Association of the caspase-7 Asp4Glu polymorphism with increased risk of adverse reaction in the gastrointestinal tract after pelvic radiotherapy in cervical cancer patients

Caspase-7 (CASP7) is one of the effector caspases responsible for cleaving intracellular substrates involved in promoting the apoptotic phenotype. Interestingly a role for CASP7 in cell cycle progression at mitosis has also been suggested. Additionally, CASP7 polymorphisms are associated with increased risk for several types of cancer such as breast cancer, endometrial cancer and lung cancer. However little is known about the association of CASP7 with individual radiosensitivity. Therefore, in this study, we analyzed the association of functional polymorphisms in CASP7 with the risk of an adverse reaction in the intestinal tract after radiotherapy.A total of 208 cervical cancer patients who had been treated with pelvic radiotherapy were genetically analyzed. Early gastrointestinal reactions were graded using the National Cancer Institute Common Toxicity Criteria, and patients were dichotomized into a lower-grade (LG) group (! Grade = 0 or 1, n = 150) and a higher-grade (HG) group (Grade = 2 or 3, n = 58). Three SNPs with minor allele frequencies of more than 5% in our healthy control samples, rs12415607 (C-1222A), rs11593766 (T398G, Asp4Glu), and rs2227310 (C1151G, Asp255Glu), were subjected to genotype and haplotype analyses in the cervical cancer patients.Among these 3 SNPs, only rs11593766 was found to be associated with a risk of adverse reaction in the intestinal tract. The frequency of the G allele of this SNP was significantly higher in the HG group (18%) than in the LG group (9%; odds ratio [OR], 2.24; 95% confidence interval [CI], 1.18-4.21; P = 0.016). The GG and TG genotypes of rs11593766 were significantly associated with an increased risk of adverse reaction in the intestinal tract (OR, 2.15; 95% CI, 1.04-4.44; P = 0.038). No significant haplotype including rs11593766 was detected. Diplotypes of NPAT-ATM and AURKA have also been reported to con t! ribute to the risk of adverse intestinal reaction after radiotherapy, and we found that patients who had two or more of the NPAT-ATM, AURKA or CASP7 risk genotypes showed higher risk than other patients (OR, 3.60; 95% CI, 1.83-7.19; P = 0.00007).Our results suggest that the rs11593766 GG and TG genotypes (Glu/Glu or Asp/Glu) of CASP7 might contribute to the individual risk of adverse intestinal reaction after radiotherapy.14th International Congress of Radiation Research(ICRR’2011

Association of polymorphisms in hyaluronan receptor CD44 with radiotherapy effectiveness in patients with cervical cancer

Purpose: Hyaluronan (HA), a polysaccharide, is synthesized by a hyaluronan synthase (HAS). HA interacts with cells in dynamic processes such as embryogenesis and oncogenesis through interactions with several types of surface receptors like CD44 that play a role in regulating important signaling pathways, including the PI3K pathway. To identify predictive markers for radiotherapy effectiveness in cervical cancer, we have been analyzing the expression and genetic variation of some key genes such as FGF2, CD44, and HAS1. This study sought to determine the association between polymorphisms in CD44 and HAS1 genes with radiotherapy effectiveness in patients with cervical cancer.Materials and Methods: The study population comprised 121 cervical cancer patients who were treated with pelvic radiotherapy (the median dose of external beam = 50.6 Gy [range, 45.0 - 60.6 Gy] and median dose of brachytherapy = 24.0 Gy [range, 19.0 - 36.5 Gy]). The patients were defined as good (n = 82, mean age = 61 years [range, 32-83 years]) or poor (n = 39, mean age = 54 years [36-82 years]) responders on the basis of their 2-year disease-free survival. Genomic DNA was obtained from their blood samples and was genotyped using 19 SNPs in CD44 and 4 SNPs in HAS1. The association between each SNP and prognosis was evaluated by multivariate logistic regression analysis conditioned on the data pertaining to smoking, histological classification (squamous cell carcinoma/adenocarcinoma), and the International Federation of Gynecology and Obstetrics (FIGO) staging (I, II, III, IVA) of the tumors.Results: In logistic regression analysis conditioned on FIGO staging and smoking habits (the other factors did not contribute to the final model), P-values of 0.0056 was obtained for the SNP, T-2016C in CD44 (OR = 2.49, 95% CI = 1.31 - 4.76). The variant was located in the 5\u27 upstream region of the gene, suggesting that patients with the variant contribute to produce different amounts of CD44. Conclusions: Thus, radiotherapy effectiveness in patients with cervical cancer may be predicted, at least in part, by the genotype of CD44. Because of the limited sample size used in this study, further replication studies and functional analyses are required to confirm the results of the association analysis. However, the present data may be useful for analyzing the mechanisms underlying interaction between HA and CD44 and the subsequent cervical cancer-associated signaling.CSH Asia / ICMS (The International Cancer Microenvironment Society) Joint Conference on Tumor Microenvironmen

Combined Supplementation of Pre-Exercise Carbohydrate, Alanine, and Proline and Continuous Intake of Green Tea Catechins Effectively Boost Endurance Performance in Mice

Continuous intake of green tea catechins (GTC) increases fatty acid utilization as an energy source and improves endurance capacity. Conversely, the single pre-exercise intake of maltodextrin (MD) as a carbohydrate source and the gluconeogenic amino acids alanine (Ala) and proline (Pro) effectively maintain blood glucose levels and increase endurance performance. In this study, we investigated the synergistic combinational effect of these interventions on endurance performance in mice. Male BALB/c mice were fed a 0.5% GTC diet or Control diet for 8 weeks. Maximum running time was measured every 2 weeks. MD (2 g/kg body weight (B.W.)), MD (1 g/kg B.W.) + AlaPro (9:1, 1 g/kg B.W.), and vehicle were orally administrated 60 mins before measurements in each diet group. The GTC + MD + AlaPro group showed significantly higher endurance performance than the Control-Vehicle group at all measurements. Indirect calorimetry analysis during running exercise at 4 weeks in the Control and GTC groups supplemented with pre-exercise MD + AlaPro administration revealed significantly higher fat oxidation in the GTC groups compared to the Control group. The combined increase in fatty acid utilization through continuous GTC intake and pre-exercise MD + AlaPro carbohydrate energy supplementation synergistically improves endurance capacity