A Potential Role for Sirtuin-1 in Alzheimer's Disease: Reviewing the Biological and Environmental Evidence.

Sirtuin-1 (Sirt1), encoded by the SIRT1 gene, is a conserved Nicotinamide adenine dinucleotide (NAD+) dependent deacetylase enzyme, considered as the master regulator of metabolism in humans. Sirt1 contributes to a wide range of biological pathways via several mechanisms influenced by lifestyle, such as diet and exercise. The importance of a healthy lifestyle is of relevance to highly prevalent modern chronic diseases, such as Alzheimer's disease (AD). There is growing evidence at multiple levels for a role of Sirt1/SIRT1 in AD pathological mechanisms. As such, this review will explore the relevance of Sirt1 to AD pathological mechanisms, by describing the involvement of Sirt1/SIRT1 in the development of AD pathological hallmarks, through its impact on the metabolism of amyloid-ß and degradation of phosphorylated tau. We then explore the involvement of Sirt1/SIRT1 across different AD-relevant biological processes, including cholesterol metabolism, inflammation, circadian rhythm, and gut microbiome, before discussing the interplay between Sirt1 and AD-related lifestyle factors, such as diet, physical activity, and smoking, as well as depression, a common comorbidity. Genome-wide association studies have explored potential associations between SIRT1 and AD, as well as AD risk factors and co-morbidities. We summarize this evidence at the genetic level to highlight links between SIRT1 and AD, particularly associations with AD-related risk factors, such as heart disease. Finally, we review the current literature of potential interactions between SIRT1 genetic variants and lifestyle factors and how this evidence supports the need for further research to determine the relevance of these interactions with respect to AD and dementia.

Sleep, Sirtuin 1 and Alzheimer's disease: A review.

Sleep plays a major role in brain health, and cognition. Disrupted sleep is a well-described symptom of Alzheimer's disease (AD). However, accumulating evidence suggests suboptimal sleep also increases AD risk. The deacetylase Sirtuin 1 (Sirt 1), encoded by the SIRT1 gene, impacts sleep via its relationship to wake-sleep neurotransmitters and somnogens. Evidence from animal and human studies supports a significant and complex relationship between sleep, Sirt 1/ SIRT1 and AD. Numerous hypotheses attempt to explain the critical impact of Sirt 1/ SIRT1 on wake- and sleep- promoting neurons, their related mechanisms and neurotransmitters. However, there is a paucity of studies assessing the interaction between sleep and Sirt 1/ SIRT1, as a principal component of sleep regulation, on AD pathology. In this review, we explore the potential association between Sirt 1/ SIRT1, sleep, and AD aetiology. Given sleep is a likely modifiable risk factor for AD, and recent studies suggest Sirt 1/ SIRT1 activation can be modulated by lifestyle or dietary approaches, further research in this area is required to explore its potential as a target for AD prevention and treatment.

Association of a variant in the tumor necrosis factor alpha gene with risk of cervical cancer.

Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine involved in the regulation of the immune system and potentially the progression of cervical neoplastic lesions. In this study, we aimed to explore the possible relationship between polymorphisms of the TNF-α gene and susceptibility to cervical cancer. The relationship between a single nucleotide polymorphism (SNP) in the TNF-α gene (rs1800629) and the risk of cervical cancer was evaluated in a total of 445 subjects with (n = 153), or without (n = 292) cancer. Genotyping was performed using a Taq-Man based real time PCR method. Logistic regression analysis showed that individuals with AG/AA genotypes had an increased risk of cervical cancer compared to those with a GG genotype (OR 3.79, 95% CI 2.4-5.7, < 0.001). Our findings demonstrated that a genetic variant in the TNF-α gene (rs1800629) was associated with increased level and risk of developing cervical cancer, suggesting its potential use as a genetic risk factor for cervical neoplasia.

The association between genetic variants in the genes for cytochrome P450 B1 and ATP-binding cassette transporter genes and breast cancer risk.

Breast cancer is among the most common malignancies in women. Recent studies have shown that polymorphisms in genes involved in the metabolism and transport of anticancer drugs are associated with outcomes of several malignancies, e.g., breast cancer. In this study we evaluate whether CYP1B1/rs1056836 and ABCB1/rs2032582 gene variants are associated with breast cancer. Eighty eight cases and 200 controls, were genotyped for polymorphisms of the CYP1B1 and ABCB1 genes using Taqman®-based methods. Logistic regression was also used to test the associations between breast cancer risk and the various genotypes involved. The GG genotype of rs2032582 locus had a frequency of 43.5% with 0.38 MAF; while the GT and TT genotypes in the control group were 40% and 16.5%, respectively. The GG, GT and TT genotype frequencies in the patients with breast cancer were 45.5%, 12.5% and 26.1%, respectively. An association was observed between the TT genotype of ABCB1/rs2032582 locus and a larger breast cancer tumor size (P < 0.05). However, neither the relationship between the CYP1B1 polymorphism and breast cancer type nor the risk of breast cancer were statistically significant. Our data suggest a potential association of the ABCB1 genetic variant with breast cancer tumor size, however further investigation in a larger population is necessary to show its value as a risk stratification biomarker.

Association of cyclin-dependent kinase inhibitor 2A/B with increased risk of developing breast cancer.

There is a growing body of data reporting the association of genetic alterations in chromosome 9P21 with the risk of developing cancer. In the current study, we studied the association of a genetic variant in CDKN2A/B, rs1333049, with the risk of developing breast cancer. A total of 339 participants with and without breast cancer entered to the study. Genotyping was done by the TaqMan real-time polymerase chain reaction (RT-PCR) method and gene expression analysis was ran by RT-PCR. Our data showed that the minor allele homozygote in the total population was 10%, whereas for heterozygote was 38%. The dominant genetic model demonstrated that individuals with breast cancer had advanced TNM classification. Moreover, the logistic regression revealed that individuals who had CC/CG genotypes might have an enhanced risk of developing breast cancer when compared to the holders of GG genotype (e.g., OR = 2.8; 95% CI,1.4-5.4; p = .001), after regulated for confounders; age and body mass index. Furthermore, our analysis showed that the CDKN2A/B gene was downregulated in patients (p < .001). We showed a meaningful relationship of CDKN2A/B with the risk of breast cancer, cancer, showing the importance of studies in great sample size and several centers for studying the value of the marker as a risk classification in the management of patients with breast cancer.

Leptin level decreases after treatment with the combination of Radiofrequency and Ultrasound cavitation in response to the reduction in adiposity.

BACKGROUND: Obesity and overweight are major public health problem. Different-strategies have been developed for body contouring including Radiofrequency(RF) and Ultrasound(US). The aim of this study was to investigate changes in serum-leptin as a potential-modulator of food/energy intake, in overweight-women receiving RF/US and diet-therapy as well as the effect of therapy on modulation of lipid-profile and body-fat-mass. METHODS: Fifty overweight-females were enrolled in current randomized-clinical-trial and randomly divided into two groups. The case group received RF/US twice a week for 5 weeks with a low calorie diet whilst the control-group received just a low calorie diet. Demographic, biochemical markers as well as serum-leptin were determined. RESULTS: The level of leptin was reduced from 1.29 ±â€¯0.32 ng/ml to 1.14 ±â€¯0.34 ng/ml in case group, before and after therapy, respectively, whilst no significant differences were observed in the serum leptin levels of subjects in the control group. The combination of RF and US decreased the leptin-level. In particular, the mean reduction of abdominal-circumference and waist-circumference was significant (P < 0.05) after therapy. This reduction was inversely correlated with LDL levels. Weight was reduced in case and control groups and in both was significant, but no statistically significant differences were detected for weight between the groups(P < 0.93). CONCLUSION: Our findings demonstrated the reduction of the leptin after treatment with the combination of Radiofrequency/Ultrasound cavitation, which was associated with reduced body-fat-mass.

Association of a genetic variant in ATP-binding cassette sub-family B member 1 gene with poor prognosis in patients with squamous cell carcinoma of the esophagus.

Esophageal cancer is a common cause of death from cancer in men and the eighth most prevalent cancer globally. The morbidity and mortality rates are four times higher in men than in women. Genetic factors are among the susceptibility factors for squamous cell carcinoma of the esophagus. The rs2032582 polymorphism is a triallelic missense variant of the ABCB1 gene, that has been reported to be associated with several cancers. Here we have explored the association of the ABCB1 rs2032582 polymorphism with esophageal squamous cell carcinoma (ESCC) for the first time in a total of 251 subjects, with and without ESCC. Data from patient's record were obtained from the Mashhad University of Medical Sciences, and were used to recruit ESCC patients into the study. A total of 89 ESCC patients and 162 healthy controls were included. DNAs were extracted and genotyped using a TaqMan real-time PCR-based method. Caplan Meier method was applied to analyze patients overall survival, and progression-free survival and log-rank were used in order to compare the results. Logistic regression was used to calculate the association between risk of ESCC and different genotypes. Our data showed that patients with ESCC had a higher frequency of a T/A (TT/TA/AA) genotype for rs2032592 than individuals with GG-genotype. There were no associations between BMI and genotypic frequencies. Furthermore patients with TT/TA/AA genotypes had a poorer disease-free survival (P = 0.016) in comparison with GG genotype. We found a significant association of the ABCB1 rs2032582 polymorphism with prognosis, although further studies in a larger and multicenter setting are needed to value these findings. © 2019 IUBMB Life, 71(9):1252-1258, 2019.

High-density lipoprotein lipid peroxidation as a molecular signature of the risk for developing cardiovascular disease: Results from MASHAD cohort.

High-density lipoprotein (HDL) function rather than level may better predict cardiovascular disease (CVD). However, the contribution of the impaired antioxidant function of HDL that is associated with increased HDL lipid peroxidation (HDLox) to the development of clinical CVD remains unclear. We have investigated the association between serum HDLox with incident CVD outcomes in Mashhad cohort. Three-hundred and thirty individuals who had a median follow-up period of 7 years were recruited as part of the cohort. The primary end point was cardiovascular event, including myocardial infarction, stable angina, unstable angina, or coronary revascularization. In both univariate/multivariate analyses adjusted for traditional CVD risk factors, HDLox was an independent risk factor for CVD (odds ratio, 1.62; 95% confidence interval, 1.41-1.86; p < 0.001). For every increase in HDLox by 0.1 unit, there was an increase in CVD risk by 1.62-fold. In an adjusted analysis, there was a >2.5-fold increase in cardiovascular risk in individuals with HDLox higher than cutoff point of 1.06 compared to those with lower scores, suggesting HDLox > 1.06 is related to the impaired HDL oxidant function and in turn exposed to elevated risk of CVD outcomes (hazard ratio, 2.72; 95% CI, 1.88-3.94). Higher HDLox is a surrogate measure of reduced HDL antioxidant function that positively associated with cardiovascular events in a population-based cohort.

Therapeutic potential of toll-like receptors in treatment of gynecological cancers.

Toll-like receptors (TLRs) play an important role in the innate and adaptive immune system. They are expressed in various regions of the female reproductive tract, and their regulation may be involved in the pathogenesis of gynecological lesions. There is growing evidence that ligands for several TLRs are potentially anticancer agents, some of which have already been approved by the FDA, and these compounds are now undergoing clinical evaluation. There is a rationale for using these ligands as adjuvants in the treatment or prevention of gynecological cancer. Some TLR agonists that are of potential interest in the treatment of gynecological lesions include imiquimod, motolimod, cervarix, and CpG-oligodeoxynucleotides (ODNs). In this review, we outline the different functions of TLRs in gynecological cancer with particular emphasis on the value of TLR agonists as a potential therapeutic target in the treatment of gynecological cancer. © 2019 IUBMB Life, 71(5):549-564, 2019.

Human T lymphotropic virus type 1 and risk of cardiovascular disease: High-density lipoprotein dysfunction versus serum HDL-C concentrations.

High-density lipoprotein (HDL) is thought to be protective against cardiovascular disease (CVD), and HDL dysfunction is considered to be a risk factor for CVD. It is unclear whether there is an association between Human T lymphotropic virus type 1 (HTLV1) infection and CVD risk. We have assessed HDL lipid peroxidation (HDLox) as a marker of HDL dysfunction and CVD risk in a subgroup of the MASHAD cohort study. One hundred and sixty two individuals including 50 subjects positive for HTLV1 infection and 112 individuals negative for HTLV1 infection were recruited. Anthropometric and biochemical parameters including serum hs-CRP, fasted lipid profile (HDL-C, LDL, triglycerides, and cholesterol), and fasting blood glucose were determined. Serum HDLox was also measured in the study participants. Multivariate analyses were used to evaluate the association between serum HDLox and HTLV1 infection. None of the traditional CVD risk factors were associated with HTLV1 infection, including serum HDL-C. However, serum HDLox was independently associated with the presence of HTLV1 infection. Logistic regression analysis showed that subjects who were positive for HTLV1 infection were also significantly more likely than uninfected individuals to have higher HDLox (odds ratio 9.35, 95%CI: 3.5-24.7; P < 0.001). HDLox was increased approximately 20% (P < 0.001) in infected subjects compared to the uninfected group. Serum HDLox is a marker of CVD risk factor and increased in individuals affected by HTLV1 infection compared to healthy subjects. © 2019 BioFactors, 45(3):374-380, 2019.

A variant in CYP2R1 predicts circulating vitamin D levels after supplementation with high-dose of vitamin D in healthy adolescent girls.

AIM: The determinants of serum vitamin D seems to be the environmental factors (dietary and supplementary intake and exposure to ultraviolet light) and genetic factors. We aimed to study the relationship between a vitamin D-associated genetic polymorphism and serum 25(OH)D concentrations in healthy adolescent girls in Iran, and its effects on a high-dose supplement of vitamin D. MATERIAL AND METHOD: A total of 616 healthy adolescent girls with mean age 15 received 50,000 IU of vitamin D3 weekly over 9 weeks. Serum vitamin D levels and other metabolic factors were measured at baseline and after the intervention. The genotyping of the CYP2R1 variant (rs10741657) was performed by TaqMan genotyping assays. RESULTS: Regardless of the genetic background, at baseline, 87% of adolescent girls were vitamin D deficient (serum 25(OH)D level < 50 nmol/l). High-dose supplementation with VitD reduced the proportion of girls who were deficient substantially to about 24%. The genetic analysis revealed that although at baseline there was not a gene-vitamin D association ( p trend = 0.1), the response to supplementation appeared to be modulated by this variant ( p trend < 0.001). However, other anthropometric and biochemical measures were not affected by this intervention, over this short period. Serum 25(OH)D was increased in all participants although the carriers of the minor A allele seemed to be better responders so that the percentages of the change serum vitamin D in the holder of AA and AG genotypes were 539.4 ± 443.1 and 443.7 ± 384.6, respectively, compared with those with common GG genotype (363.3 ± 354.0). Our regression analysis revealed that the probability of an increase in serum 25(OH)D in a participant with AA genotype was 2.5-fold greater than those with a GG genotype (OR = 2.5 (1.4-4.4); p value = 0.002). CONCLUSION: Based on our findings, it appears that the rs10741657 variant of the CYP2R1 gene modulates the response to high-dose of vitamin D supplementation.

Associations of vitamin D binding protein variants with the vitamin D-induced increase in serum 25-hydroxyvitamin D.

BACKGROUND: Vitamin D deficiency is a global problem that may be improved by vitamin D supplementation; however, the individual's response to the intervention varies. We aimed to investigate possible genetic factors that may modify the impact of environmental exposure on vitamin D status. The candidate gene variant we investigated was the Gc gene-rs4588 polymorphism at the vitamin D receptor (DBP) locus. METHODS: A total of 619 healthy adolescent Iranian girls received 50000 IU of vitamin D3 weekly for 9 weeks. Serum 25(OH) D concentrations, metabolic profiles and dietary intake were measured at baseline and after 9 weeks of supplementation. The genotypes of the DBP variant (rs4588) were analyzed using the TaqMan genotyping assay. RESULTS: Our results revealed that the rs4588 polymorphism might be associated with serum 25-hydroxy vitamin D both at baseline (p value = 0.03) and after intervention (p value = 0.008). It seemed that the outcome of the intervention was gene-related so that the subjects with common AA genotype were a better responder to vitamin D supplementation (Changes (%) 469.5 (427.1) in AA carriers vs. 335.8 (530) in GG holders), and carriers of the less common GG genotype experienced a rise in fasting blood glucose after 9 weeks (Changes (%) 0 (1.5)). Our findings also showed that the statistical interaction between this variant and supplementation was statistically significant (intervention effect p-value<0.001 and p-value SNP effect = 0.03). The regression model also revealed that after adjusted for potential confounders, likelihood of affecting serum 25(OH)D in individuals who were homozygous for the uncommon allele G was less than those homozygous for the more common AA genotype (OR = 4.407 (1.82-8.89); p = 0.001). CONCLUSION: Serum vitamin 25(OH) D following vitamin 25(OH) D3 supplementation appears to be modified by genetic background. The Gc genetic variant, rs4588 encoding the vitamin D receptor seems to influence the response to vitamin D supplementation.

A genetic variant in the cytochrome P450 family 2 subfamily R member 1 determines response to vitamin D supplementation.

BACKGROUND: Globally, about 1 billion people have inadequate levels of serum vitamin D and it is prevalent in all ethnicities and age groups. Few foods naturally contain sufficient vitamin D; therefore, most people get their requirements through supplementation. Hence vitamin D status is affected by genetic and environmental determinants including season of measurement, diet habitual, health status, body mass index and concurrent medication. Further studies are necessary to understand how genetic variation influences vitamin D metabolism. We aimed to explore the association between a potential vitamin D-related polymorphism (the rs10766197 polymorphism in the CYP2R1 gene) with the response to supplementation of vitamin D in 253 healthy Iranian girls. MATERIAL AND METHOD: A total of 253 healthy subjects received 50,000 IU of vitamin D3 weekly for 9 weeks. Serum 25(OH)D concentrations and metabolic profiles were measured at baseline and after 9 weeks of supplementation. The genotypes of the CYP2R1 variant (rs10766197) were identified using TaqMan genotyping assays. RESULTS: Serum 25(OH)D during the supplementation, increased in all individuals. Subjects with a AA major genotype at this locus had higher vitamin D concentrations after intervention (Changes (%) 448.4% ± 425% in AA vs 382.7% ± 301% in GG). This genetic variant modulated the response to supplementation (p < 0.001 and p-value SNP = 0.05). Regression analysis showed that the probability of affecting serum 25(OH)D, in individuals who had homozygous major allele GG was two-fold higher than carriers of the uncommon allele A (OR = 2.1 (1-4.2); p = 0.03). Interestingly, the Hs-CRP was reduced in AA carries while was elevated in individuals with GG and AG genotypes, after high-dose vitamin D supplementation. CONCLUSION: Changes in serum vitamin D and metabolic profile following high dose supplementation with vitamin D were associated with CYP2R1 polymorphism. Although carriers of the common G allele showed a greater response in the serum vitamin D.

Association of a genetic variant in AKT1 gene with features of the metabolic syndrome.

Metabolic syndrome (MetS) is a clustering of metabolic abnormalities that is associated with increased risk of developing cardiovascular disease and type 2 diabetes. There is growing body of data showing the associations of genetic variants of the genes involved in the PI3K/AKT/mTOR pathway with diabetes and obesity. We aimed to investigate the association between MetS and its components with the genetic polymorphism in AKT1, rs1130233 (T > C). Total of 618 participants, recruited from Mashhad stroke and heart atherosclerosis disorder cohort (MASHAD study). Patients with MetS were defined by using international diabetes federation (IDF) criteria (n = 326) and those without MetS (n = 261) were recruited. Anthropometric and biochemical parameters were measured in all subjects. Genetic analysis for the rs1130233 polymorphism was performed, using the ABI-StepOne instruments with SDS version-2.0 software. Individuals with MetS had a significantly higher levels of BMI, waist-circumference, total cholesterol, triglyceride, high sensitivity-c reactive protein (hs-CRP) and blood-pressure, and lower concentrations of high density lipoprotein (HDL-C), compared to non-MetS individuals (P < 0.05). The association between the rs1130233 and MetS was not significant. Subjects with a CC or CT genotypes had a significantly higher serum hs-CRP-level (OR: 1.5; 95% CI (1.05-2.1), P = 0.02). Additionally, subjects who carried the TC genotype had a higher BMI compared to the CC genotype (p value = 0.045). Our findings demonstrated that AKT1, rs1130233 (T > C) polymorphism was associated with major components of MetS such as hs-CRP, and BMI, indicating further investigation in a multi-center setting to explore its value as an emerging biomarker of risk stratification marker.

A genetic variant in CDKN2A/2B locus was associated with poor prognosis in patients with esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is among the leading causes of cancer related death. Despite of extensive efforts in identifying valid cancer prognostic biomarkers, only a very small number of markers have been identified. Several genetic variants in the 9p21 region have been identified that are associated with the risk of multiple cancers. Here, we explored the association of two genetic variants in the 9p21 region, CDKN2A/B, rs10811661, and rs1333049 for the first time in 273 subjects with, or without ESCC. We observed that the patients with ESCC had a higher frequency of a TT genotype for rs10811661 than individuals in the control group, and this polymorphism was also associated with tumor size. Moreover, a CC genotype for the rs1333049 polymorphism was associated with a reduced overall survival (OS) of patients with ESCC. In particular, patients with a CC (rs1333049) genotype had a significantly shorter OS (CC genotype: 34.5 ± 8.9 months vs. CG+GG: 47.7 ± 5.9 months; p value = 0.03). We have also shown the association of a novel genetic variant in CDKN2B gene with clinical outcome of patients with ESCC. Further investigations are warranted in a larger population to explore the value of emerging markers as a risk stratification marker in ESCC.

Association of TNF-308 G>A polymorphism located in tumor necrosis factor a with the risk of developing cervical cancer and results of pap smear.

Tumor necrosis factor a (TNFa) is an inflammatory cytokine that plays a crucial role in the immune response and the progression of cervical lesions. There is a growing body of data evaluating the value of a genetic variant in the TNFa gene with the risk of developing cervical cancer. The aim of this study was to explore the association of a variant, TNF-308 G>A, residing in the TNFa gene with cervical cancer. A total of 91 women with cervical cancer and 161 women as the control group were recruited. DNA was extracted, and Taqman®-probes-based assay was used for genotyping. Our results showed that the minor allele frequency was 0.3 in total population, and the frequency of minor allele A was more in the case group compared with the control. The regression models in different genetic models also revealed that the allele A is a potential risk factor for the development of cervical cancer. In particular, in the dominant model, patients with AG and AA genotypes had a higher risk of developing cervical cancer with odds ratio (OR) of 2.75 (95% confidence interval [CI]: 1.57-4.83, <0.001) and OR of 7.27 (95%CI: 2.5-20.8, <0.001), compared with the GG genotype. Moreover, a similar outcome was obtained for smear test results. Our study demonstrated that TNF-308 G>A located on TNF-a was associated with the risk of cervical cancer, supporting further studies in a larger population and multicenter setting to show the value of emerging markers as risk stratification biomarkers in cervical cancer.

High-density lipoprotein functionality and breast cancer: A potential therapeutic target.

Breast cancer is a major cause of death globally, and particularly in developed countries. Breast cancer is influenced by cholesterol membrane content, by affecting the signaling pathways modulating cell growth, adherence, and migration. Furthermore, steroid hormones are derived from cholesterol and these play a key role in the pathogenesis of breast cancer. Although most findings have reported an inverse association between serum high-density lipoprotein (HDL)-cholesterol level and the risk of breast cancer, there have been some reports of the opposite, and the association therefore remains unclear. HDL is principally known for participating in reverse cholesterol transport and has an inverse relationship with the cardiovascular risk. HDL is heterogeneous, with particles varying in composition, size, and structure, which can be altered under different circumstances, such as inflammation, aging, and certain diseases. It has also been proposed that HDL functionality might have a bearing on the breast cancer. Owing to the potential role of cholesterol in cancer, its reduction using statins, and particularly as an adjuvant during chemotherapy may be useful in the anticancer treatment, and may also be related to the decline in cancer mortality. Reconstituted HDLs have the ability to release chemotherapeutic drugs inside the cell. As a consequence, this may be a novel way to improve therapeutic targeting for the breast cancer on the basis of detrimental impacts of oxidized HDL on cancer development.

Therapeutic potential of targeting the Wnt/ß-catenin pathway in the treatment of pancreatic cancer.

The Wnt/ß-catenin pathway is an important, dysregulated pathway in several tumor types, including pancreatic ductal adenocarcinoma. Although the activation of this pathway is an important component of normal development, its aberrant activation resulting from activating or inactivating mutations in the CTNNB1 gene locus, or in the negative regulators AXIN and APC involving stabilization of ß-catenin, and activation of target genes leads to a more aggressive phenotype, suggesting its potential value as a therapeutic target in the treatment of pancreatic ductal adenocarcinoma. A number of small molecule and biologic agents have now been developed for targeting this pathway. This review summarizes the current knowledge about the therapeutic potential of targeting the Wnt pathway with particular emphasis on preclinical/clinical studies in the treatment of pancreatic ductal adenocarcinoma.

Association of rs6921438 A

BACKGROUND: Genome-wide association studies (GWAS) have identified common variants at the Vascular-Endothelial-Growth-Factor (VEGF) gene locus, which appear to be associated with plasma VEGF concentrations. These factors are among the major risk factors for cardiovascular disease and metabolic syndrome (MetS). We have investigated the association between serum VEGF concentrations and a VEGF genetic variant (rs6921438 A

A genetic polymorphism in the CYP1B1 gene in patients with squamous cell carcinoma of the esophagus: an Iranian Mashhad cohort study recruited over 10 years.

AIM: Esophageal cancer is the eighth most common cancer globally and the seventh most common cause of cancer-related deaths in men. Recent studies have shown that CYP450, family 1, subfamily B, polypeptide 1, which plays a role in the metabolism of xenobiotics, is associated with several cancers. Therefore, in the present study we investigated the association between a genetic variant, CYP1B1-rs1056836 gene, with the clinical characteristics of patients with squamous cell carcinoma of the esophagus (ESCC). METHOD: In this study, 117 patients with ESCC and 208 healthy controls were recruited. DNA was extracted and genotyped using real-time PCR-based TaqMan. Kaplan-Meier curves were utilized to assess overall and progression-free survival. To evaluate the relationship between clinicopathological data, genotypic frequencies, disease prognosis and survival, Pearson's χ2 and t-test were used. Logistic regression was utilized to assess the association between the risk of ESCC and genotypes. RESULTS: The genotypic frequency for GG, GC and CC were 58.6, 29.8 and 11.5%, respectively, in the healthy subjects and 51.8, 36.14 and 12% in the ESCC group. An association between the GG genotype and stage of ESCC was found. Also, statistically significant results were not found for this variation and risk of ESCC. CONCLUSION: Our findings suggest a relationship between the CYP1B1-rs1056836 genetic polymorphism and clinical features of ESCC, supporting further studies in larger populations in different ethnic groups, taking into account potentially important environmental factors such as diet.