hormone-releasing hormone (GHRH) have demonstrated inhibitory effects on the growth of various types of cancers expressing the pituitary type of GHRH receptors (pGHRH-R) and/or its active splice variant 1 (SV1). In this study, we investigated the effectiveness of the treatment of MDA-MB-231 human triple-negative breast cancer (TNBC) with GHRH antagonist JMR-132 alone or in combination with docetaxel. Receptor expression in the MDA-MB-231 human breast cancer cell line was evaluated by reverse transcription-polymerase chain reaction (RT-PCR). Cell viability assays were performed on MDA-MB-231 cells treated with JMR-132, docetaxel or in combination. For studies in vivo, a subcutaneous nude mouse xenograft model was used. JMR-132 was administered s.c. at a dose of 10 µg/day and docetaxel at a dose of 10 mg/kg i.p. given on day 1 and 5. Similar regimens were used for the combination of both substances. At the end of the experiment, an mRNA-based human cancer pathway array including 84 major genes was performed on the tumor tissue of mice treated with JMR-132 to elucidate the mechanism of action of GHRH antagonists in vivo. The in vitro proliferation studies revealed that JMR-132 and docetaxel decreased the cell viability in a dose-dependent manner. The combination of both treatments produced a significantly greater inhibition of cell viability compared to the single agents. Treatment of nude mice bearing MDA-MB-231 xenografts with JMR-132 and docetaxel significantly (p<0.05) inhibited tumor growth by 46 and 50%, respectively. Treatment with the combination of JMR-132 and docetaxel led to an inhibition of tumor volume by 71.6% (p<0.001). Polymerase chain reaction array analysis revealed that JMR-132 interacts with signal transduction pathways involved in proliferation, apoptosis and angiogenesis. Our results suggest that GHRH antagonists in combination with taxanes may enhance the efficacy of treatment for patients with TNBC expressing the SV1 and/or the pGHRH receptor.

Nonalcoholic fatty liver disease: an independent risk factor for colorectal neoplasia.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of insulin resistance (IR), and IR is associated with an increased risk of colorectal carcinoma (CRC). Increased echogenicity suggesting NAFLD is a frequent incidental finding on ultrasound examination. We aimed to systematically evaluate whether NAFLD is an independent risk factor for colonic neoplasia. PATIENTS AND METHODS: One thousand two hundred and eleven patients (603 males, 60.6 ± 9.6 years; 608 females, 61.1 ± 10.3 years) who underwent screening colonoscopy according to national screening recommendations for CRC were evaluated in a cross-sectional study. Colorectal adenomas were classified as tubular adenoma, advanced adenoma (villous features, size ≥ 1 cm or high-grade dysplasia) or carcinoma. NAFLD was diagnosed by increased echogenicity on ultrasound examination after serological exclusion of infectious, immunological, hereditary or alcoholic aetiology. RESULTS: Nonalcoholic fatty liver disease was diagnosed in 367 (60.8%) males and in 265 (43.5%) females. The total rate of adenomas was increased in subjects with NAFLD (243/367 vs. 107/236 in males, P = 0.010; 94/265 vs. 78/343 in females; P = 0.014). In particular, more tubular adenomas (127/367 vs. 56/236; P = 0.006), adenomas of the rectum (40/367 vs. 8/236; P = 0.004) and more cancers (6/367 vs. 1/236; P < 0.001) were observed in males with NAFLD. In females with NAFLD, more tubular adenomas (59/265 vs. 48/343; P = 0.011) and adenomas of the proximal colon (51/265 vs. 40/343; P = 0.041) were observed. Multivariate regression analyses demonstrated an independent association of colorectal adenomas with hepatic steatosis after adjustment for age, sex, body mass index and glucose intolerance (OR 1.47; 95% CI 1.079-2.003; P = 0.015). CONCLUSION: Patients with NAFLD undergoing screening colonoscopy reveal significantly more CRC precursor lesions and early CRC compared with subjects without NAFLD. This elevated risk is independent from other manifestations of IR. These findings suggest that detecting fatty liver on ultrasound should heighten the awareness for referral to screening colonoscopy.

Iron stores, liver transaminase levels and metabolic risk in healthy teenagers.

BACKGROUND: Iron overload may contribute to the pathogenesis of insulin resistance. We aimed to investigate the relationship among iron stores, liver transaminases and components of the metabolic syndrome in healthy teenagers in a cross-sectional study. MATERIAL AND METHODS: We determined body mass index (BMI), waist-to-hip-ratio (WHR), blood pressure, liver ultrasound, serum lipids, insulin, fasting glucose, liver transaminase levels, hsCRP, iron parameters in 325 of 341 (95.3%) students (234 men, 16.7 +/- 1.7 years; 91 women, 16.5 +/- 1.7 years) of one single high school. Male and female study participants were allocated to increasing quartiles of body iron stores as assessed by sTfr/ferritin and alanine aminotranspeptidase (ALT) levels, and the distribution of cardiometabolic risk factors along quartiles was analysed. Regression analysis was performed to confirm the independent relationship between parameters. RESULTS: In male students, BMI, WHR, systolic and diastolic blood pressure, serum triglyceride levels and hsCRP were higher in the top sTfR/ferritin and ALT quartiles compared with the lowest quartiles (P < 0.01 for all parameters). In female students, sTfR/ferritin were not associated with antropomorphic cardiometabolic risk factors but with insulin resistance (HOMA-IR, P = 0.046). Moreover, ALT levels were independently related to BMI, waist and hip circumference, systolic blood pressure, serum triglyceride and insulin concentrations (P < 0.05 for all parameters) in female students. CONCLUSION: These results provide evidence for linkage among body iron stores, transaminase activity and the prevalence of cardiometabolic risk factors in apparently healthy, non-obese adolescents even within the range of normal laboratory and anthropomorphic values and suggest that iron stores should be investigated as a potentially modifiable risk factor in healthy teenagers.

Contribution of anti-cyclic citrullinated peptide antibody and rheumatoid factor to the diagnosis of arthropathy in haemochromatosis.

OBJECTIVE: To investigate the prevalence of antibodies to cyclic citrullinated peptide (anti-CCP) and rheumatoid factor in patients with hereditary haemochromatosis (HHC) and to evaluate their diagnostic reliability in distinguishing HHC-associated arthropathy from rheumatoid arthritis. METHODS: Anti-CCP antibodies and rheumatoid factor levels were determined by ELISA in sera from 87 patients with HHC homozygous for the C282Y mutation of the HFE gene, 31 patients with rheumatoid arthritis and 162 healthy controls. RESULTS: Of the 87 patients with HHC, 32 (36.8%) had joint involvement. Anti-CCP antibodies were detected in only 1 patient (1.1%) with HHC, who had no joint disease, and in (1.2%) healthy controls. In total, 18 (58.1%) patients with rheumatoid arthritis displayed anti-CCP reactivity (p<0.001). Rheumatoid factor was detected in 10 (11.5%) patients with HHC compared with 7 (4.3%) healthy control subjects (p = 0.03) and 21 of 31 (65.6%) patients with rheumatoid arthritis. CONCLUSIONS: Testing for anti-CCP antibodies discriminates HHC arthropathy from rheumatoid arthritis, as these patients were consistently anti-CCP negative. Thus, HHC arthropathy should be considered in the differential diagnosis of CCP-negative arthritis.