Enhanced Cancer Risk Research Articles

HIF-1α rs11549465 C>T polymorphism contributes to increased cancer susceptibility: Evidence from 49 studies.

HIF-1α (hypoxia-inducible factor-1α) is a transcriptional factor that participates in the regulation of oxygen homeostasis. Despites numbers of case-control studies working on this area, the actual relationship of HIF-1α gene generic variant rs11549465 C>T imposing on cancer susceptibility remains unveiled. To get a better understanding of such relationship, this meta-analysis was carried out by incorporating all eligible case-control studies. Qualified articles were acquired from PubMed, CNKI, EMBASE, PMC, and Wanfang database update to April 2019. Odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were employed to estimate the relationship of interest. Heterogeneity tests, sensitivity analyses and publication bias assessments were also carried out to ensure the strength of our conclusion. A total of 46 articles with 49 studies including 12920 cases and 13363 controls were included. The results indicated that HIF-1α rs11549465 C>T was significantly related to the increased risk of overall cancer under four genetic models (TT vs. CC: OR=2.06, 95% CI=1.34-3.16; TT vs. CC/CT: OR=2.42, 95% CI=1.60-3.65; CT/TT vs. CC: OR=1.21, 95% CI=1.04-1.40; T vs. C: OR=1.29, 95% CI=1.12-1.48). Furthermore, enhanced cancer risk was detected after stratification by cancer type, ethnicity, the source of controls and HWE. These results suggest that HIF-1α rs11549465 C>T polymorphism may predispose to cancer susceptibility.

Single nucleotide polymorphisms in the MYLKP1 pseudogene are associated with increased colon cancer risk in African Americans.

IntroductionPseudogenes are paralogues of functional genes historically viewed as defunct due to either the lack of regulatory elements or the presence of frameshift mutations. Recent evidence, however, suggests that pseudogenes may regulate gene expression, although the functional role of pseudogenes remains largely unknown. We previously reported that MYLKP1, the pseudogene of MYLK that encodes myosin light chain kinase (MLCK), is highly expressed in lung and colon cancer cell lines and tissues but not in normal lung or colon. The MYLKP1 promoter is minimally active in normal bronchial epithelial cells but highly active in lung adenocarcinoma cells. In this study, we further validate MYLKP1 as an oncogene via elucidation of the functional role of MYLKP1 genetic variants in colon cancer risk.MethodsProliferation and migration assays were performed in MYLKP1-transfected colon and lung cancer cell lines (H441, A549) and commercially-available normal lung and colon cells. Fourteen MYLKP1 SNPs (MAFs >0.01) residing within the 4 kb MYLKP1 promoter region, the core 1.4 kb of MYLKP1 gene, and a 4 kb enhancer region were selected and genotyped in a colorectal cancer cohort. MYLKP1 SNP influences on activity of MYLKP1 promoter (2kb) was assessed by dual luciferase reporter assay.ResultsCancer cell lines, H441 and A549, exhibited increased MYLKP1 expression, increased MYLKP1 luciferase promoter activity, increased proliferation and migration. Genotyping studies identified two MYLKP1 SNPs (rs12490683; rs12497343) that significantly increase risk of colon cancer in African Americans compared to African American controls. Rs12490683 and rs12497343 further increase MYLKP1 promoter activity compared to the wild type MYLKP1 promoter.ConclusionMYLKP1 is a cancer-promoting pseudogene whose genetic variants differentially enhance cancer risk in African American populations.

Genetic Variant Arg399Gln G>A of XRCC1 DNA Repair Gene Enhanced Cancer Risk Among Indian Population: Evidence from Meta-analysis and Trial Sequence Analyses.

The X-ray repair cross-complementation group 1 (XRCC1) gene plays an important role in base excision repair pathway. Several studies have reported contradictory results for XRCC1 exon 10 (Arg399Gln, G23990A, rs25487) gene polymorphism and cancer risk in Indian population, making it difficult to interpret them. Therefore, we have conducted a meta-analysis to evaluate the more precise association between XRCC1 exon 10 G>A gene polymorphism and risk of cancer by published studies. We searched PubMed (Medline) and Google scholar web databases to cover all studies published on association between XRCC1 exon 10 G>A gene polymorphism and cancer risk until August 2016. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to appraise the strength of association. Heterogeneity, publication bias and sensitivity analysis were also assessed. Twenty-five published studies had fulfilled the inclusion criteria comprising 4131 confirmed cancer cases and 5013 controls. When all studies were polled together, overall significant association was found between XRCC1 exon 10 G>A polymorphism and cancer risk in variant allele carrier (A vs. G: OR 1.217, 95% CI 1.056-1.402, p=0.007), homozygous (AA vs. GG: OR 1.359, 95% CI 1.036-1.783, p=0.027), dominant (AA+AG vs. GG OR 1.208, 95% CI 1.006-1.450, p=0.043) and recessive (AA vs. AG+GG: OR 1.315, 95% CI 1.029-1.680, p=0.029) genetic models. Further sensitivity analysis supported the stability of our result by showing similar ORs before and after removal of a single study. The present meta-analysis suggested that the XRCC1 exon 10 G>A polymorphism contribute cancer risk in Indian population, and supports that individuals with risk allele A and AA genotype are at higher risk of developing cancer.

Metal Exposure and Associated Health Risk to Human Beings by Street Dust in a Heavily Industrialized City of Hunan Province, Central China.

Fifty-five urban street dust samples were collected from Zhuzhou, an industrial city in central China and analyzed for a range of toxic elements. Potential carcinogenic and non-carcinogenic health effects on children and adults due to exposure to street dust were assessed. Concerning the two subgroups, the child cohort is confronted with considerably greater health risks than adults. According to the Hazard Quotient (HQ) method, ingestion of dust particles poses primary risk to children and adults, followed by dermal contact and inhalation for all of the metals investigated except Hg, for which inhalation of its elemental vapor constitute a slightly higher risk than ingestion. For children, Pb, As, Cd, Cr, Hg and Sb exposure were deemed as the highest contributors to non-cancer health risks, while As and Cr represent an enhanced cancer risk for children. For adults, risk indicator values for both cancer and non-cancer effects obtained were within the safety threshold. In a comparison with other locations within and outside mainland China, exposure to arsenic is prominent for the population of Zhuzhou, indicating more attention and preventive actions should been taken.

Genetic association between IL-27 rs153109 polymorphism and cancer risk in Chinese population: a meta-analysis

IL-27 plays an important role in anti-cancer activity. The -964A/G polymorphism in IL-27 gene has been implicated in susceptibility to cancer, but the results were conflicting. The aim of this study was to assess the association between this polymorphism and cancer risk. Pubmed and Wanfang database were searched for all publications concerning IL-27 -964A/G polymorphism and cancer risk. Odds ratio (OR) and 95% confidence interval (CI) were used to assess the strength of association. Statistical analysis was performed using Stata 11.0 software. A total of eight case–control studies including 2044 cancer cases and 2197 controls were identified. Overall, significant association between IL-27 -964A/G polymorphism and cancer risk was observed (GG versus AA: OR = 1.26, 95% CI = 1.03–1.52; GG versus AG + AA: OR = 1.20, 95% CI = 1.00–1.44). In subgroup analysis based on cancer type, significant association was found in colorectal cancer (GG versus AA: OR = 1.55, 95% CI = 1.07–2.27; AG versus AA: OR = 1.31, 95% CI = 1.02–1.67). The current meta-analysis suggests that IL-27 -964A/G polymorphism might enhance cancer risk. However, large-scale and well-designed studies are still needed to confirm the result of our meta-analysis. The association of IL-27 polymorphism with colorectal cancer may provide insight for future therapies.

Association of Genomic Instability with HbA1c levels and Medication in Diabetic Patients

Diabetes Mellitus type 2 (DM2) is associated with increased cancer risk. Instability of the genetic material plays a key role in the aetiology of human cancer. This study aimed to analyse genomic instability with the micronucleus cytome assay in exfoliated buccal cells depending on glycated haemoglobin (HbA1c) levels and medication in 146 female DM2 patients. The occurrence of micronuclei was significantly increased in DM2 patients compared to healthy controls. Furthermore, it was doubled in DM2 patients with HbA1c > 7.5% compared to subjects with HbA1c ≤ 7.5%. Positive correlations were found between micronuclei frequencies and HbA1c as well as fasting plasma glucose. Patients under insulin treatment showed a two-fold increase in micronuclei frequencies compared to subjects under first-line medication (no drugs or monotherapy with non-insulin medication). However, after separation of HbA1c (cut-off 7.5%) only patients with severe DM2 characterised by high HbA1c and insulin treatment showed higher micronuclei frequencies but not patients with insulin treatment and low HbA1c. We demonstrated that the severity of DM2 accompanied by elevated micronuclei frequencies predict a possible enhanced cancer risk among female DM2 patients. Therapy, therefore, should focus on a strict HbA1c control and personalised medical treatments.

A CDK2 activity signature predicts outcome in CDK2-low cancers.

The role of cyclin-dependent kinase 2 (CDK2) in cancer is controversial. A major hurdle is the availability of tools to easily assess its activity across many samples. Here, we introduce a transcriptional signature to specifically track CDK2 activity. It responds to genetic and chemical perturbations in the CDK-RB-E2F axis, correlates with mitotic rate in vitro and in vivo and reacts rapidly to changes in CDK2 activity during cell cycle progression. We find that CDK2 activity is specifically elevated in human testes, mirroring its critical function in mice, and report very distinct profiles across human cancers. Increased CDK2 activity decreases risk in colon cancer, but elevates poor outcome two- to fivefold in specific tumors, including low grade glioma, kidney, thyroid, adrenocortical and prostate cancer. These are typically 'CDK2-low' cancers, suggesting that above a certain threshold CDK2 promotes progression, but further increases do not influence outcome. Multivariate analysis revealed that the CDK2 signature is the most important predictive feature in these cancers versus dozens of other clinical parameters, such as tumor grade or mitotic index. Thus, transcriptome data provides a novel, straightforward method to monitor CDK2 activity, implicates key roles for the kinase in a subset of human tissues and tumors and enhances cancer risk prediction. The strategy used here for CDK2 could be applied to other kinases that influence transcription.

Metformin Protects Kidney Cells From Insulin-Mediated Genotoxicity In Vitro and in Male Zucker Diabetic Fatty Rats.

Hyperinsulinemia is thought to enhance cancer risk. A possible mechanism is induction of oxidative stress and DNA damage by insulin, Here, the effect of a combination of metformin with insulin was investigated in vitro and in vivo. The rationales for this were the reported antioxidative properties of metformin and the aim to gain further insights into the mechanisms responsible for protecting the genome from insulin-mediated oxidative stress and damage. The comet assay, a micronucleus frequency test, and a mammalian gene mutation assay were used to evaluate the DNA damage produced by insulin alone or in combination with metformin. For analysis of antioxidant activity, oxidative stress, and mitochondrial disturbances, the cell-free ferric reducing antioxidant power assay, the superoxide-sensitive dye dihydroethidium, and the mitochondrial membrane potential-sensitive dye 5,5',6,6'tetrachloro-1,1',3,3'-tetraethylbenzimidazol-carbocyanine iodide were applied. Accumulation of p53 and pAKT were analyzed. As an in vivo model, hyperinsulinemic Zucker diabetic fatty rats, additionally exposed to insulin during a hyperinsulinemic-euglycemic clamp, were treated with metformin. In the rat kidney samples, dihydroethidium staining, p53 and pAKT analysis, and quantification of the oxidized DNA base 8-oxo-7,8-dihydro-2'-deoxyguanosine were performed. Metformin did not show intrinsic antioxidant activity in the cell-free assay, but protected cultured cells from insulin-mediated oxidative stress, DNA damage, and mutation. Treatment of the rats with metformin protected their kidneys from oxidative stress and genomic damage induced by hyperinsulinemia. Metformin may protect patients from genomic damage induced by elevated insulin levels. This may support efforts to reduce the elevated cancer risk that is associated with hyperinsulinemia.

Obesity, Diabetes and Cancer: A Mechanistic Perspective.

Nearly 35% of adults and 20% of children in the United States are obese, defined as having a body mass index (BMI) ≥ 30 kg/m2. Obesity is an established risk factor for many cancers, and obesity-associated metabolic perturbations often manifest in Type 2 diabetes mellitus and/or the metabolic syndrome. As part of the growth-promoting, proinflammatory microenvironment of the obese and/or diabetic state, crosstalk between macrophages, adipocytes, and epithelial cells occurs via metabolically-regulated hormones, cytokines, and other mediators to enhance cancer risk and/or progression. This review synthesizes the evidence on key biological mechanisms underlying the associations between obesity, diabetes and cancer, with particular emphasis on enhancements in growth factor signaling, inflammation, and vascular integrity processes. These interrelated pathways represent mechanistic targets for disrupting the obesity-diabetes-cancer link, and several diabetes drugs, such as metformin and rosiglitazone, are being intensely studied for repurposing as cancer chemopreventive agents.

Abstract P5-14-02: Efficacy of tabebuia avellandae extract on a cell culture model for triple negative breast cancer

Abstract Background: The triple negative breast cancer (TNBC), a molecular subtype of clinical breast cancer consisting of epithelial cells that lack estrogen receptor-α (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2) expression, is non-responsive to either endocrine therapy or HER-2 targeted therapy. Chemotherapy is frequently associated with long-term systemic toxicity, acquired tumor resistance and resultant compromised treatment efficacy. These aspects emphasize a need to identify efficacious non-toxic agents for secondary prevention/therapy of TNBC. Non-fractionated aqueous extract from the inner bark of the Tabebuia avellandae (TA) tree found in the Amazon rainforest, available as a dietary supplement under the name of Taheebo or Pau d’arco, has documented efficacy in a cell culture model for the Luminal A breast cancer subtype, as well as for several other cancers. Present study examines the inhibitory effects of the TA extract, and identifies possible mechanistic targets for its efficacy in a cell culture model for TNBC. Nutritional Supplement, Experimental Model and Biomarkers: Lyophilized powder of non-fractionated TA extract from Taheebo Japan, Osaka, Japan, provides the source material for the study. The ER-/PR-/HER-2- MDA-MB-231 cell line represents the cell culture model for TNBC. Anchorage dependent growth, cell cycle progression, status of cell cycle regulatory proteins and anchorage independent colony formation, represent the quantitative biomarkers for efficacy. Results: Relative to the non-tumorigenic 184-B5 human mammary epithelial cells, the tumor derived MDA-MB-231 cells exhibited decreased population doubling time, increased saturation density, decreased G1: S+G2/M ratio and increased S+G2/M: Sub G0 ratio, indicating loss of homeostatic growth control. Additionally, unlike 184-B5 cells, MDA-MB-231 cells exhibited increased anchorage independent growth in vitro and tumor development in vivo, indicating enhanced cancer risk. Treatment of MDA-MB-231 cells with TA resulted in a substantial dose dependent cytostatic growth arrest (IC50:1.0%; IC90: 2.5%). Cell cycle analysis of TA treated cells revealed G1 arrest, leading to a progressive dose dependent increase in the G1: S+G2/M ratio. Mechanistically, TA decreased Cyclin D1 expression and attenuated RB phosphorylation, predicting Cyclin D-CDK4-pRB pathway as a molecular target for efficacy. Furthermore, TA effectively inhibited anchorage independent growth in a dose dependent manner. Conclusions: Present data demonstrated pronounced efficacy of TA as a naturally occurring nutritional substance in a cell culture model for TNBC, and validated TA as a promising non-toxic natural agent for secondary prevention/therapy of clinical TNBC. Citation Format: Nitin T Telang, Hareesh B Nair, George YC Wong. Efficacy of tabebuia avellandae extract on a cell culture model for triple negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-14-02.

Cellular Metabolism of Estradiol in Models for Select Molecular Subtypes of Clinical Breast Cancer

The mitogenic ovarian steroid hormone 17β-estradiol (E2) is associated with progression of Estrogen Receptor Positive (ER+) breast cancer, and ER represents a major therapeutic target for endocrine therapy. In addition to the ER dependent signal transduction, cellular oxidative metabolism of the ER ligand E2 generates several metabolites with pleotropic growth modulatory effects on breast cancer cells, providing valuable leads for novel therapeutic approach. The molecular classification of clinical breast cancer has defined cancer subtypes based on differential expression of the genes for hormones and growth factor receptors, thereby facilitating subtype targeted therapeutic interventions. However, de novo or acquired resistance to conventional endocrine and targeted small molecule based treatment limits the therapeutic efficacy and promotes therapy resistant disease progression. These aspects emphasize the need for identification of new efficacious non-toxic lead compounds. The present review summarizes critical experiments conducted to i) develop and optimize human tissue derived cell culture models for select molecular subtypes of clinical breast cancer, ii) determine the status of homeostatic growth control, cellular metabolism of 17β-estradiol (E2) and cancer risk in the developed models, and iii) evaluate the therapeutic efficacy and identify possible mechanisms of action of select herbal extracts/phyto-chemical. Additionally, this review discusses the evidence for the role of E2 metabolism in breast carcinogenesis and therapy. The data generated from the cell culture experiments demonstrate that the models for select molecular sub-types exhibit aberrant hyperproliferation, altered cellular metabolism of E2 and enhanced cancer risk. Select mechanistically distinct herbal extracts and natural phyto-chemical at their respective maximum cytostatic concentrations modulate cellular metabolism of E2 favoring generation of anti-proliferative metabolites and inhibit anchorage independent growth, thus reducing cancer risk. Collectively, these data validate the present mechanism based cell culture approach to identify and prioritize novel efficacious lead compounds for subtype targeted therapy of clinical breast cancer.

A review of cancer risk prediction models with genetic variants.

Cancer risk prediction models are important in identifying individuals at high risk of developing cancer, which could result in targeted screening and interventions to maximize the treatment benefit and minimize the burden of cancer. The cancer-associated genetic variants identified in genome-wide or candidate gene association studies have been shown to collectively enhance cancer risk prediction, improve our understanding of carcinogenesis, and possibly result in the development of targeted treatments for patients. In this article, we review the cancer risk prediction models that have been developed for popular cancers and assess their applicability, strengths, and weaknesses. We also discuss the factors to be considered for future development and improvement of models for cancer risk prediction.

UV radiation and the skin.

UV radiation (UV) is classified as a “complete carcinogen” because it is both a mutagen and a non-specific damaging agent and has properties of both a tumor initiator and a tumor promoter. In environmental abundance, UV is the most important modifiable risk factor for skin cancer and many other environmentally-influenced skin disorders. However, UV also benefits human health by mediating natural synthesis of vitamin D and endorphins in the skin, therefore UV has complex and mixed effects on human health. Nonetheless, excessive exposure to UV carries profound health risks, including atrophy, pigmentary changes, wrinkling and malignancy. UV is epidemiologically and molecularly linked to the three most common types of skin cancer, basal cell carcinoma, squamous cell carcinoma and malignant melanoma, which together affect more than a million Americans annually. Genetic factors also influence risk of UV-mediated skin disease. Polymorphisms of the melanocortin 1 receptor (MC1R) gene, in particular, correlate with fairness of skin, UV sensitivity, and enhanced cancer risk. We are interested in developing UV-protective approaches based on a detailed understanding of molecular events that occur after UV exposure, focusing particularly on epidermal melanization and the role of the MC1R in genome maintenance.

Ionizing Radiation–Induced γ-H2AX Activity in Whole Blood Culture and the Risk of Lung Cancer

Phenotypic biomarkers of DNA damage repair may enhance cancer risk prediction. The γ-H2AX formed at the sites of double-strand break (DSB) after ionizing radiation is a specific marker of DNA damage. In an ongoing case-control study, the baseline and ionizing radiation-induced γ-H2AX levels in peripheral blood lymphocytes (PBL) from frequency-matched 306 untreated patients with lung cancer and 306 controls were measured by a laser scanning cytometer-based immunocytochemical method. The ratio of ionizing radiation-induced γ-H2AX level to the baseline was used to evaluate interindividual variation of DSB damage response and to assess the risk of lung cancer by using unconditional multivariable logistic regression with adjustment of age, sex, ethnicity, smoking status, family history of lung cancer, dust exposure, and emphysema. The mean γ-H2AX ratio was significantly higher in cases than controls (1.46 ± 0.14 vs. 1.41 ± 0.12, P < 0.001). Dichotomized at the median in controls, high γ-H2AX ratio was significantly associated with increased risk of lung cancer [OR = 2.43; 95% confidence interval (CI): 1.66-3.56]. There was also a significant dose-response relationship between γ-H2AX ratio and lung cancer risk in quartile analysis. Analysis of joint effects with other epidemiologic risk factors revealed elevated risk with increasing number of risk factors. γ-H2AX activity as shown by measuring DSB damage in ionizing radiation-irradiated PBLs may be a novel phenotypic marker of lung cancer risk. γ-H2AX assay is a robust and quantifiable image-based cytometer method that measures mutagen-induced DSB response in PBLs as a potential biomarker in lung cancer risk assessment.

Genome-Wide Association Study Reveals Novel Genetic Determinants of DNA Repair Capacity in Lung Cancer

Suboptimal cellular DNA repair capacity (DRC) has been shown to be associated with enhanced cancer risk, but genetic variants affecting the DRC phenotype have not been comprehensively investigated. In this study, with the available DRC phenotype data, we analyzed correlations between the DRC phenotype and genotypes detected by the Illumina 317K platform in 1,774 individuals of European ancestry from a Texas lung cancer genome-wide association study. The discovery phase was followed by a replication in an independent set of 1,374 cases and controls of European ancestry. We applied a generalized linear model with single nucleotide polymorphisms as predictors and DRC (a continuous variable) as the outcome. Covariates of age, sex, pack-years of smoking, DRC assay-related variables, and case-control status of the study participants were adjusted in the model. We validated that reduced DRC was associated with an increased risk of lung cancer in both independent datasets. Several suggestive loci that contributed to the DRC phenotype were defined in ERCC2/XPD, PHACTR2, and DUSP1. In summary, we determined that DRC is an independent risk factor for lung cancer, and we defined several genetic loci contributing to DRC phenotype.

Abstract IA11A: Tumor heterogeneity: Making the most of diversity.

Abstract Initial genome wide association studies (GWAS) of common cancers focused on combining all available cases in order to maximize the statistical power of the studies. While many genome wide significant associations (p &amp;lt; 5 × 10−8) were observed, this approach overlooked the possibility that certain genetic risk factors might have greater effects in specific populations. With this in mind more recent studies have focused on associations between common genetic variants and disease in populations other than those of northern European ancestry. In addition, GWAS of predisposed individuals, such as carriers of BRCA1 and BRCA2 mutations, have been conducted based on the hypothesis that unique modifiers of breast and ovarian cancer risk might influence disease in these populations. More recently, associations with histological subtypes of tumors have been observed for a number of different cancer types. In the setting of breast cancer, specific associations with estrogen receptor status of tumors and even triple negative tumors (estrogen receptor, progesterone receptor, and HER2 negative) have been reported. Ongoing studies further suggest that specific associations with histochemical markers and tumor grade may also exist in the general population. Here we will discuss recent associations between genetic variants and subpopulations of disease using breast cancer as a model, and consider the importance of these findings for an improved understanding of the etiology of breast cancer and enhanced cancer risk assessment. Citation Format: Fergus J. Couch. Tumor heterogeneity: Making the most of diversity. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA11A.

Impact of Two Common Xeroderma Pigmentosum Group D (XPD) Gene Polymorphisms on Risk of Prostate Cancer

BackgroundDNA repair genes (eg: xeroderma pigmentosum group D, XPD) may affect the capacity of encoded DNA repair enzymes to effectively remove DNA adducts or lesions, which may result in enhanced cancer risk. The association between XPD gene polymorphisms and the susceptibility of prostate cancer (PCa) was inconsistent in previous studies.Methodology/Principal FindingsA meta-analysis based on 9 independent case-control studies involving 3165 PCa patients and 3539 healthy controls for XPD Gln751Lys SNP (single nucleotide polymorphism) and 2555 cases and 3182 controls for Asn312Asp SNP was performed to address this association. Meanwhile, odds ratio (OR) and 95% confidence intervals (CIs) were used to evaluate this relationship. Statistical analysis was performed with STATA10.0. No significant association was found between XPD Gln751Lys SNP and PCa risk. On the other hand, in subgroup analysis based on ethnicity, associations were observed in Asian (eg. Asn vs. Asp: OR = 1.34, 95%CI = 1.16–1.55; Asn/Asn+Asn/Asp vs. Asp/Asp: OR = 1.23, 95%CI = 1.07–1.42) and African (eg. Asn vs. Asp: OR = 1.31, 95%CI = 1.01–1.70; Asn/Asn vs. Asp/Asp: OR = 1.71, 95%CI = 1.03–7.10) populations for Asn312Asp SNP. Moreover, similar associations were detected in hospital-based controls studies; the frequency of Asn/Asn genotype in early stage of PCa men was poorly higher than those in advanced stage of PCa men (OR = 1.45, 95%CI = 1.00–2.11).Conclusion/SignificanceOur investigations demonstrate that XPD Asn312Asp SNP not the Gln751Lys SNP, might poorly increase PCa risk in Asians and Africans, moreover, this SNPs may associate with the tumor stage of PCa. Further studies based on larger sample size and gene-environment interactions should be conducted to determine the role of XPD gene polymorphisms in PCa risk.

Protons sensitize epithelial cells to mesenchymal transition.

Proton radiotherapy has gained more favor among oncologists as a treatment option for localized and deep-seated tumors. In addition, protons are a major constituent of the space radiation astronauts receive during space flights. The potential for these exposures to lead to, or enhance cancer risk has not been well studied. Our objective is to study the biological effects of low energy protons on epithelial cells and its propensity to enhance transforming growth factor beta 1 (TGFβ1)-mediated epithelial-mesenchymal transition (EMT), a process occurring during tumor progression and critical for invasion and metastasis. Non-transformed mink lung epithelial cells (Mv1Lu) and hTERT- immortalized human esophageal epithelial cells (EPC) were used in this study. EMT was identified by alterations in cell morphology, EMT-related gene expression changes determined using real-time PCR, and EMT changes in specific cellular markers detected by immunostaining and western blotting. Although TGFβ1 treatment alone is able to induce EMT in both Mv1Lu and EPC cells, low energy protons (5 MeV) at doses as low as 0.1 Gy can enhance TGFβ1 induced EMT. Protons alone can also induce a mild induction of EMT. SD208, a potent TGFβ Receptor 1 (TGFβR1) kinase inhibitor, can efficiently block TGFβ1/Smad signaling and attenuate EMT induction. We suggest a model for EMT after proton irradiation in normal and cancerous tissue based on our results that showed that low and high doses of protons can sensitize normal human epithelial cells to mesenchymal transition, more prominently in the presence of TGFβ1, but also in the absence of TGFβ1.

Growth Signals, Inflammation, and Vascular Perturbations

Nearly 35% of adults and 20% of children in the United States are obese, defined as a body mass index ≥ 30 kg/m(2). Obesity, which is accompanied by metabolic dysregulation often manifesting in the metabolic syndrome, is an established risk factor for many cancers. Within the growth-promoting, proinflammatory environment of the obese state, cross talk between macrophages, adipocytes, and epithelial cells occurs via obesity-associated hormones, cytokines, and other mediators that may enhance cancer risk and progression. This review synthesizes the evidence on key biological mechanisms underlying the obesity-cancer link, with particular emphasis on obesity-associated enhancements in growth factor signaling, inflammation, and vascular integrity processes. These interrelated pathways represent possible mechanistic targets for disrupting the obesity-cancer link.

Enhancement of natural radioactivity in fertilized soil of Faisalabad, Pakistan

BACKGROUND, GOAL, AND SCOPE: Natural radioactivity in phosphate rock (PR) is transferred to phosphate fertilizer (PF) during the manufacturing process of the PF. The continuous addition of the PF to the cultivated soil accumulates the radionuclides in the land and increases the level of radioactivity in the soil. The purpose of the present study was to investigate the enhanced level of accumulated radioactivity due to the continuous addition of the PF in the farmlands of Nuclear Institute of Agriculture and Biology (NIAB) at Faisalabad in Pakistan. The selected study area consisted of the highly fertilized farmlands and an unfertilized barren land of the NIAB. The understudy area is very fertile for the growth of various types of crops; therefore, four agricultural research institutes have been established at Faisalabad and NIAB is one of those. The NIAB has developed various research farmlands at different places in Pakistan. The crop yield has been increased by adding various fertilizers in the farmlands. The addition of the PF accompanied with the radionuclides enhances radioactivity in the fields. Human being is exposed directly or indirectly to this radiological hazard. A prolong exposure may become a cause of health risk. The area of study consisted of three types of lands: the land under cultivation for the last 40 and 30 years called Site 1 and Site 2, respectively, and the barren land was called Site 3. A total of 75 soil samples were collected within the crop rooting zone (up to 25 cm deep) of the soil of the NIAB farms. The samples were dried, pulverized to powder, sealed in plastic containers, and stored to achieve equilibrium between (226)Ra and (222)Rn. Activity concentrations of the radionuclides (238)U ((226)Ra), (232)Th, and (40)K in soil samples were determined by using a high resolution gamma ray spectrometry system, consisting of an high purity germanium detector coupled through a spectroscopy amplifier with a PC based MCA installed with Geni-2000 software. The measured activity concentration levels of (40)K were 662 ± 15, 615 ± 17, and 458 ± 20 Bq kg(-1), (226)Ra were 48 ± 6, 43 ± 5, and 26 ± 4 Bq kg(-1), and that of (232)Th were 39 ± 5, 37 ± 5, 35 ± 5 Bq kg(-1), respectively, in the soil of the Sites 1, 2, and 3. Gamma dose rate 1 m above the soil surface was 55, 51, and 40 nGy h(-1) from Sites 1, 2, and 3, respectively. External dose rates in the rooms constructed of the bricks made of the soil from Sites 1, 2, and 3 were 161, 149, and 114 nGyh(-1), respectively. Activity concentration values of (40)K and (226)Ra in the soil of Sites 1 and 2 were higher than that in the soil of Site 3. The relative rise of (40)K was 43 % and 34 % and that of (226)Ra was 85 % and 65 % respectively in these sites. Activity concentrations of (232)Th in all these sites were in the background range. Gamma dose rate 1 m above soil surface of Sites 1 and 2 was 40 % and 30 % respectively higher than that from the soil of Site 3. The rise in activity of (40)K and (226)Ra and gamma dose from the Site 1 was greater than that from the Site 2. The least activity and dose were observed from the Site 3. Gamma dose in the dwellings made of fertilized soil bricks of Site 1 and Site 2 were respectively calculated to be 41 % and 32 % higher than that in the abodes made of unfertilized soil bricks of Site 3. Activity concentrations of (226)Ra and (40)K were observed to be enhanced in the fertilized farmlands of the NIAB. Outdoor and indoor gamma dose as radiological hazard were found to be increasing with the continuous addition of PF in the understudy farmlands. It is recommended that naturally occurring radioactive metal should be removed during the process of manufacturing of the PF from the PR. PROSPECTIVE: The rise in radioactivity in the farmlands due to the addition of the PF can be a source of direct or indirect exposure to radiation that may enhance cancer risk of the exposed individuals.