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Journal Cover Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
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   Hybrid Journal Hybrid journal (It can contain Open Access articles)
     ISSN (Print) 0027-5107
     Published by Elsevier Homepage  [2563 journals]   [SJR: 0.324]   [H-I: 11]
  • Inherited variability in a master regulator polymorphism (rs4846126)
           associates with survival in 5-FU treated colorectal cancer patients
    • Abstract: Publication date: Available online 7 June 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Barbara Pardini , Justo Lorenzo Bermejo , Alessio Naccarati , Cornelia Di Gaetano , Fabio Rosa , Carine Legrand , Jan Novotny , Pavel Vodicka , Rajiv Kumar
      Background Treatment with 5-fluorouracil (5-FU) is known to improve survival in many cancers including colorectal cancer. Response to the treatment, overall survival and recurrence show inter-individual variation. Methods In this study we employed a strategy to search eQTL variants influencing the expression of a large number of genes. We identified four single nucleotide polymorphisms, defined as master regulators of transcription, and genotyped them in a set of 218 colorectal cancer patients undergoing adjuvant 5-FU based therapy. Results Our results showed that the minor allele variant of the rs4846126 polymorphism was associated with poor overall and progression-free survival. Patients that were homozygous for the variant allele showed an over two fold increased risk of death (HR 2.20 95%CI 1.05-4.60) and progression (HR 2.88, 95% 1.47-5.63). The integration of external information from publicly available gene expression repositories suggested that the rs4846126 polymorphism deserves further investigation. This variant potentially regulates the gene expression of 273 genes with some of them possibly associated to the patient's response to 5-FU treatment or colorectal cancer. Conclusions Present results show that mining of public data repositories in combination with own data can be a fruitful approach to identify markers that affect therapy outcome. In particular, a genetic screen of master regulators may help in order to search for the polymorphisms involved in treatment response in cancer patients.

      PubDate: 2014-06-08T16:18:34Z
  • Impact of abasic site orientation within nucleosomes on human APE1
           endonuclease activity
    • Abstract: Publication date: Available online 6 June 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): John M. Hinz
      Glycosylases responsible for recognizing DNA lesions and initiating Base Excision Repair (BER) are impeded by the presence of histones, which are essential for compaction of the genetic material in the nucleus. Abasic sites are an abundant mutagenic lesion in the DNA, arising spontaneously and as the product of glycosylase activity, making it a common intermediate in BER. The apurinic/apyrimidinic endonuclease 1 (APE1) recognizes abasic sites and cleaves the DNA backbone adjacent to the lesion, creating the single-strand break essential for the subsequent steps of BER. In this study the endonuclease activity of human APE1 was measured on reconstituted nucleosome core particles (NCPs) with DNA containing enzymatically-created abasic sites (AP) or the abasic site analog tetrahydrofuran (TF) at different rotational positions relative to the histone core surface. The presence of histones on the DNA reduced APE1 activity overall, and the magnitude was greatly influenced by differences in orientation of the lesions along the DNA gyre relative to the histone core. Abasic moieties oriented with their phosphate backbones adjacent to the underlying histones (In) were cleaved less efficiently than those oriented away from the histone core (Out) or between the In and Out orientations (Mid). The impact on APE1 at each orientation was very similar between the AP and TF lesions, highlighting the dependability of the TF abasic analog in APE1 activity measurements in nucleosomes. Measurement of APE1 binding to the NCP substrates reveals a substantial reduction in its interaction with nucleosomes compared to naked DNA, also in a lesion orientation-dependent manner, reinforcing the concept that reduction in APE1 activity on nucleosomes is due to occlusion from its abasic DNA substrate by the histones. These results suggest that APE1 activity in nucleosomes, like BER glycosylases, is primarily regulated by its chance interactions with transiently exposed lesions

      PubDate: 2014-06-08T16:18:34Z
  • Acute and chronic administration of gold nanoparticles cause dna damage in
           the cerebral cortex of adult rats
    • Abstract: Publication date: Available online 6 June 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Eria Cardoso , Gislaine Tezza Rezin , Elton Torres Zanoni , Frederico de Souza Notoya , Daniela Dimer Leffa , Adriani Paganini Damiani , Francine Daumann , Juan Carlos Ortiz Rodriguez , Roberto Benavides , Luciano da Silva , Vanessa M. Andrade , Marcos Marques da Silva Paula
      The use of gold nanoparticles is increasing in medicine; however, their toxic effects remain to be elucidated. Studies show that gold nanoparticles can cross the blood–brain barrier, as well as accumulate in the brain. Therefore, this study was undertaken to better understand the effects of gold nanoparticles on rat brains. DNA damage parameters were evaluated in the cerebral cortex of adult rats submitted to acute and chronic administration of gold nanoparticles of two different diameters: 10 and 30nm. During acute administration, adult rats received a single intraperitoneal injection of either gold nanoparticles or saline solution. During chronic administration, adult rats received a daily single injection for 28 days of the same gold nanoparticles or saline solution. Twenty-four hours after either single (acute) or last injection (chronic), the rats were euthanized by decapitation, their brains removed, and the cerebral cortices isolated for evaluation of DNA damage parameters. Our study showed that acute administration of gold nanoparticles in adult rats presented higher levels of damage frequency and damage index in their DNA compared to the control group. It was also observed that gold nanoparticles of 30nm presented higher levels of damage frequency and damage index in the DNA compared to the 10nm ones. When comparing the effects of chronic administration of gold nanoparticles of 10 and 30nm, we observed that occured significant different index and frequency damage, comparing with control group. However, there is no difference between the 10 and 30nm groups in the levels of DNA damage for both parameters of the Comet assay. Results suggest that gold nanoparticles for both sizes cause DNA damage for chronic as well as acute treatments, although a higher damage was observed for the chronic one

      PubDate: 2014-06-08T16:18:34Z
  • Expression and Methylation of DNA Repair Genes in Lens Epithelium Cells of
           Age-related Cataract
    • Abstract: Publication date: Available online 6 June 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Fei Li , Yong Wang , Guowei Zhang , Jing Zhou , Ling Yang , Huaijin Guan
      The development of age-related cataract (ARC) is associated with DNA damage of the lens epithelial cells (LECs). This study aimed to investigate the expression level of DNA repair genes in LECs of ARC and examine whether any altered expression observed could result from DNA methylation of the promoter region of the genes. The expression levels of DNA repair genes were evaluated by microarray analysis. The results were further confirmed by qRT-PCR. DNA methylation of genes with altered expression was determined by Bisulfite-specific (BSP) PCR. The mRNA levels of 10 DNA repair genes were decreased and the level of 1 DNA repair gene was increased in LECs of ARC patients compared with controls. The promoter region of the MGMT gene was hypermethylated in ARC tissue compared to controls. The data provides evidence that altered expression of DNA repair genes is associated with pathogenesis of ARC. DNA methylation of MGMT may regulate the expression of the gene and be involved in the development of ARC.

      PubDate: 2014-06-08T16:18:34Z
    • Abstract: Publication date: July 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 765

      PubDate: 2014-06-02T15:10:06Z
  • A functional perspective of Nitazoxanide as a potential anticancer drug
    • Abstract: Publication date: Available online 1 June 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Nicola Di Santo , Jessie Ehrisman
      Cancer is a group of diseases characterized by uncontrolled cell proliferation, evasion of cell death and the ability to invade and disrupt vital tissue function. The classic model of carcinogenesis describes successive clonal expansion driven by the accumulation of mutations that eliminate restraints on proliferation and cell survival. It has been proposed that during cancer's development, the loose-knit colonies of only partially differentiated cells display some unicellular/prokaryotic behavior reminiscent of robust ancient life forms. The seeming “regression” of cancer cells involves changes within metabolic machinery and survival strategies. This atavist change in physiology enables cancer cells to behave as selfish “neo-endo-parasites” that exploit the tumor stromal cells in order to extract nutrients from the surrounding microenvironment. In this framework, it is conceivable that anti-parasitic compounds might serve as promising anticancer drugs. Nitazoxanide (NTZ), a thiazolide compound, has shown antimicrobial properties against anaerobic bacteria, as well as against helminths and protozoa. NTZ has also been successfully used to promote Hepatitis C virus (HCV) elimination by improving interferon signaling and promoting autophagy. More compelling however are the potential anti-cancer properties that have been observed. NTZ seems to be able to interfere with crucial metabolic and pro-death signaling such as drug detoxification, unfolded protein response (UPR), autophagy, anti-cytokine activities and c-Myc inhibition. In this article, we review the ability of NTZ to interfere with integrated survival mechanisms of cancer cells and propose that this compound might be a potent addition to the current chemotherapeutic strategy against cancer.

      PubDate: 2014-06-02T15:10:06Z
  • Mechanistic perspectives on cancer chemoprevention/chemotherapeutic
           effects of thymoquinone
    • Abstract: Publication date: Available online 27 May 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Juthika Kundu , Kyung-Soo Chun , Okezie I. Aruoma , Joydeb Kumar Kundu
      The bioactive natural products (secondary metabolites) are widely known to possess therapeutic value for the prevention and treatment of various chronic diseases including cancer. Thymoquinone (2-methyl-5-isopropyl-1,4-benzoquinone; TQ), a monoterpene present in black cumin seeds, exhibits pleiotropic pharmacological activities including antioxidant, anti-inflammatory, antidiabetic and antitumor effects. TQ inhibits experimental carcinogenesis in a wide range of animal models and has been shown to arrest the growth of various cancer cells in culture as well as xenograft tumors in vivo. The mechanistic basis of anticancer effects of TQ includes the inhibition of carcinogen metabolizing enzyme activity and oxidative damage of cellular macromolecules, attenuation of inflammation, induction of cell cycle arrest and apoptosis in tumor cells, blockade of tumor angiogenesis, and suppression of migration, invasion and metastasis of cancer cells. TQ shows synergistic and/or potentiating anticancer effects when combined with clinically used chemotherapeutic agents. At the molecular level, TQ targets various components of intracellular signaling pathways, particularly a variety of upstream kinases and transcription factors, which are aberrantly activated during the course of tumorigenesis.

      PubDate: 2014-06-02T15:10:06Z
  • Noninvasive measurement of aristolochic acid-DNA adducts in urine samples
           from aristolochic acid-treated rats by liquid chromatography coupled
           tandem mass spectrometry: Evidence for DNA repair by nucleotide-excision
           repair mechanisms
    • Abstract: Publication date: Available online 29 May 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Elvis M.K. Leung , Wan Chan
      Nephrotoxic aristolochic acids (AAs) form covalently bonded DNA adducts upon metabolic activation. In this work, a non-invasive approach to detect AAs exposure by quantifying urinary excreted DNA-AA adducts is presented. The developed method entails solid-phase extraction (SPE) enrichment of the urine-excreted DNA-AAs adducts, addition of internal standard, and quantification by liquid chromatography coupled tandem mass spectrometric (LC–MS/MS) analysis. Quantitative analysis revealed 7-(deoxyadenosine-N 6-yl)-aristolactam II and 7-(deoxyguanosine-N 2-yl)-aristolactam I that were previously detected as major DNA-AA adducts in different organs of AA-dosed rats, were detected as the major urine excreted adducts. Lower levels of 7-(deoxyadenosine-N 6-yl)-aristolactam I and 7-(deoxyguanosine-N 2-yl)-aristolactam II were also detected in the collected urine samples. The identities of the detected urinary DNA-AA adducts were confirmed by comparing chromatographic retention time with synthetic standards, by high-accuracy MS, and MS/MS analyses. LC–MS/MS analysis of the urine samples collected from the AAs-dosed rats demonstrated a time-dependent decrease in the urinary adduct levels, indicating the urinary DNA-AA adduct levels were reflective of the tissue adduct levels. It is expected that the developed approach of detecting urinary DNA-AA adducts will facilitate further carcinogenesis investigations of AAs.

      PubDate: 2014-06-02T15:10:06Z
  • Silibinin inhibits fibronectin induced motility, invasiveness and survival
           in human prostate carcinoma PC3 cells via targeting integrin signaling
    • Abstract: Publication date: Available online 23 May 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Gagan Deep , Rahul Kumar , Anil K. Jain , Chapla Agarwal , Rajesh Agarwal
      Prostate cancer (PCA) is the 2nd leading cause of cancer-related deaths among men in the United States. Preventing or inhibiting metastasis-related events through non-toxic agents could be a useful approach for lowering high mortality among PCA patients. We have earlier reported that natural flavonoid silibinin possesses strong anti-metastatic efficacy against PCA however, mechanism/s of its action still remains largely unknown. One of the major events during metastasis is the replacement of cell-cell interaction with integrins-based cell-matrix interaction that controls motility, invasiveness and survival of cancer cells. Accordingly, here we examined silibinin effect on advanced human PCA PC3 cells’ interaction with extracellular matrix component fibronectin. Silibinin (50-200μM) treatment significantly decreased the fibronectin (5μg/ml)-induced motile morphology via targeting actin cytoskeleton organization in PC3 cells. Silibinin also decreased the fibronectin-induced cell proliferation and motility but significantly increased cell death in PC3 cells. Silibinin also inhibited the PC3 cells invasiveness in Transwell invasion assays with fibronectin or cancer associated fibroblasts (CAFs) serving as chemoattractant. Importantly, PC3-luc cells cultured on fibronectin showed rapid dissemination and localized in lungs following tail vein injection in athymic male nude mice; however, in silibinin-treated PC3-luc cells, dissemination and lung localization was largely compromised. Molecular analyses revealed that silibinin treatment modulated the fibronectin-induced expression of integrins (α5, αV, β1 and β3), actin-remodeling (FAK, Src, GTPases, ARP2 and cortactin), apoptosis (cPARP and cleaved caspase 3), EMT (E-cadherin and β-catenin), and cell survival (survivin and Akt) related signaling molecules in PC3 cells. Furthermore, PC3-xenograft tissue analyses confirmed the inhibitory effect of silibinin on fibronectin and integrins expression. Together, these results showed that silibinin targets PCA cells’ interaction with fibronectin and inhibits their motility, invasiveness and survival; thus further supporting silibinin use in PCA intervention including its metastatic progression.

      PubDate: 2014-05-26T00:41:08Z
    • Abstract: Publication date: May–June 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volumes 763–764

      PubDate: 2014-05-15T17:48:12Z
  • DNA damage and S phase arrest induced by Ochratoxin A in human embryonic
           kidney cells (HEK 293)
    • Abstract: Publication date: Available online 9 May 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Qian Yang , Xiaoyun He , Xiaohong Li , Wentao Xu , Yunbo Luo , Xuan Yang , Yan Wang , Yingcong Li , Kunlun Huang
      Ochratoxin A (OTA) is a ubiquitous mycotoxin with potential nephrotoxic, hepatotoxic and immunotoxic effects. The mechanisms underlying the nephrotoxicity of OTA remain obscure. To investigate DNA damage and the changes of the cell cycle distribution induced by OTA, human embryonic kidney cells (HEK 293 cells) were incubated with various concentrations of OTA for 24h in vitro. The results indicated that OTA treatment led to the production of reactive oxygen species (ROS) and to a decrease of the mitochondrial membrane potential (ΔΨm). OTA-induced DNA damage in HEK 293 cells was evidenced by DNA comet tail formation and increased expression of γ-H2AX. In addition, OTA could induce cell cycle arrest at the S phase in HEK 293 cells. The expression of key cell cycle regulatory factors that were critical to the S phase, including cyclin A2, cyclin E1 and CDK2, were further detected. The expression of cyclin A2, cyclin E1 and CDK2 were significantly decreased by OTA treatment at both the mRNA and protein levels. The apoptosis of HEK 293 cells after OTA treatment was observed using Hoechst 33342 staining. The results confirmed that OTA did induce apoptosis in HEK 293 cells. In conclusion, our results provided new insights into the molecular mechanisms by which OTA might promote nephrotoxicity.

      PubDate: 2014-05-10T12:42:58Z
  • Dose- and time-dependent changes of micronucleus frequency and gene
           expression in the progeny of irradiated cells: Two components in
           radiation-induced genomic instability'
    • Abstract: Publication date: Available online 3 May 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Katriina Huumonen , Merja Korkalainen , Eeva Boman , Janne Heikkilä , Anne Höytö , Tapani Lahtinen , Jukka Luukkonen , Matti Viluksela , Jonne Naarala , Jukka Juutilainen
      Murine embryonic C3H/10T½ fibroblasts were exposed to X-rays at doses of 0.2, 0.5, 1, 2 or 5Gy. To follow the development of radiation-induced genomic instability (RIGI), the frequency of micronuclei was measured with flow cytometry at 2 days after exposure and in the progeny of the irradiated cells at 8 and 15 days after exposure. Gene expression was measured at the same points in time by PCR arrays profiling the expression of 84 cancer-relevant genes. The micronucleus results showed a gradual decrease in the slope of the dose–response curve between days 2 and 15. The data were consistent with a model assuming two components in RIGI. The first component is characterized by dose-dependent increase in micronuclei. It may persist more than ten cell generations depending on dose, but eventually disappears. The second component is more persistent and independent of dose above a threshold higher than 0.2Gy. Gene expression analysis 2 days after irradiation at 5Gy showed consistent changes in genes that typically respond to DNA damage. However, the consistency of changes decreased with time, suggesting that non-specificity and increased heterogeneity of gene expression are characteristic to the second, more persistent component of RIGI.

      PubDate: 2014-05-06T04:19:40Z
  • Nucleotide excision repair related gene polymorphisms and genetic
           susceptibility, chemotherapeutic sensitivity and prognosis of gastric
    • Abstract: Publication date: Available online 24 April 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Jingwei Liu , Caiyun He , Chengzhong Xing , Yuan Yuan
      Human genomic DNA is in a dynamic balance of damage and repair. Cells employ multiple and specific repair pathways, such as nucleotide excision repair (NER), as unrepaired DNA damage has deleterious consequences and could give rise to carcinogenesis. Gene polymorphisms play a crucial role in predicting the risk and prognosis of cancer. Polymorphisms of NER-related genes could alter the ability of NER to effectively monitor and repair DNA damage, and thus may be associated with genetic susceptibility, chemotherapeutic sensitivity and prognosis of cancer. In recent years, increasing studies have focused on the association between polymorphisms of NER genes and gastric cancer, the world's fourth most common cancer and the second most common cause for cancer-related death. Here we reviewed the recent studies on the associations between polymorphisms of NER genes and gastric cancer from perspectives of genetic susceptibility, chemotherapeutic sensitivity and prognosis.

      PubDate: 2014-04-26T04:20:20Z
  • Alpha particle induced DNA damage and repair in normal cultured thyrocytes
           of different proliferation status
    • Abstract: Publication date: Available online 21 April 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Madeleine Nordén Lyckesvärd , Ulla Delle , Helena Kahu , Sture Lindegren , Holger Jensen , Tom Bäck , John Swanpalmer , Kecke Elmroth
      Childhood exposure to ionizing radiation increases the risk of developing thyroid cancer later in life and this is suggested to be due to higher proliferation of the young thyroid. The interest of using high-LET alpha particles from Astatine-211 (211At), concentrated in the thyroid by the same mechanism as 131I [1], in cancer treatment has increased during recent years because of its high efficiency in inducing biological damage and beneficial dose distribution when compared to low-LET radiation. Most knowledge of the DNA damage response in thyroid is from studies using low-LET irradiation and much less is known of high-LET irradiation. In this paper we investigated the DNA damage response and biological consequences to photons from Cobolt-60 (60Co) and alpha particles from 211At in normal primary thyrocytes of different cell cycle status. For both radiation qualities the intensity levels of γH2AX decreased during the first 24h in both cycling and stationary cultures and complete repair was seen in all cultures but cycling cells exposed to 211At. Compared to stationary cells alpha particles were more harmful for cycling cultures, an effect also seen at the pChk2 levels. Increasing ratios of micronuclei per cell nuclei were seen up to 1Gy 211At. We found that primary thyrocytes were much more sensitive to alpha particle exposure compared with low-LET photons. Calculations of the relative biological effectiveness yielded higher RBE for cycling cells compared with stationary cultures at a modest level of damage, clearly demonstrating that cell cycle status influences the relative effectiveness of alpha particles.

      PubDate: 2014-04-26T04:20:20Z
  • Diabetes as a risk factor to cancer: Functional role of fermented papaya
           preparation as phytonutraceutical adjunct in the treatment of diabetes and
    • Abstract: Publication date: Available online 24 April 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Okezie I Aruoma , Jhoti Somanah , Emmanuel Bourdon , Philippe Rondeau , Theeshan Bahorun
      Oncologists and diabetologists quote scientific data from epidemiological and in-vitro studies to show that high levels of insulin and glucose, in combination with oxidative stress and chronic inflammation, can heighten the risk of developing cancer amongst patients with diabetics. Although the cancers that have been consistently associated with type 2 diabetes include pancreatic, colorectal, breast and liver cancer, the preponderance of the disease risk factors such as obesity, inflammation, hyperglycemia, hyperinsulinaemia (as a result of insulin resistance and oxidative β-cell damage) and the indirect influence of anti-diabetic medications are increasingly being defined. Fermented papaya preparation (FPP) has defined antioxidant and immune-modulating potentials. The ability of FPP influence signaling cascades associated with cell growth and survival presents a rational for chemopreventive adjunct that can be used in combination with traditional redox based therapies that target oxidative stress in the cancer micro environment. It is further suggested that the demonstrated efficacy FPP to control blood glucose, excessive inflammation and modulate free radical-induced oxidative damage which are triggers of liver, bladder, breast and prostate cancers in type 2 diabetics, may favorably mitigate the side effects of ensuing diabetes and cancer therapy. What remains paramount is early cancer detection and early determination of propensity risks for diabetes. The education of patients, proper dietary management and compliance with therapeutic regime directed at cancer and diabetes encapsulate challenges of global magnitude.

      PubDate: 2014-04-26T04:20:20Z
  • Individual telomere length decay in patients with spondyloarthritis
    • Abstract: Publication date: Available online 24 April 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): María Tamayo , Sonia Pértega , Alejandro Mosquera , Montserrat Rodríguez , Francisco J. Blanco , José Luis Fernández-Sueiro , Jaime Gosálvez , José Luis Fernández
      Telomere length was sequentially determined in peripheral blood leukocytes (PBL) from patients with ankylosing spondylitis (AS; n=44) and psoriatic arthritis (PsA; n=42) followed through 2.93±0.99 years, using a quantitative PCR (qPCR) assay. The initial telomere size from PsA patients was higher than those with cutaneous psoriasis only (n=53), possibly due to the inflammatory condition. The qPCR assay was sensitive enough to evidence a significant telomere length shortening in PBL from practically all subjects and PsA patients showed a higher rate of loss of telomere sequence than patients with AS during the follow-up time.

      PubDate: 2014-04-26T04:20:20Z
  • Polymeric nanomicelles for sustained delivery of anti-cancer drugs
    • Abstract: Publication date: Available online 24 April 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Roubeena Jeetah , Archana Bhaw-Luximon , Dhanjay Jhurry
      In the first section of this paper, theexisting and emerging nanotechnology-based cancer therapies–nanoparticles, drug conjugates, nanomicelles - are reviewed. In a second part, we present our original andunpublished findings on the sustained release of anti-cancer drugs such as paclitaxel, doxorubicin and camptothecin using block copolymer micelles [PEG-b-poly(dioxanone-co-methyl dioxanone)]. Copolymers with variable lengths of hydrophobic and hydrophilic blocks have been synthesized and successfully loaded with paclitaxel, doxorubicin and camptothecin anti-cancer drugs, with micelles size in the range 130-300nm. Drug encapsulation efficiencies varied between 15% and 70% depending on drug and copolymer composition. The drug binding constants, which give a good insight into drug encapsulation and release, were evaluated from UV spectroscopy as we reported previously for anti-TB drugs. Through variation of the methyl dioxanone content of the copolymer, our systems can be tailored for sustained release of the different drugs.

      PubDate: 2014-04-26T04:20:20Z
  • Free radical scavenging, antioxidant and cancer chemoprevention by grape
           seed proanthocyanidin: An overview
    • Abstract: Publication date: Available online 19 April 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Debasis Bagchi , Anand Swaroop , Harry G. Preuss , Manashi Bagchi
      A large number of investigations have demonstrated a broad spectrum of pharmacological and therapeutic benefits of grape seed proanthocyanidins (GSP) against oxidative stress and degenerative diseases including cardiovascular dysfunctions, acute and chronic stress, gastrointestinal distress, neurological disorders, pancreatitis, various stages of neoplastic processes and carcinogenesis including detoxification of carcinogenic metabolites. GSP exhibited potent free radical scavenging abilities in both in vitro and in vivo models. GSP exerted significant in vivo protection against structurally diverse drug and chemical-induced hepatotoxicity, cardiotoxicity, neurotoxicity, nephrotoxicity and spleentoxicity. GSP also protected against idarubicin and 4-hydroxyperoxy-cyclophosphamide-induced cytotoxicity towards human normal liver cells. GSP exhibited selective cytotoxicity towards selected human cancer cells, while enhancing the growth and viability of normal cells. GSP exhibited potent modulatory effects of pro-apoptotic and apoptotic regulatory bcl-XL, p53, c-myc, c-JUN, JNK-1 and CD36 genes. Long-term exposure to GSP may serve as a novel chemoprotectant against three stages of DMN-induced liver carcinogenesis and tumorigenesis including initiation, promotion and progression. GSP may selectively protect against oxidative stress, genomic integrity and cell death patterns in vivo. These results demonstrate that GSP may serve as a novel therapeutic intervention against carcinogenesis.

      PubDate: 2014-04-21T02:06:28Z
  • Genistein Inhibits Phorbol Ester-Induced NF-κB Transcriptional
           Activity and COX-2 Expression by Blocking the Phosphorylation of p65/Rel
           in Human Mammary Epithelial Cells
    • Abstract: Publication date: Available online 15 April 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Myung-Hoon Chung , Do-Hee Kim , Hye-Kyung Na , Jung-Hwan Kim , Ha-Na Kim , Guy Haegeman , Young-Joon Surh
      Genistein, an isoflavone present in soy products, has chemopreventive effects on mammary carcinogenesis. In the present study, we have investigated the effects of genistein on phorbol ester-induced expression of cyclooxygenase-2 (COX-2) that plays an important role in the pathophysiology of inflammation-associated carcinogenesis. Pretreatment of cultured human breast epithelial (MCF10A) cells with genistein reduced COX-2 expression induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). There are multiple lines of evidence supporting that the induction of COX-2 is regulated by the eukaryotic transcription factor NF-κB. Genistein failed to inhibit TPA-induced nuclear translocation and DNA binding of NF-κB as well as degradation of IκB. However, genistein abrogated the TPA-induced transcriptional activity of NF-κB as determined by the luciferase reporter gene assay. Genistein inhibited phosphorylation of the p65 subunit of NF-κB and its interaction with cAMP regulatory element-binding protein-binding protein (CBP)/p300 and TATA-binding protein (TBP). TPA-induced NF-κB phosphorylation was abolished by pharmacological inhibition of extracellular signal-regulated kinase (ERK). Likewise, pharmacologic inhibition or dominant negative mutation of ERK suppressed phosphorylation of p65. The above findings, taken together, suggest that genistein inhibits TPA-induced COX-2 expression in MCF10A cells by blocking ERK-mediated phosphorylation of p65 and its subsequent interaction with CBP and TBP.

      PubDate: 2014-04-15T23:03:45Z
  • The association between personal sun exposure, serum vitamin D and global
           methylation in human lymphocytes in a population of healthy adults in
           South Australia
    • Abstract: Publication date: Available online 12 April 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Visalini Nair-Shalliker , Varinderpal Dhillon , Mark Clements , Bruce K. Armstrong , Michael Fenech
      Background There is a positive association between solar UV exposure and micronucleus frequency in peripheral blood lymphocytes (PBL) and this association may be stronger when serum vitamin D (25(OH)D) levels are insufficient (<50nmol/L). Micronucleus formation can result from global hypomethylation of DNA repeat sequences. The aim of this analysis was to evaluate the relationship between solar UV exposure and methylation pattern in LINE-1 repetitive elements in PBL DNA and to see if serum 25(OH)D levels modify it. Method Personal solar UV exposure was estimated from hours of outdoor exposure over 6 weeks recalled at the time of blood collection in 208 male and female participants living in South Australia. Methylation in LINE-1 repetitive elements was assessed in PBL using pyrosequencing. Results Methylation in LINE-1 decreased with increasing solar UV exposure (% decrease=0.5% per doubling of sUV; 95%CI:-0.7-0.2 p value =0.00003). Although there was no correlation between LINE-1 methylation and micronucleus frequency, there was a 4.3% increase (95% CI:0.6-8.1 p-value=0.02) in nucleoplasmic bridges and a 4.3% increase in necrosis (CI:1.9-6.8 p-value=0.0005) for every 1% increase in LINE-1 methylation. Serum 25(OH)D was not associated with DNA methylation; nor did it modify the association of solar UV with DNA methylation. Conclusion Exposure to solar UV radiation may reduce DNA methylation in circulating lymphocytes. This association does not appear to be influenced or mediated by vitamin D status.

      PubDate: 2014-04-15T23:03:45Z
  • Unique molecular alteration patterns in von Hippel-Lindau (VHL) gene in a
           cohort of sporadic renal cell carcinoma patients from Pakistan
    • Abstract: Publication date: Available online 12 April 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Shagufta Khaliq , Sadia Ajaz , Sadaf Firasat , Saba Shahid , Asad Shahzad Hasan , Gauhar Sultan , Rehan Mohsin , Altaf Hashmi , Muhammed Mubarak , Syed Ali Anwar Naqvi , Syed Adib-ul-Hasan Rizvi , Syed Qasim Mehdi , Aiysha Abid
      Background Renal cell carcinoma (RCC) is the most frequent form of kidney cancer in adults. Somatic mutations that inactivate the von Hippel-Lindau (VHL) gene are the most common cause of RCC. The frequencies of molecular changes in the VHL gene in RCCs vary among different populations. So far, a single chromosomal-based study has been reported from a South Asian population. This report presents, for the first time, the somatic changes and promoter hypermethylation in VHL in a cohort of 300 RCC patients from Pakistan. Methods To identify mutations in the VHL gene, direct DNA sequencing was carried out. Epigenetic silencing was investigated by using methylation-specific polymerase chain reaction. Results Our data showed molecular alterations in the VHL gene in 163 (54%) renal cell carcinoma patients. Somatic mutations were found in 87 (29%) patients and 35 novel mutations were identified. VHL promoter hyper-methylation analysis showed epigenetic changes in 106 (35%) out of 300 patients. Patients who had no evidence of molecular alterations in the VHL gene were significantly younger than patients who carried some molecular change. Molecular alterations in the VHL gene were not restricted to clear-cell RCCs (ccRCCs). Conclusions This is the first report that identifies molecular aberrations in the VHL gene from a South Asian population. The frequency of somatic mutation is lower and that of promoter hypermethylation is higher when compared with data from other parts of the world. The data has important implications in the population-specific application of tailored preventive and therapeutic regimens in non-familial RCCs.

      PubDate: 2014-04-15T23:03:45Z
  • Activation of DNA damage repair pathways in response to nitrogen
           mustard-induced DNA damage and toxicity in skin keratinocytes
    • Abstract: Publication date: Available online 13 April 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Swetha Inturi , Neera Tewari-Singh , Chapla Agarwal , Carl W. White , Rajesh Agarwal
      Nitrogen mustard (NM), a structural analog of chemical warfare agent sulfur mustard (SM), forms adducts and crosslinks with DNA, RNA and proteins. Here we studied the mechanism of NM-induced skin toxicity in response to double strand breaks (DSBs) resulting in cell cycle arrest to facilitate DNA repair, as a model for developing countermeasures against vesicant-induced skin injuries. NM exposure of mouse epidermal JB6 cells decreased cell growth and caused S-phase arrest. Consistent with these biological outcomes, NM exposure also increased comet tail extent moment and the levels of DNA DSB repair molecules phospho H2A.X Ser139 and p53 Ser15 indicating NM-induced DNA DSBs. Since DNA DSB repair occurs via non homologous end joining pathway (NHEJ) or homologous recombination repair (HRR) pathways, next we studied these two pathways and noted their activation as defined by an increase in phospho- and total DNA-PK levels, and the formation of Rad51 foci, respectively. To further analyze the role of these pathways in the cellular response to NM-induced cytotoxicity, NHEJ and HRR were inhibited by DNA-PK inhibitor NU7026 and Rad51 inhibitor BO2, respectively. Inhibition of NHEJ did not sensitize cells to NM-induced decrease in cell growth and cell cycle arrest. However, inhibition of the HRR pathway caused a significant increase in cell death, and prolonged G2M arrest following NM exposure. Together, our findings, indicating that HRR is the key pathway involved in the repair of NM-induced DNA DSBs, could be useful in developing new therapeutic strategies against vesicant-induced skin injury.

      PubDate: 2014-04-15T23:03:45Z
  • Interplay between base excision repair activity and toxicity of
           3-methyladenine DNA glycosylases in an  E. coli complementation
    • Abstract: Publication date: Available online 4 April 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Christopher J. Troll , Suraj Adhikary , Marie Cueff , Ileena Mitra , Brandt F. Eichman , Manel Camps
      DNA glycosylases carry out the first step of base excision repair by removing damaged bases from DNA. The N3-methyladenine (3MeA) DNA glycosylases specialize in alkylation repair and are either constitutively expressed or induced by exposure to alkylating agents. To study the functional and evolutionary significance of constitutive versus inducible expression, we expressed two closely related yeast 3MeA DNA glycosylases—inducible S. cerevisiae MAG and constitutive S. pombe Mag1—in a glycosylase-deficient E. coli strain. In both cases, constitutive expression conferred resistance to alkylating agent exposure. However, in the absence of exogenous alkylation, high levels of expression of both glycosylases were deleterious. We attribute this toxicity to excessive glycosylase activity, since suppressing spMag1 expression correlated with improved growth in liquid culture, and spMag1 mutants exhibiting decreased glycosylase activity showed improved growth and viability. Selection of a random spMag1 mutant library for increased survival in the presence of exogenous alkylation resulted in the selection of hypomorphic mutants, providing evidence for the presence of a genetic barrier to the evolution of enhanced glycosylase activity when constitutively expressed. We also show that low levels of 3MeA glycosylase expression improve fitness in our glycosylase-deficient host, implying that 3MeA glycosylase activity is likely necessary for repair of endogenous lesions. These findings suggest that 3MeA glycosylase activity is evolutionarily conserved for repair of endogenously produced alkyl lesions, and that inducible expression represents a common strategy to rectify deleterious effects of excessive 3MeA activity in the absence of exogenous alkylation challenge.

      PubDate: 2014-04-05T13:11:06Z
    • Abstract: Publication date: April 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 762

      PubDate: 2014-04-05T13:11:06Z
  • Apoptosis inducing lead compounds isolated from marine organisms of
           potential relevance in Cancer Treatment
    • Abstract: Publication date: Available online 28 March 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Rima Beesoo , Vidushi Neergheen-Bhujun , Ranjeet Bhagooli , Theeshan Bahorun
      Apoptosis is a critical defense mechanism against the formation and progression of cancer and exhibits distinct morphological and biochemical traits. Targeting apoptotic pathways becomes an intriguing strategy for the development of chemotherapeutic agents particularly if the process is selective to cancer cells. Marine natural products have become important sources in the discovery of antitumor drugs, especially when recent technological and methodological advances have increased the scope of investigations of marine organisms. A high number of individual compounds from diverse organisms have induced apoptosis in several tumor cell lines via a number of mechanisms. Here, we review the effects of selected marine natural products and their synthetic derivatives on apoptosis signaling pathways in association with their pharmacological properties. Providing an outlook into the future, we also examine the factors that contribute to new discoveries and the difficulties associated with translating marine-derived compounds into clinical trials.

      PubDate: 2014-03-31T08:32:14Z
  • Damaging and protective bystander cross-talk between human lung cancer and
           normal cells after proton microbeam irradiation
    • Abstract: Publication date: Available online 28 March 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Sejal Desai , Alisa Kobayashi , Teruaki Konishi , Masakazu Oikawa , Badri N. Pandey
      Most of the studies of radiation-induced bystander effects (RIBE) have been focused on understanding the radiobiological changes observed in bystander cells in response to the signals from irradiated cells in a normal cell population with implications to radiation risk assessment. However, reports on RIBE with relevance to cancer radiotherapy especially investigating the bidirectional and criss-cross bystander communications between cancer and normal cells are limited. Hence, in present study employing co-culture approach, we have investigated the bystander cross-talk between lung cancer (A549) and normal (WI38) cells after proton-microbeam irradiation using γ-H2AX foci fluorescence as a measure of DNA double-strand breaks (DSBs). We observed that in A549–A549 co-cultures, irradiated A549 cells exert damaging effects in bystander A549 cells, which were found to be mediated through gap junctional intercellular communication (GJIC). However, in A549–WI38 co-cultures irradiated A549 did not affect bystander WI38 cells. Rather, bystander WI38 cells induced inverse protective signalling (rescue effect) in irradiated A549 cells, which was independent of GJIC. On the other hand, in response to irradiated WI38 cells neither of the bystander cells (A549 or WI38) showed significant increase in γ-H2AX foci. The observed bystander signalling between tumour and normal cells may have potential implications in therapeutic outcome of cancer radiotherapy.
      Graphical abstract image

      PubDate: 2014-03-31T08:32:14Z
  • Nonhomologous DNA end joining and chromosome aberrations in human
           embryonic lung fibroblasts treated with environmental pollutants
    • Abstract: Publication date: Available online 30 March 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Pavel Rossner , Andrea Rossnerova , Olena Beskid , Nana Tabashidze , Helena Libalova , Katerina Uhlirova , Jan Topinka , Radim J. Sram
      In order to evaluate the ability of a representative polycyclic aromatic hydrocarbon (PAH) and PAH-containing complex mixtures to induce double strand DNA breaks (DSBs) and repair of damaged DNA in human embryonic lung fibroblasts (HEL12469 cells), we investigated the effect of benzo[a]pyrene (B[a]P) and extractable organic matter (EOM) from ambient air particles <2.5μm (PM2.5) on nonhomologous DNA end joining (NHEJ) and induction of stable chromosome aberrations (CAs). PM2.5 was collected in winter and summer 2011 in two Czech cities differing in levels and sources of air pollutants. The cells were treated for 24h with the following concentrations of tested chemicals: B[a]P: 1μM, 10μM, 25μM; EOMs: 1μg/ml, 10μg/ml, 25μg/ml. We tested several endpoints representing key steps leading from DSBs to the formation of CAs including histone H2AX phosphorylation, levels of proteins Ku70, Ku80 and XRCC4 participating in NHEJ, in vitro ligation activity of nuclear extracts of the HEL12469 cells and the frequency of stable CAs assessed by whole chromosome painting of chromosomes 1, 2, 4, 5, 7 and 17 using fluorescence in situ hybridization. Our results show that 25μM of B[a]P and most of the tested doses of EOMs induced DSBs as indicated by H2AX phosphorylation. DNA damage was accompanied by induction of XRCC4 expression and an increased frequency of CAs. Translocations most frequently affected chromosome 7. We observed only a weak induction of Ku70/80 expression as well as ligation activity of nuclear extracts. In summary, our data suggest the induction of DSBs and NHEJ after treatment of human embryonic lung fibroblasts with B[a]P and complex mixtures containing PAHs.

      PubDate: 2014-03-31T08:32:14Z
  • Hydrogen sulfide (H2S)/cystathionine γ-lyase (CSE) pathway
           contributes to the proliferation of hepatoma cells
    • Abstract: Publication date: Available online 20 March 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Yan Pan , Shuang Ye , Dexiao Yuan , Jianghong Zhang , Yang Bai , Chunlin Shao
      Hydrogen sulfide (H2S)/cystathionine γ-lyase (CSE) pathway has been demonstrated to play vital roles in physiology and pathophysiology. However, its role in tumor cell proliferation remains largely unclear. Here we found that CSE over-expressed in hepatoma HepG2 and PLC/PRF/5 cells. Inhibition of endogenous H2S/CSE pathway drastically decreased the proliferation of HepG2 and PLC/PRF/5 cells, and it also enhanced ROS production and mitochondrial disruption, pronounced DNA damage and increased apoptosis. Moreover, this increase of apoptosis was associated with the activation of p53 and p21 accompanied by a decreased ratio of Bcl-2/Bax and up-regulation of phosphorylated c-Jun N-terminal kinase (JNK) and caspase-3 activity. In addition, the negative regulation of cell proliferation by inhibition of H2S/CSE system correlated with the blockage of cell mitogenic and survival signal transduction of epidermal growth factor receptor (EGFR) via down-regulating the extracellular-signal-regulated kinase 1/2 (ERK1/2) activation. These results demonstrate that H2S/CSE and its downstream pathway contribute to the proliferation of hepatoma cells, and inhibition of this pathway strongly suppress the excessive growth of hepatoma cells by stimulating mitochondrial apoptosis and suppressing cell growth signal transduction.

      PubDate: 2014-03-21T23:21:09Z
  • A ΔdinB mutation that sensitizes Escherichia coli to the lethal
           effects of UV and X-radiation
    • Abstract: Publication date: Available online 20 March 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Mei-Chong W. Lee , Magdalena Franco , Doris M. Vargas , Deborah A. Hudman , Steven J. White , Robert G. Fowler , Neil J. Sargentini
      The DinB (PolIV) protein of Escherichia coli participates in several cellular functions. We investigated a dinB mutation, Δ(dinB-yafN)883(::kan) [referred to as ΔdinB883], which strongly sensitized E. coli cells to both UV- and X-radiation killing. Earlier reports indicated dinB mutations had no obvious effect on UV radiation sensitivity which we confirmed by showing that normal UV radiation sensitivity is conferred by the ΔdinB749 allele. Compared to a wild-type strain, the ΔdinB883 mutant was most sensitive (160-fold) in early to mid-logarithmic growth phase and much less sensitive (twofold) in late log or stationary phases, thus showing a growth phase-dependence for UV radiation sensitivity. This sensitizing effect of ΔdinB883 is assumed to be completely dependent upon the presence of UmuDC protein; since the ΔdinB883 mutation did not sensitize the ΔumuDC strain to UV radiation killing throughout log phase and early stationary phase growth. The DNA damage checkpoint activity of UmuDC was clearly affected by ΔdinB883 as shown by testing a umuC104 ΔdinB883 double-mutant. The sensitivities of the ΔumuDC strain and the ΔdinB883 ΔumuDC double-mutant strain were significantly greater than for the ΔdinB883 strain, suggesting that the ΔdinB883 allele only partially suppresses UmuDC activity. The ΔdinB883 mutation partially sensitized (fivefold) uvrA and uvrB strains to UV radiation, but did not sensitize a ΔrecA strain. A comparison of the DNA sequences of the ΔdinB883 allele with the sequences of the Δ(dinB-yafN)882(::kan) and ΔdinB749 alleles, which do not sensitize cells to UV radiation, revealed ΔdinB883 is likely a “gain-of-function” mutation. The ΔdinB883 allele encodes the first 54 amino acids of wild-type DinB followed by 29 predicted residues resulting from the continuation of the dinB reading frame into an adjacent insertion fragment. The resulting polypeptide is proposed to interfere directly or indirectly with UmuDC function(s) involved in protecting cells against the lethal effects of radiation.

      PubDate: 2014-03-21T23:21:09Z
  • Reciprocal bystander effect between α-irradiated macrophage and
           hepatocyte is mediated by cAMP through a membrane signaling pathway
    • Abstract: Publication date: Available online 20 March 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Mingyuan He , Chen Dong , Yuexia Xie , Jitao Li , Dexiao Yuan , Yang Bai , Chunlin Shao
      Irradiated cells can induce biological effects on vicinal non-irradiated bystander cells, meanwhile the bystander cells may rescue the irradiated cells through a feedback signal stress. To elucidate the nature of this reciprocal effect, we examined the interaction between α-irradiated human macrophage cells U937 and its bystander HL-7702 hepatocyte cells using a cell co-culture system. Results showed that after 6h of cell co-culture, mitochondria depolarization corresponding to apoptosis was significantly induced in the HL-7702 cells, but the formation of micronuclei in the irradiated U937 cells was markedly decreased compared to that without cell co-culture treatment. This reciprocal effect was not observed when the cell membrane signaling pathway was blocked by filipin that inhibited cAMP transmission from bystander cells to irradiated cells. After treatment of cells with exogenous cAMP, forskolin (an activator of cAMP) or KH-7 (an inhibitor of cAMP), respectively, it was confirmed that cAMP communication from bystander cells to targeted cells could mitigate radiation damage in U739 cells, and this cAMP insufficiency in the bystander cells contributed to the enhancement of bystander apoptosis. Moreover, the bystander apoptosis in HL-7702 cells was aggravated by cAMP inhibition but it could not be evoked when p53 of HL-7702 cells was knocked down no matter of forskolin and KH-7 treatment. In conclusion, this study disclosed that cAMP could be released from bystander HL-7702 cells and compensated to α-irradiated U937 cells through a membrane signaling pathway and this cAMP communication played a profound role in regulating the reciprocal bystander effects.

      PubDate: 2014-03-21T23:21:09Z
  • Bipyridine (2,2′-dipyridyl) potentiates Escherichia coli lethality
           induced by nitrogen mustard mechlorethamine
    • Abstract: Publication date: Available online 13 March 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): T.A.M. De Alencar , T.C. Wilmart-Gonçalves , L.S. Vidal , R.S. Fortunato , A.C. Leitão , C. Lage
      Alkylating agents are used in anti-tumor chemotherapy because they bind covalently to DNA and generate adducts that may lead to cell death. Bifunctional (HN2) and monofunctional (HN1) nitrogen are two such agents, and HN2 was the first drug successfully employed in anti-leukemia chemotherapy. Currently, HN2 is used either alone or combined with other drugs to treat Hodgkin's disease. It is well known that several crosslinking agents require metabolic activation via reactive oxygen species (ROS) to exert their lethal effects. The objective of this work was therefore to determine whether the abovementioned mustards would also require metabolic activation to exert lethal action against Escherichia coli. For this purpose, we measured survival following exposure to HN2 in E. coli strains that were deficient in nucleotide excision repair (uvrA NER mutant), base excision repair (xthA nfo nth fpg BER mutant) or superoxide dismutase (sodAB mutant) activity. We also performed the same experiments in cells pretreated with an iron chelator (2,2’-dipyridyl, DIP). The NER and BER mutants were only sensitive to HN2 treatment (survival rates similar to those of the wild-type were achieved with 5-fold lower HN2 doses). However, wild-type and sodAB strains were not sensitive to treatment with HN2. In all tested strains, survival dropped by 2.5-fold following pretreatment with DIP compared to treatment with HN2 alone. Furthermore, DIP treatment increased ROS generation in both wild type and sodAB-deficient strains. Based on these data and on the survival of the SOD-deficient strain, we suggest that the increased production of ROS caused by Fe2+ chelation may potentiate the lethal effects of HN2 but not HN1. This potentiation may arise as a consequence of enhancement in the number of or modification of the type of lesions formed. No sensitization was observed for the non-crosslinkable HN2 analog, HN1.

      PubDate: 2014-03-16T20:15:18Z
  • Reduced repair capacity of a DNA clustered damage site comprised of
           8-oxo-7,8-dihydro-2′-deoxyguanosine and 2-deoxyribonolactone results
           in an increased mutagenic potential of these lesions
    • Abstract: Publication date: Available online 11 March 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Siobhan Cunniffe , Peter O’Neill , Marc M. Greenberg , Martine E. Lomax
      A signature of ionizing radiation is the induction of DNA clustered damaged sites. Non-double strand break (DSB) clustered damage has been shown to compromise the base excision repair pathway, extending the lifetimes of the lesions within the cluster, compared to isolated lesions. This increases the likelihood the lesions persist to replication and thus increasing the mutagenic potential of the lesions within the cluster. Lesions formed by ionizing radiation include 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) and 2-deoxyribonolactone (dL). dL poses an additional challenge to the cell as it is not repaired by the short-patch base excision repair pathway. Here we show recalcitrant dL repair is reflected in mutations observed when DNA containing it and a proximal 8-oxodGuo is replicated in Escherichia coli. 8-oxodGuo in close proximity to dL on the opposing DNA strand results in an enhanced frequency of mutation of the lesions within the cluster and a 20 base sequence flanking the clustered damage site in an E. coli based plasmid assay. In vitro repair of a dL lesion is reduced when compared to the repair of an abasic (AP) site and a tetrahydrofuran (THF), and this is due mainly to a reduction in the activity of polymerase β, leading to retarded FEN1 and ligase 1 activities. This study has given insights in to the biological effects of clusters containing dL.

      PubDate: 2014-03-16T20:15:18Z
  • Rad51C: A novel suppressor gene modulates the risk of head and neck cancer
    • Abstract: Publication date: Available online 12 March 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Peter Gresner , Jolanta Gromadzinska , Ewa Twardowska , Konrad Rydzynski , Wojciech Wasowicz
      We conducted a case–control study to investigate the possible association between the head and neck cancer (HNC) and genetic variability of Rad51C tumor suppressor gene. Eight polymorphic sites spanning over non-coding regions of Rad51C promoter, exon 1 and intron 1 were genotyped in 81 HNC cases and 156 healthy controls using the real-time PCR technique. One investigated site turned out to be not polymorphic, while among the remaining seven sites a significant HNC risk-increasing effect was found for rs16943176 (c.-118G>A), rs12946397 (c.-26C>T) and rs17222691 (c.145+947C>T) on both allelic (OR=1.8; p <0.05) and genotypic (OR=2.0; p <0.05) level. Furthermore, our data seem to provide marginal evidence, that this effect might possibly be confined to women only (OR=2.8; p =0.05 for allelic and OR=3.7; p =0.05 for genotypic comparisons). These SNPs were found to co-segregate together forming two distinct, HNC risk-modulating haplotypes. The genetic variability of Rad51C might thus be of relevance with respect to HNC risk.

      PubDate: 2014-03-16T20:15:18Z
    • Abstract: Publication date: March 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 761

      PubDate: 2014-03-11T12:51:43Z
  • Nucleotide excision repair gene polymorphisms, meat intake and colon
           cancer risk
    • Abstract: Publication date: Available online 6 March 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Susan E. Steck , Lesley M. Butler , Temitope Keku , Samuel Antwi , Joseph Galanko , Robert S. Sandler , Jennifer J. Hu
      Purpose Much of the DNA damage from colon cancer-related carcinogens, including heterocyclic amines (HCA) and polycyclic aromatic hydrocarbons (PAH) from red meat cooked at high temperature, are repaired by the nucleotide excision repair (NER) pathway. Thus, we examined whether NER non-synonymous single nucleotide polymorphisms (nsSNPs) modified the association between red meat intake and colon cancer risk. Methods The study consists of 244 African-American and 311 white colon cancer cases and population-based controls (331 African Americans and 544 whites) recruited from 33 counties in North Carolina from 1996 to 2000. Information collected by food frequency questionnaire on meat intake and preparation methods were used to estimate HCA and benzo(a)pyrene (BaP, a PAH) intake. We tested 7 nsSNPs in 5 NER genes: XPC A499V and K939Q, XPD D312N and K751Q, XPF R415Q, XPG D1104H, and RAD23B A249V. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression. Results Among African Americans, we observed a statistically significant positive association between colon cancer risk and XPC 499 AV + VV genotype (OR=1.7, 95% CI: 1.1, 2.7, AA as referent), and an inverse association with XPC 939 QQ (OR=0.3, 95%CI: 0.2, 0.8, KK as referent). These associations were not observed among whites. For both races combined, there was interaction between the XPC 939 genotype, well-done red meat intake and colon cancer risk (OR=1.5, 95% CI=1.0, 2.2 for high well-done red meat and KK genotype as compared to low well-done red meat and KK genotype, p interaction =0.05). Conclusions Our data suggest that NER nsSNPs are associated with colon cancer risk and may modify the association between well-done red meat intake and colon cancer risk.

      PubDate: 2014-03-11T12:51:43Z
           ESSENTIAL OIL)
    • Abstract: Publication date: Available online 10 March 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): André Luiz Ventura Sávio , Glenda Nicioli da Silva , Elaine Aparecida de Camargo , Daisy Maria Fávero Salvadori
      Allyl isothiocyanate (AITC) is present in plants of the cruciferous family and is abundant in mustard seed. Due to its high bioavailability in urine after ingestion, AITC has been considered a promising antineoplastic agent against bladder cancer. Because TP53 mutations are the most common alterations in bladder cancer cells and are frequently detected in in situ carcinomas, in this study, we investigated whether the AITC effects in bladder cancer cells are dependent on the TP53 status. Two bladder transitional carcinoma cell lines were used: RT4, with wild-type TP53; and T24, mutated TP53 gene. AITC was tested at concentrations of 0.005, 0.0625, 0.0725, 0.0825, 0.0925, 0.125 and 0.25μM in cytotoxicity, cell and clonogenic survival assays, comet and micronucleus assays and for its effects on cell cycle and apoptosis by flow cytometry and on TP53 gene expression. The data showed increased primary DNA damage in both cell lines; however, lower concentrations of AITC were able to induce genotoxicity in the mutant cells for the TP53 gene. Furthermore, the results demonstrated increased apoptosis and necrosis rates in the wild-type cells, but not in mutated TP53 cells, and cell cycle arrest in the G2 phase for mutated cells after AITC treatment. No significant differences were detected in TP53 gene expression in the two cell lines. In conclusion, AITC caused cell cycle arrest, increased apoptosis rates and varying genotoxicity dependent on the TP53 status. However, we cannot rule out the possibility that those differences could reflect other intrinsic genetic alterations in the examined cell lines, which may also carry mutations in genes other than TP53. Therefore, further studies using other molecular targets need to be performed to better understand the mechanisms by which AITC may exert its antineoplastic properties against tumor cells.

      PubDate: 2014-03-11T12:51:43Z
  • A novel mutation in the thyroglobulin gene that causes goiter and dwarfism
           in Wistar Hannover GALAS rats
    • Abstract: Publication date: Available online 28 February 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Akira Sato , Kuniya Abe , Misako Yuzuriha , Sakiko Fujii , Naofumi Takahashi , Hitoshi Hojo , Shoji Teramoto , Hiroaki Aoyama
      Outbred stocks of rats have been used extensively in biomedical, pharmaceutical and/or toxicological studies as a model of genetically heterogeneous human populations. One of such stocks is the Wistar Hannover GALAS rat. However, the colony of Wistar Hannover GALAS rat has been suspected of keeping a problematic mutation that manifests two distinct spontaneous abnormalities, goiter and dwarfism, which often confuses study results. We have successfully identified the responsible mutation, a guanine to thymine transversion at the acceptor site (3′ end) of intron 6 in the thyroglobulin (Tg) gene (Tg c.749−1G>T ), that induces a complete missing of exon 7 from the whole Tg transcript by mating experiments and subsequent molecular analyses. The following observations confirmed that Tg c.749−1G>T /Tg c.749−1G>T homozygotes manifested both dwarfism and goiter, while Tg c.749−1G>T /+ heterozygotes had only a goiter with normal appearance, suggesting that the mutant phenotypes inherit as an autosomal semi-dominant trait. The mutant phenotypes, goiter and dwarfism, mimicked those caused by typical endocrine disrupters attacking the thyroid. Hence a simple and reliable diagnostic methodology has been developed for genomic DNA-based genotyping of animals. The diagnostic methodology reported here would allow users of Wistar Hannover GALAS rats to evaluate their study results precisely by carefully interpreting the data obtained from Tg c.749−1G>T /+ heterozygotes having externally undetectable thyroidal lesions.

      PubDate: 2014-03-01T07:39:18Z
  • Chromosome loss caused by DNA fragmentation induced in main nuclei and
           micronuclei of human lymphoblastoid cells treated with colcemid
    • Abstract: Publication date: Available online 27 February 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Mika Yamamoto , Akihiro Wakata , Yoshinobu Aoki , Yoichi Miyamae , Seiji Kodama
      Aneuploidy, a change in the number of chromosomes, plays an essential role in tumorigenesis. Our previous study demonstrated that a loss of a whole chromosome is induced in human lymphocytes by colcemid, a well-known aneugen. Here, to clarify the mechanism for colcemid-induced chromosome loss, we investigated the relationship between chromosome loss and DNA fragmentation in human lymphoblastoid cells treated with colcemid (an aneugen) compared with methyl methanesulfonate (MMS; a clastogen). We analyzed the number of fluorescence in situ hybridization (FISH) signals targeted for a whole chromosome 2 in cytokinesis-blocked binucleated TK6 cells and WTK-1 cells treated with colcemid and MMS, and concurrently detected DNA fragmentation by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Results revealed that DNA fragmentation occurred in 60% of all binucleated TK6 cells harboring colcemid-induced chromosome loss (30% of micronuclei and 30% of main nuclei). DNA fragmentation was observed in colcemid-induced micronuclei containing a whole chromosome but not in MMS-induced micronuclei containing chromosome fragments. In contrast, colcemid-induced nondisjunction had no effect on induction of DNA fragmentation, suggesting that DNA fragmentation was triggered by micronuclei containing a whole chromosome but not by micronuclei containing chromosome fragments or nondisjunction. In addition, the frequency of binucleated cells harboring chromosome loss with DNA fragmentation in micronuclei or main nuclei was higher in wild-type p53 TK6 cells than in mutated-p53 WTK-1 cells treated with colcemid. Taken together, these present and previous results suggest that colcemid-induced chromosome loss is caused by DNA fragmentation, which is triggered by a micronucleus with a whole chromosome and controlled by the p53-dependent pathway.

      PubDate: 2014-03-01T07:39:18Z
  • The Impact of Homologous Recombination Repair Deficiency on Depleted
           Uranium Clastogenicity in Chinese Hamster Ovary Cells: XRCC3 Protects
    • Abstract: Publication date: Available online 19 February 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Amie L. Holmes , Kellie Joyce , Hong Xie , Carolyne Falank , John M. Hinz , John Pierce Wise Sr.
      Depleted uranium (DU) is extensively used in both industry and military applications. The potential for civilian and military personnel exposure to DU is rising, but there are limited data on the potential health hazards of DU exposure. Previous laboratory research indicates DU is a potential carcinogen, but epidemiological studies remain inconclusive. DU is genotoxic, inducing DNA double strand breaks, chromosome damage and mutations, but the mechanisms of genotoxicity or repair pathways involved in protecting cells against DU-induced damage remain unknown. The purpose of this study was to investigate the effects of homologous recombination repair deficiency on DU-induced genotoxicity using RAD51D and XRCC3-deficient Chinese hamster ovary (CHO) cell lines. Cells deficient in XRCC3 (irs1SF) also exhibited similar cytotoxicity after DU exposure compared to wild-type (AA8) and XRCC3-complemented (1SFwt8) cells, but DU induced more break-type and fusion-type lesions in XRCC3-deficient cells compared to wild-type and XRCC3-complemented cells. Surprisingly, loss of RAD51D did not affect DU-induced cytotoxicity or genotoxicity. DU induced selective X-chromosome fragmentation irrespective of RAD51D status, but loss of XRCC3 nearly eliminated fragmentation observed after DU exposure in wild-type and XRCC3-complemented cells. Thus, XRCC3, but not RAD51D, protects cells from DU-induced breaks and fusions and also plays a role in DU-induced chromosome fragmentation.

      PubDate: 2014-02-19T20:56:56Z
  • Illegitimate V(D)J recombination-mediated deletions in Notch1 and Bcl11b
           are not sufficient for extensive clonal expansion and show minimal age or
           sex bias in frequency or junctional processing
    • Abstract: Publication date: Available online 14 February 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Devin P. Champagne , Penny E. Shockett
      Illegitimate V(D)J recombination at oncogenes and tumor suppressor genes is implicated in formation of several T cell malignancies. Notch1 and Bcl11b, genes involved in developing T cell specification, selection, proliferation, and survival, were previously shown to contain hotspots for deletional illegitimate V(D)J recombination associated with radiation-induced thymic lymphoma. >Interestingly, these deletions were also observed in wild-type animals. In this study, we conducted frequency, clonality, and junctional processing analyses of Notch1 and Bcl11b deletions during mouse development and compared results to published analyses of authentic V(D)J rearrangements at the T cell receptor beta (TCRβ) locus and illegitimate V(D)J deletions observed at the human, nonimmune HPRT1 locus not involved in T cell malignancies. We detect deletions in Notch1 and Bcl11b in thymic and splenic T cell populations, consistent with cells bearing deletions in the circulating lymphocyte pool. Deletions in thymus can occur in utero, increase in frequency between fetal and postnatal stages, are detected at all ages examined between fetal and 7 months, exhibit only limited clonality (contrasting with previous results in radiation-sensitive mouse strains), and consistent with previous reports are more frequent in Bcl11b, partially explained by relatively high Recombination Signal Information Content (RIC) scores. Deletion junctions in Bcl11b exhibit greater germline nucleotide loss, while in Notch1 palindromic (P) nucleotides are more abundant, although average P nucleotide length is similar for both genes and consistent with results at the TCRβ locus. Non-templated (N) nucleotide insertions appear to increase between fetal and postnatal stages for Notch1, consistent with normal terminal deoxynucleotidyl transferase (TdT) activity; however, neonatal Bcl11b junctions contain elevated levels of N insertions. Finally, contrasting with results at the HPRT1 locus, we find no obvious age or gender bias in junctional processing, and inverted repeats at recessed coding ends (Pr nucleotides) correspond mostly to single-base additions consistent with normal TdT activity.

      PubDate: 2014-02-14T12:03:13Z
  • Mesenchymal Stem Cells and Cancer: Friends or Enemies'
    • Abstract: Publication date: Available online 7 February 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): In-Sun Hong , Hwa-Yong Lee , Kyung-Sun Kang
      There is increasing evidence that mesenchymal stem cells (MSCs) have the ability to migrate and engraft into tumor sites and exert stimulatory effects on cancer cell growth, invasion and even metastasis through direct and/or indirect interaction with tumor cells. However, these pro-tumorigenic effects of MSCs are still being discovered and may even involve opposing effects. MSCs can be friends or enemies of cancer cells: they may stimulate tumor development by regulating immune surveillance, growth, and angiogenesis. On the other hand, they may inhibit tumor growth by inhibiting survival signaling such as Wnt and Akt pathway. MSCs have also been proposed as an attractive candidate for the delivery of anti-tumor agents, owing to their ability to home into tumor sites and to secrete cytokines. Detailed information about the mutual interactions between tumor cells and MSCs will undoubtedly lead to safer and more effective clinical therapy for tumors. In this article, we summarize a number of findings to provide current information on the potential roles of MSCs in tumor development; we then discuss the therapeutic potential of engineered MSCs to reveal any meaningful clinical applications.
      Graphical abstract image

      PubDate: 2014-02-10T05:08:51Z
  • Investigating the Mechanisms of Ribonucleotide Excision Repair in
           Escherichia coli
    • Abstract: Publication date: Available online 1 February 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Alexandra Vaisman , John P. McDonald , Stephan Noll , Donald Huston , Gregory Loeb , Myron F. Goodman , Roger Woodgate
      Low fidelity Escherichia coli DNA polymerase V (pol V/UmuD2C) is best characterized for its ability to perform translesion synthesis (TLS). However, in recA730 lexA(Def) strains, the enzyme is expressed under optimal conditions allowing it to compete with the cell's replicase for access to undamaged chromosomal DNA and leads to a substantial increase in spontaneous mutagenesis. We have recently shown that a Y11A substitution in the “steric gate” residue of UmuC reduces both base and sugar selectivity of pol V, but instead of generating an increased number of spontaneous mutations, strains expressing umuC_Y11A are poorly mutable in vivo. This phenotype is attributed to efficient RNase HII-initiated repair of the misincorporated ribonucleotides that concomitantly removes adjacent misincorporated deoxyribonucleotides. We have utilized the ability of the pol V steric gate mutant to promote incorporation of large numbers of errant ribonucleotides into the E.coli genome to investigate the fundamental mechanisms underlying ribonucleotide excision repair (RER). Here, we demonstrate that RER is normally facilitated by DNA polymerase I (pol I) via classical “nick translation”. In vitro, pol I displaces 1–3 nucleotides of the RNA/DNA hybrid and through its 5→3 (exo/endo) nuclease activity releases ribo- and deoxyribonucleotides from DNA. In vivo, umuC_Y11A-dependent mutagenesis changes significantly in polymerase-deficient, or proofreading-deficient polA strains, indicating a pivotal role for pol I in ribonucleotide excision repair (RER). However, there is also considerable redundancy in the RER pathway in E. coli. Pol I's strand displacement and FLAP- exo/endonuclease activities can be facilitated by alternate enzymes, while the DNA polymerization step can be assumed by high-fidelity pol III. We conclude that RNase HII and pol I normally act to minimize the genomic instability that is generated through errant ribonucleotide incorporation, but that the “nick-translation” activities encoded by the single pol I polypeptide can be undertaken by a variety of back-up enzymes.

      PubDate: 2014-02-05T03:25:12Z
    • Abstract: Publication date: February 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 760

      PubDate: 2014-01-31T22:21:27Z
  • Does bacterial infection cause genome instability and cancer in the host
    • Abstract: Publication date: Available online 25 January 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Olga Kovalchuk , Paul Walz , Igor Kovalchuk
      Research of the past several decades suggests that bacterial infection can lead to genome instability of the host cell often resulting in cancer development. However, there is still a substantial lack of knowledge regarding possible mechanisms involved in the development of genomic instability. Several questions remain unanswered, namely: Why has the causative relationship between the bacterial infection and cancer been established only for a small number of cancers' What is the mechanism responsible for the induction of genome instability and cancer' Is the infection process required to cause genome instability and cancer' In this review, we present a hypothesis that the bacterial infection, exposure to heat-killed bacteria or even some bacterial determinants may trigger genome instability of exposed and distal cells, and thus may cause cancer. We will discuss the mechanisms of host responses to the bacterial infection and present the possible pathways leading to genome instability and cancer through exposure to bacteria.

      PubDate: 2014-01-27T12:20:35Z
  • Frequent POLE1 p.S297F mutation in Chinese patients with ovarian
           endometrioid carcinoma
    • Abstract: Publication date: Available online 25 January 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Yang Zou , Fa-Ying Liu , Huai Liu , Feng Wang , Wei Li , Mei-Zhen Huang , Yan Huang , Xiao-Qun Yuan , Xiao-Yun Xu , Ou-Ping Huang , Ming He
      The catalytic subunit of DNA polymerase epsilon (POLE1) functions primarily in nuclear DNA replication and repair. Recently, POLE1 mutations were detected frequently in colorectal and endometrial carcinomas while with lower frequency in several other types of cancer, and the p.P286R and p.V411L mutations were the potential mutation hotspots in human cancers. Nevertheless, the mutation frequency of POLE1 in ovarian cancer still remains largely unknown. Here, we screened a total of 251 Chinese samples with distinct subtypes of ovarian carcinoma for the presence of POLE1 hotspot mutations by direct sequencing. A heterozygous somatic POLE1 mutation, p.S297F (c.890C>T), but not p.P286R and p.V411L hotspot mutations observed in other cancer types, was identified in 3 out of 37 (8.1%) patients with ovarian endometrioid carcinoma, this mutation was evolutionarily highly conserved from Homo sapiens to Schizosaccharomyces. Of note, the POLE1 mutation coexisted with mutation in the ovarian cancer-associated PPP2R1A (Protein phosphatase 2, regulatory subunit A, α) gene in a 46-year-old patient, who was also diagnosed with ectopic endometriosis in the benign ovary. In addition, a 45-year-old POLE1-mutated ovarian endometrioid carcinoma patient was also diagnosed with uterine leiomyoma while the remaining 52-year-old POLE1-mutated patient showed no additional distinctive clinical manifestation. In contrast to high frequency of POLE1 mutations in ovarian endometrioid carcinoma, no POLE1 mutations were identified in patients with other subtypes of ovarian carcinoma. Our results showed for the first time that the POLE1 p.S297F mutation, but not p.P286R and p.V411L hotspot mutations observed in other cancer types, was frequent in Chinese ovarian endometrioid carcinoma, but absent in other subtypes of ovarian carcinoma. These results implicated that POLE1 p.S297F mutation might be actively involved in the pathogenesis of ovarian endometrioid carcinoma, but might be not actively involved in other subtypes of ovarian carcinoma.

      PubDate: 2014-01-27T12:20:35Z
  • A common variant in pre-miR-146 is associated with coronary artery disease
           risk and its mature miRNA expression
    • Abstract: Publication date: Available online 19 January 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Xing-dong Xiong , Miook Cho , Xiu-ping Cai , Jie Cheng , Xia Jing , Jin-ming Cen , Xinguang Liu , Xi-li Yang , Yousin Suh
      MiRNAs are small non-coding RNAs that play an important role in numerous physiological processes. Common single nucleotide polymorphisms (SNPs) in pre-miRNAs may change their property through altering miRNAs expression and/or maturation, resulting in diverse functional consequences. To date, the role of genetic variants in pre-miRNAs on coronary artery disease (CAD) risk remain poorly understood. Here we aimed to evaluate the influence of three common SNPs in pre-miRNAs (miR-146a rs2910164 G>C, miR-196a2 rs11614913 C>T, miR-499 rs3746444 T>C) on individual susceptibility to CAD in a Chinese population of 295 CAD patients and 283 controls. Genotyping was performed using polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) method. In a logistic regression analysis, we detected an association of rs2910164 in pre-miR-146a with the CAD risk; compared with the GG homozygotes, the GC heterozygotes [odds ratio (OR)=1.89, 95% confidence interval (CI)=1.06-3.36, P =0.029] and the CC homozygotes (OR=1.83, 95% CI=1.01-3.32, P =0.046) genotype were statistically significantly associated with the increased risk for CADs. As we used further genotype association models, we found a similar trend of the association in recessive model (OR=1.86, 95% CI=1.09-3.19, P =0.023). We also found that the genotypes of miR-146a rs2910164 were associated with its mature miRNA expression by analyzing 23 PBMC samples from CAD patients. Individuals carrying rs11614913 GC or CC genotypes showed 3.2-fold higher expression compared to GG genotype carriers (P <0.05). We observed no association of the other two SNPs in miR-196a2 (rs11614913) and miR-499 (rs3746444) with the CAD incidence. Our data provide the first evidence that the miR-146a rs2910164 polymorphism is associated with increased risk of CAD in Chinese Han population, which may be through influencing the expression levels of the miRNA.

      PubDate: 2014-01-23T04:31:39Z
  • p53-Dependent Suppression of Genome Instability in Germ Cells
    • Abstract: Publication date: Available online 7 January 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Shinji Otozai , Tomoko Ishikawa-Fujiwara , Shoji Oda , Yasuhiro Kamei , Haruko Ryo , Ayuko Sato , Taisei Nomura , Hiroshi Mitani , Tohru Tsujimura , Hidenori Inohara , Takeshi Todo
      Radiation increases mutation frequencies at tandem repeat loci. Germline mutations in γ-ray-irradiated medaka fish (Oryzias latipes) were studied, focusing on the microsatellite loci. Mismatch-repair genes suppress microsatellite mutation by directly removing altered sequences at the nucleotide level, whereas the p53 gene suppresses genetic alterations by eliminating damaged cells. The contribution of these two defense mechanisms to radiation-induced microsatellite instability was addressed. The spontaneous mutation frequency was significantly higher in msh2 -/− males than in wild-type fish, whereas there was no difference in the frequency of radiation-induced mutations between msh2 -/− and wild-type fish. By contrast, irradiated p53 -/− fish exhibited markedly increased mutation frequencies, whereas their spontaneous mutation frequency was the same as that of wild-type fish. In the spermatogonia of the testis, radiation induced a high level of apoptosis both in wild-type and msh2 -/− fish, but negligible levels in p53 -/− fish. The results demonstrate that the msh2 and p53 genes protect genome integrity against spontaneous and radiation-induced mutation by two different pathways: direct removal of mismatches and elimination of damaged cells.

      PubDate: 2014-01-11T07:17:32Z
  • The Radiomimetic Compound Streptonigrin Induces Persistent Telomere
           Dysfunction in Mammalian Cradiomimetic compound streptonigrin induces
           persistent telomere dysfunction in mammalian cells
    • Abstract: Publication date: Available online 6 January 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Natalia S. Paviolo , Daniel C. Castrogiovanni , Alejandro D. Bolzán
      We analyzed the chromosomal aberrations involving telomeres in the progeny of mammalian cells exposed to the radiomimetic compound streptonigrin (SN) in order to determine if this antineoplastic drug induces long-term telomere instability. To this end, rat cells (ADIPO-P2 cell line, derived from adipose cells from Sprague-–Dawley rat) were treated with a single concentration of SN (100ng/ml), and chromosomal aberrations were analyzed 18h and 10 and 15 days after treatment by using PNA-FISH with a pan-telomeric probe [Cy3-(CCCTAA)3] to detect (TTAGGG)n repeats. Cytogenetic analysis revealed a higher frequency of telomere dysfunction-related aberrations (additional telomeric FISH signals, extra-chromosomal telomeric FISH signals, and telomere FISH signal loss and duplications) in SN-exposed cultures vs. untreated cultures at every time points analyzed. The yield of SN-induced aberrations remained very similar at 18h, 10 days as well as 15 days after treatment. Thus, our data demonstrate that SN induces persistent telomere dysfunction in mammalian cells. Moreover, we found that the level of telomerase activity in SN-treated cells was significantly lower (up to 77%) than that of untreated control cells at each time points analyzed. This fact suggests that telomerase could be involved in SN-induced telomere dysfunction.

      PubDate: 2014-01-11T07:17:32Z
  • The strategies to control prostate cancer by chemoprevention approaches
    • Abstract: Publication date: Available online 2 January 2014
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Harold Ting , Gagan Deep , Chapla Agarwal , Rajesh Agarwal
      Prostate cancer (PCA) is the most commonly diagnosed cancer in men in the United States with growing worldwide incidence. Despite intensive investment in improving early detection, PCA often escapes timely detection and mortality remains high; this malignancy being the second highest cancer-associated mortality in American men. Collectively, health care costs of PCA results in an immense financial burden that is only expected to grow. Additionally, even in cases of successful treatment, PCA is associated with long-term and pervasive effects on patients. A proactive alternative to treating PCA is to prevent its occurrence and progression prior to symptomatic malignancy. This may serve to address the issue of burgeoning healthcare costs and increasing number of sufferers. One potential regimen in service of this alternative is PCA chemoprevention. Here, chemical compounds with cancer preventive efficacy are identified on the basis of their potential in a host of categories: their historical medicinal use, correlation with reduced risk in population studies, non-toxicity, their unique chemical properties, or their role in biological systems. PCA chemopreventive agents are drawn from multiple broad classes of chemicals, themselves further subdivided based on source or potential effect, with most derived from natural products. Many such compounds have shown efficacy, varying from inhibiting deregulated PCA cell signaling, proliferation, epithelial to mesenchymal transition (EMT), invasion, metastasis, tumor growth and angiogenesis and inducing apoptosis. Overall, these chemopreventive agents show great promise in PCA pre-clinical models, though additional work remains to be done in effectively translating these findings into clinical use.

      PubDate: 2014-01-07T07:18:53Z
  • Induction of genomic instability, oxidative processes, and mitochondrial
           activity by 50Hz magnetic fields in human SH-SY5Y neuroblastoma cells
    • Abstract: Publication date: Available online 26 December 2013
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Jukka Luukkonen , Anu Liimatainen , Jukka Juutilainen , Jonne Naarala
      Epidemiological studies have suggested that exposure to 50Hz magnetic fields (MF) increases the risk of childhood leukemia, but there is no mechanistic explanation for carcinogenic effects. In two previous studies we have observed that a 24-h pre-exposure to MF alters cellular responses to menadione-induced DNA damage. The aim of this study was to investigate the cellular changes that must occur already during the first 24h of exposure to MF, and to explore whether the MF-induced changes in DNA damage response can lead to genomic instability in the progeny of the exposed cells. In order to answer these questions, human SH-SY5Y neuroblastoma cells were exposed to a 50-Hz, 100-μT MF for 24h, followed by 3-h exposure to menadione. The main finding was that MF exposure was associated with increased level of micronuclei, used as an indicator of induced genomic instability, at 8 and 15 days after the exposures. Other delayed effects in MF-exposed cells included increased mitochondrial activity at 8 days, and increased reactive oxygen species (ROS) production and lipid peroxidation at 15 days after the exposures. Oxidative processes (ROS production, reduced glutathione level, and mitochondrial superoxide level) were affected by MF immediately after the exposure. In conclusion, the present results suggest that MF exposure disturbs oxidative balance immediately after the exposure, which might explain our previous findings on MF altered cellular responses to menadione-induced DNA damage. Persistently elevated levels of micronuclei were found in the progeny of MF-exposed cells, indicating induction of genomic instability.

      PubDate: 2013-12-30T07:15:52Z
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