Genetic contribution of caspase-8 variants and haplotypes to breast cancer risk and prognosis: a case-control study in Iran.

PURPOSE: Multiple genome-wide and candidate-gene association studies have been conducted to search for common risk variants of breast cancer. Recent large meta-analyses and consolidating evidence have highlighted the role of the caspase-8 gene in breast cancer pathogenesis. Therefore, this study aimed to identify common variations and haplotypes associated with risk and overall survival of breast cancer with respect to underlying susceptibility variants in the CASP8 gene region in a group of the Iranian population. METHODS: In a case-control study with a total of 1008 samples (455 cases and 553 controls), genotyping of 12 candidate polymorphisms, consisting of rs3834129, rs2037815, rs7608692, rs12990906, rs3769821, rs6435074, rs3754934, rs3817578, rs10931936, rs1045485, rs1045487, and rs13113, were performed using PCR-based methods, including ARMS-PCR, AS-PCR, RFLP-PCR, HRM-PCR, and TaqMan-PCR. RESULTS: rs3834129, rs3754934, rs12990906, and rs10931936 were associated with the risk and overall survival of breast cancer. Several haplotypes were also identified an associated with a higher risk of breast cancer, including a three-SNP haplotype rs3817578-rs10931936-rs1045485 [p < 0.001, OR = 1.78(1.32-2.41)]. rs3754934-C allele showed an association with a lower risk of death in all patients [p = 0.022; HR = 0.46(0.23-0.89)] and in the hormone-receptor-positive group [p = 0.038; HR = 0.37(0.14-0.95)], as well as CC genotype in the hormone-receptor-positive group [p = 0.002; HR = 0.09(0.02-0.43)]. CONCLUSION: The present study suggests a diagnostic and prognostic role of CASP8 gene variations in breast cancer. The risky haplotypes are likely to have one or more underlying breast cancer susceptibility alleles. Understanding the mode of action of these alleles will aid individual-level risk prediction. It also may help identify at-risk patients to provide them with better surveillance.

The impact of CYP19A1 variants and haplotypes on breast cancer risk, clinicopathological features and prognosis.

BACKGROUND: Different genetic variants in hormone-regulating pathways have been identified to influence the risk of breast cancer. This study aimed to evaluate the association of CYP19A1 rs10046 and rs700519 polymorphisms with the risk, clinicopathological factors and prognosis of breast cancer. METHODS: In a case-control study, rs10046 and rs700519 polymorphisms were genotyped using ARMS-PCR and high-resolution melting (HRM), respectively, in a total of 702 females. Statistical analysis and evaluation of haplotypes and linkage disequilibrium were performed using SPSS v16, PHASE and 2LD. RESULTS: Although no association of rs700519 with breast cancer was observed, rs10046 in different genetic models as well as C-C/C-T and C-C/C-C diplotypes, revealed the association with the risk of breast cancer (p < 0.05). Moreover, the rs700519-C allele was shown to be associated with longer overall survival. In contrast, the T-T haplotype conferred s a shorter overall survival. rs700519-C allele was also significantly associated with menarche age. CONCLUSION: Based on the identified independent association between CYP19A1 diplotypes and rs700519-C allele with the risk and prognosis of the disease, the gene region and its genetic variants may have a diagnostic and prognostic role in breast cancer development. Further confirmation using other variants in this locus can validate these findings.

Synergistic effects of polyaniline and pulsed electromagnetic field to stem cells osteogenic differentiation on polyvinylidene fluoride scaffold.

Repairing the lost or damaged mandible is very difficult and time-consuming, so there is a great hope for tissue engineering to accelerate it. At the present study, electrospinning was applied to fabricate polyvinylidene fluoride (PVDF) and PVDF-polyaniline (PANI) composite scaffolds. In addition, extremely low frequency pulsed electromagnetic field (PEMF) was applied for treating the stem cells derived from dental pulp (DPSCs) when cultured on the nanofibrous scaffolds. Osteoinductive property of the fabricated PVDF, PVDF-PANI scaffold at the presence and absence of the PEMF was investigated by evaluating the common osteogenic differentiation markers in seeded-DPSCs on the scaffold. Results demonstrated that cell attachment, protein adsorption and cells viability were increased when PEMF was applied. In addition, ALP activity, calcium content, osteogenic genes and protein evaluations confirmed that PEMF could significantly increase osteoinductivity of the PVDF while composite with PANI. According to the results, the use of polymers with piezoelectricity and conductivity features plus PEMF exposure has a promising potential to improve the current treatment methods in bone and mandibular defects.

Targeted therapies in pancreatic cancer: Promises and failures.

Pancreatic ductal adenocarcinoma (PDAC) is an incidence rate nearly equal to its mortality rate. The poor prognosis of the disease can be explained by the absence of effective biomarkers for screening and early detection, together with the aggressive behavior and resistance to the currently available chemotherapy. The therapeutic failure can also be attributed to the inter-/intratumor genetic heterogeneity and the abundance of tumor stroma that occupies the majority of the tumor mass. Gemcitabine is used in the treatment of PDAC; however, the response rate is less than 12%. A recent phase III trial revealed that the combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin could be an option for the treatment of metastatic PDAC patients with good performance status, although these approaches can result in high toxicity level. Further investigations are required to develop innovative anticancer agents that either improve gemcitabine activity, within novel combinatorial approaches or acts with a better efficacy than gemcitabine. The aim of the current review is to give an overview of preclinical and clinical studies targeting key dysregulated signaling pathways in PDAC.