The association of LRP5 (rs556442) polymorphism with body composition and obesity in postmenopausal women

AimThe main of this study was to investigate the association between the rs566442 (V1119V) coding polymorphism of Low-density lipoprotein receptor-related protein 5 (LRP5) with obesity and basal metabolic rate in Iranian postmenopausal women.MethodsThis cross-sectional study was performed on 350 postmenopausal women with a mean age of 57.8 years (SD ± 6.14). Body composition was analyzed by bioelectrical impedance analysis (BIA) resistance. Obesity was defined based on Body mass index (BMI) ≥30 kg/m2. To determine the genotype of SNP (rs556442), PCR-RFLP assay was performed and confirmed by sequencing. DNA samples from participants were genotyped using the RFLP-PCR method.ResultsAmong the study population 37.1% (130) were obese. G allele had minor-allele frequency of 0.38% in our population. The frequency of genotypes in our study population was 12.9% (45 person) GG, 35.7% (125 person) AA and 51.4% (180) GA. After adjusting age and menopausal age, only basal metabolic rate showed significantly higher in GG group compare to other groups (p = 0.02). Our data showed basal metabolic rate was higher in obese women with GG genotype in comparison to obese women with AG and AA genotypes.DiscussionThe findings of this study suggest that the GG genotype of SNP (rs556442) could protective role in obese women through the association with BMR.     

Ki67 Frequency in Breast Cancers without Axillary Lymph Node Involvement and its Relation with Disease-free Survival

Background: Breast cancer prognosis is influenced by several histopathology and clinical factors including expression of Ki67 which may have a predictive role in lymph node negative breast cancer patients. The aim of this study was to assess Ki67 expression in breast cancers without axillary lymph node involvement and to evaluate its prognostic value with regard to disease-free survival. Materials and Methods: Subjects were selected from non-metastatic invasive breast cancer patients who were referred to the oncology department of Ghaem hospital during 1 April 2001 to 1 April 2008. Ki67 levels were measured using immunohistochemistry (IHC) and compared with clinicopathological features. The relation of Ki67 expression with disease-free survival was also analysed. Results: A total of 106 women with a mean age of 49 were examined. Some 94.3% were classified as having invasive ductal carcinomas and the mean tumour diameter at the time of diagnosis was 2.8 cm. Some 50.9% of cases were ER positive and 47.2% were PR positive. P53 expression was positive in 48.1% of the cases. According to the IHC results, only 8.5% of the patients were Her2/neu positive. Ki67 was positive in 66 (62.3%) with a significant relation to lower age (p=0.0229) and P53 positivity (p=0.005). After an average of 40-months follow up, 13 (12.3%) demonstrated recurrence, most commonly systemic. Of 13 cases with relapse, 10 patients (77%) were Ki67 positive. Conclusions: In our population Ki67 appeared to be an independent prognostic factor for three-year survival. However, we stress that a survival study with a bigger sample size would help to support this conclusion.     

Effects of a novel Nodal-targeting monoclonal antibody in melanoma

Nodal is highly expressed in various human malignancies, thus supporting the rationale for exploring Nodal as a therapeutic target. Here, we describe the effects of a novel monoclonal antibody (mAb), 3D1, raised against human Nodal. In vitro treatment of C8161 human melanoma cells with 3D1 mAb shows reductions in anchorage-independent growth and vasculogenic network formation. 3D1 treated cells also show decreases of Nodal and downstream signaling molecules, P-Smad2 and P-ERK and of P-H3 and CyclinB1, with an increase in p27. Similar effects were previously reported in human breast cancer cells where Nodal expression was generally down-regulated; following 3D1 mAb treatment, both Nodal and P-H3 levels are reduced. Noteworthy is the reduced growth of human melanoma xenografts in Nude mice treated with 3D1 mAb, where immunostaining of representative tumor sections show diminished P-Smad2 expression. Similar effects both in vitro and in vivo were observed in 3D1 treated A375SM melanoma cells harboring the active BRAF(V600E) mutation compared to treatments with IgG control or a BRAF inhibitor, dabrafenib. Finally, we describe a 3D1-based ELISA for the detection of Nodal in serum samples from cancer patients. These data suggest the potential of 3D1 mAb for selecting and targeting Nodal expressing cancers.     

New insights into cathepsin D in mammary tissue development and remodeling

Cathepsin D (CatD) is a lysosomal aspartyl endopeptidase originally considered a “house keeping enzyme” involved in the clearance of unwanted proteins. However, recent studies have revealed CatD''s involvement in apoptosis and autophagy, thus signifying an important function in the proper development and maintenance of multi-cellular organs.In the mammary gland, matrix degradation and the remodeling process are orchestrated by proteolytic enzymes, but the role of CatD at distinct developmental stages has remained mostly unexplored. Based on our previous studies we sought to address the role of this endopeptidase in mammary gland development and remodeling. By employing a mouse model, we report a previously unidentified participation of CatD in different stages of mammary gland development. Our findings reveal that CatD undergoes distinct protein processing at different stages of mammary gland development, and this customized processing results in differential enzymatic activity (constitutive and low pH activatable) best fitting particular stage(s) of development. In addition, at the onset of involution the N-glycan structure of this endopeptidase switches from a mixed high mannose and hybrid structure to an almost exclusively high mannose type, but reverts back to the original N-glycan composition by day 4 of involution. Our findings illuminate (at least in part) the “raison d''être” for CatD''s numerous and highly regulated proteolytic processing steps from the pro-form to the mature enzyme. In the mammary gland, specific cleavage product(s) perform specialized function(s) befitting each stage of remodeling.It is noteworthy that deregulated synthesis, secretion and glycosylation of CatD are hallmarks of cancer progression. Thus, identifying the role of CatD in a dynamic normal tissue undergoing highly regulated cycles of remodeling could provide valuable information illuminating the deregulation of CatD associated with cancer development and metastasis.Key words: mammary gland, cathepsin D, enzymatic activity, proteolytic cleavage, N-glycan structures     

Dietary patterns interact with chromosome 9p21 rs1333048 polymorphism on the risk of obesity and cardiovascular risk factors in apparently healthy Tehrani adults

Gene-dietary patterns may contribute to determining body composition and related biochemical indices. The aim of this study was to evaluate interactions between rs1333048 polymorphism and major dietary patterns on body fat percentage, general and central obesity, and related biochemical measurements. This cross-sectional study was conducted on 265 healthy Tehrani adults with mean age of 35 years (47.5% men, 52.5% women). Dietary patterns (DPs) were extracted by factor analysis. Bioelectrical impedance analysis was used for body analysis and rs1333048 was genotyped by the restriction fragment length polymorphism (PCR-RFLP) method. Three DPs were extracted: restricted refined grains DP, legumes DP and healthy DP. AA genotype compared to CC genotype had greater odds for general obesity before (OR 3.14; 95% CI 1.008–9.60, P = 0.045) and after (OR 3.11; 95% CI 1.008–9.60, P = 0.048) adjusting for potential confounders. Individuals with AA genotype were more likely to be centrally obese before (OR 2.09; 95% CI 1.006–4.35, P = 0.048) and after (OR 2.63; 95% CI 1.12–6.17, P = 0.026) controlling for potential confounders. Significant interactions were observed between Legumes DP and rs1333048 SNP on waist circumference (P = 0.047), body fat % (BFP) (P = 0.048), hs-Crp (P = 0.042), BMI (P = 0.073), WHtR (P = 0.063) and odds for general obesity (P = 0.051). Following this DP reduced all these items for individuals with CC genotype, whereas increased them for people who carry CA or AA genotypes. The findings indicate that there are significant associations between AA genotype of rs1333048 SNP and general and central obesity, and significant interaction between alleles of this SNP and major dietary patterns on the odds of general obesity, BFP, waist circumference, BMI, WHtR and hs-Crp.