eRF3a/GSPT1 12-GGC allele increases the susceptibility for breast cancer development

It is now widely recognized that translation factors are involved in cancer development and that components of the translation machinery that are deregulated in cancer cells may become targets for cancer therapy. The eukaryotic Release Factor 3 (eRF3) is a GTPase that associates with eRF1 in a complex that mediates translation termination. eRF3a/GSPT1 first exon contains a (GGC)n expansion coding for proteins with different N-terminal extremities. Herein we show that the longer allele (12-GGC) is present in 5.1% (7/137) of the breast cancer patients analysed and is absent in the control population (0/135), corresponding to an increased risk for cancer development, as revealed by Odds Ratio analysis. mRNA quantification suggests that patients with the 12-GGC allele overexpress eRF3a/GSPT1 in tumor tissues relative to the normal adjacent tissues. However, using an in vivo assay for translation termination in HEK293 cells, we do not detect any difference in the activity of the eRF3a proteins encoded by the various eRF3a/GSPT1 alleles. Although the connection between the presence of eRF3a/GSPT1 12-GGC allele and tumorigenesis is still unknown, our data suggest that the presence of the 12-GGC allele provides a potential novel risk marker for various types of cancer.

5' and 3' UTR thymidylate synthase polymorphisms modulate the risk of colorectal cancer independently of the intake of methyl group donors

Thymidylate synthase, as a rate-limiting step in DNA synthesis, catalyses the conversion of dUMP into dTMP using 5,10-methylenotetrahydrofolate as the methyl donor. Two polymorphisms have been described in this gene: a repeat polymorphism in the 5' promoter enhancer region (3R versus 2R) and a 6 bp deletion in the 3' unstranslated region. Both of these may affect protein levels. The present case control study was aimed at investigating the influence of these two polymorphisms on the development of colorectal cancer (CRC), as well as their potential interaction with folate, vitamin B6 and vitamin B12 intake. A total of 196 cases and 200 controls, matched for age and sex distribution, were included in the study. No association was found between CRC and the 28 bp repeat polymorphism, but it was observed that individuals with the 6 bp/del and del/del genotypes had a significantly lower risk of developing the disease (OR=0.47; 95% CI 0.30-0.72). A combined genotype (2R/2R; 6 bp/del+del/del) was also found, which was associated with an even lower risk of developing of the disease (OR=0.42; 95% CI 0.26-0.69). No significant interaction between these polymorphisms and vitamin intake was observed. These results indicate for the first time that the 6 bp/del allele might be a protective factor in the development of CRC, independent of the intake of methyl group donors.

The D1822V APC polymorphism interacts with fat, calcium, and fiber intakes in modulating the risk of colorectal cancer in Portuguese persons

Background - Both genetic and environmental factors affect the risk of colorectal cancer (CRC). Objective - We aimed to examine the interaction between the D1822V polymorphism of the APC gene and dietary intake in persons with CRC. Design - Persons with CRC (n = 196) and 200 healthy volunteers, matched for age and sex in a case-control study, were evaluated with respect to nutritional status and lifestyle factors and for the D1822V polymorphism. Results - No significant differences were observed in energy and macronutrient intakes. Cases had significantly (P < 0.05) lower intakes of carotenes, vitamins C and E, folate, and calcium than did controls. Fiber intake was significantly (P = 0.004) lower in cases than in controls, whereas alcohol consumption was associated with a 2-fold risk of CRC. In addition, cases were significantly (P = 0.001) more likely than were controls to be sedentary. The homozygous variant for the APC gene (VV) was found in 4.6% of cases and in 3.5% of controls. Examination of the potential interactions between diet and genotype found that a high cholesterol intake was associated with a greater risk of colorectal cancer only in noncarriers (DD) of the D1822V APC allele (odds ratio: 1.66; 95% CI: 1.00, 2.76). In contrast, high fiber and calcium intakes were more markedly associated with a lower risk of CRC in patients carrying the polymorphic allele (DV/VV) (odds ratio: 0.50; 95% CI: 0.27, 0.94 for fiber; odds ratio: 0.51; 95% CI: 0.28, 0.93 for calcium) than in those without that allele. Conclusion - These results suggest a significant interaction between the D1822V polymorphism and the dietary intakes of cholesterol, calcium, and fiber for CRC risk.

Modulation of translation factor's gene expression by histone deacetylase inhibitors in breast cancer cells

The histone deacetylase inhibitors sodium butyrate (NaBu) and trichostatin A (TSA) exhibit anti-proliferative activity by causing cell cycle arrest and apoptosis. The mechanisms by which NaBu and TSA cause apoptosis and cell cycle arrest are not yet completely clarified, although these agents are known to modulate the expression of several genes including cell-cycle- and apoptosis-related genes. The enzymes involved in the process of translation have important roles in controlling cell growth and apoptosis, and several of these translation factors have been described as having a causal role in the development of cancer. The expression patterns of the translation mechanism, namely of the elongation factors eEF1A1 and eEF1A2, and of the termination factors eRF1 and eRF3, were studied in the breast cancer cell line MCF-7 by real-time quantitative reverse transcription-polymerase chain reaction after a 24-h treatment with NaBu and TSA. NaBu induced inhibition of translation factors' transcription, whereas TSA caused an increase in mRNA levels. Thus, these two agents may modulate the expression of translation factors through different pathways. We propose that the inhibition caused by NaBu may, in part, be responsible for the cell cycle arrest and apoptosis induced by this agent in MCF-7 cells.

Cytostatics occupational exposure: genotoxic effects assessment

The use of cytostatics drugs in anticancer therapy is increasing. Health care workers can be occupationally exposed to these drugs classified as carcinogenic, mutagenic or teratogenic. Workers may be exposed to this drug, being in the hospital settings the main focus dwelled upon the pharmacy, and nursing personnel. Although the potential therapeutic benefits of hazardous drugs outweigh the risks of side effects for ill patients, exposed health care workers can have the same side effects with no therapeutic benefit. The exposure to these substances is epidemiologically linked to cancer and nuclear changes detected by the cytokinesis-block micronucleus test (CBMN). This method is extensively used in molecular epidemiology, since it determines several biomarkers of genotoxicity, such as micronuclei (MN), which are biomarkers of chromosomes breakage or loss, nucleoplasmic bridges (NPB), common biomarkers of chromosome rearrangement, poor repair and/or telomeres fusion, and nuclear buds (NBUD), biomarkers of elimination of amplified DNA.

Molecular epidemiology of Aspergillus collected from cystic fibrosis patients

Background - Aspergillus respiratory infection is a common complication in cystic fibrosis (CF) and is associated with loss of pulmonary function and allergic disease. Methods - Fifty-three Aspergillus isolates recovered from CF patients were identified to species by Internal Transcribed Spacer Region (ITS), β-tubulin, and calmodulin sequencing. Results - Three species complexes (Terrei, Nigri, and Fumigati) were found. Identification to species level gave a single Aspergillus terreus sensu stricto, one Aspergillus niger sensu stricto and 51 Aspergillus fumigatus sensu stricto isolates. No cryptic species were found. Conclusions - To our knowledge, this is the first prospective study of Aspergillus species in CF using molecular methods. The paucity of non-A. fumigatus and of cryptic species of A. fumigatus suggests a special association of A. fumigatus sensu stricto with CF airways, indicating it likely displays unique characteristics making it suitable for chronic residence in that milieu. These findings could refine an epidemiologic and therapeutic approach geared to this pathogen.

Helical tomotherapy versus 3D conformal radiotherapy in dosimetric planning for patients with localized prostate cancer

Radiotherapy is one of the therapeutics selected for localized prostate cancer, in cases where the tumour is confined to the prostate, penetrates the prostatic capsule or has reached the seminal vesicles (T1 to T3 stages). The radiation therapy can be administered through various modalities, being historically used the 3D conformal radiotherapy (3DCRT). Other modality of radiation administration is the intensity modulated radiotherapy (IMRT), that allows an increase of the total dose through modulation of the treatment beams, enabling a reduction in toxicity. One way to administer IMRT is through helical tomotherapy (TH). With this study we intent to analyze the advantages of helical tomotherapy when compared with 3DCRT, by evaluating the doses in the organs at risk (OAR) and planning target volumes (PTV).

Statistical analysis of quality control measurements in IMRT for head and neck and prostate cancer

Intensity Modulated Radiotherapy (IMRT) is a technique introduced to shape more precisely the dose distributions to the tumour, providing a higher dose escalation in the volume to irradiate and simultaneously decreasing the dose in the organs at risk which consequently reduces the treatment toxicity. This technique is widely used in prostate and head and neck (H&N) tumours. Given the complexity and the use of high doses in this technique it’s necessary to ensure as a safe and secure administration of the treatment, through the use of quality control programmes for IMRT. The purpose of this study was to evaluate statistically the quality control measurements that are made for the IMRT plans in prostate and H&N patients, before the beginning of the treatment, analysing their variations, the percentage of rejected and repeated measurements, the average, standard deviations and the proportion relations.

Human biomonitoring: biomarkers, susceptibility, and nutrigenetics

The methods of molecular biology applied in epidemiological research lead us to the realm of molecular epidemiology, where there is immense potential for the establishment of associations between cancer and exposure to risk factors in lifestyle, profession, or pollution. Human biomonitoring consists, on the one hand, in research and identification of hazardous environmental conditions and, on the other hand, in the assessment of cancer risk following exposure to such conditions. Since carcinogenesis is a lengthy process, the biomarkers used to recognize biological abnormalities are selected and developed in the realm of molecular epidemiology. Such biomarkers are quantifiable and allow for the recognition of progression from normal to abnormal biological conditions at the molecular level. They can be categorized in biomarkers of exposure, effect, and genetic susceptibility. Genotoxicity biomarkers are a particular subset of effect biomarkers and are used to assess genomic instability caused by environmental or occupational exposure, being considered useful carcinogenesis predictors.

Predictors of well-being in cancer survivors

Nearly 65% of adults diagnosed with cancer will live, at least, five years after the diagnostic. If the treatment is lengthy and disruptive, the persons can experience difficulties in returning to normal daily life. Research shows that cancer survivors suffer from more psychological distress than those who have never experienced cancer (5.6% versus 3.0%), reason why psychoeducational programs are necessary to help people return to everyday life. The objective of the present study is to identify psychosocial predictors of well being in people that survive cancer, are in stable condition, and a diagnosis of longer than three years.

Diethydithiocarbamate complexes with metals used as food suplements show diferente effects in cancer cells

Diethyldithiocarbamate (ditiocarb), a metabolite of the old anti-alcoholic drug disulfiram (Antabuse), forms proteasome-inhibiting metal complexes with copper or zinc that suppress cancer cells both in vitro and in vivo. The drug has been used in a clinical trial (NCT00742911) along with copper gluconate as a dietary supplement in patients with cancer spreading to the liver. In this study, we demonstrate the effect of synthetic complexes of disulfiram with four various metals (Mn, Fe, Cr and Cu) used as food supplements. These complexes may be spontaneously formed in the blood during the use of disulfiram with divalent metals and thus may suppress the growth of cancer in vivo. The cytotoxic effect of the compounds and the compounds' ability to inhibit the cellular proteasome were tested in the osteosarcoma cell line U2OS. After 48 h, copper and manganese complexes exhibited cytotoxic effect on the cell line, in sharp contrast to both iron and chromium complexes. (C) 2014 Faculty of Health and Social Studies, University of South Bohemia in Ceske Budejovice. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

New iron(II) cyclopentadienyl derivative complexes: synthesis and antitumor activity against human leucemia cancer cells

A new family of "Fe-II(eta(5)-C5H5)" half sandwich compounds bearing a N-heteroaromatic ligand coordinated to the iron center by a nitrile functional group has been synthesized and fully characterized by NMR and UV-Vis spectroscopy. X-ray analysis of single crystal was achieved for complexes 1 and 3, which crystallized in the monoclinic P2(1)/c and monoclinic P2(1)/n space groups, respectively. Studies of interaction of these five new complexes with plasmid pBR322 DNA by atomic force microscopy showed very strong and different types of interaction. Antiproliferative tests were examined on human leukemia cancer cells (HL-60) using the MTT assay, and the IC50 values revealed excellent antiproliferative activity compared to cisplatin. (C) 2014 Elsevier B.V. All rights reserved.

Avoiding healthy cells extinction in a cancer model

We consider a dynamical model of cancer growth including three interacting cell populations of tumor cells, healthy host cells and immune effector cells. For certain parameter choice, the dynamical system displays chaotic motion and by decreasing the response of the immune system to the tumor cells, a boundary crisis leading to transient chaotic dynamics is observed. This means that the system behaves chaotically for a finite amount of time until the unavoidable extinction of the healthy and immune cell populations occurs. Our main goal here is to apply a control method to avoid extinction. For that purpose, we apply the partial control method, which aims to control transient chaotic dynamics in the presence of external disturbances. As a result, we have succeeded to avoid the uncontrolled growth of tumor cells and the extinction of healthy tissue. The possibility of using this method compared to the frequently used therapies is discussed. (C) 2014 Elsevier Ltd. All rights reserved.

Bisphenol A at the reference level counteracts doxorubicin transcriptional effects on cancer related genes in HT29 cells

Human exposure to Bisphenol A (BPA) results mainly from ingestion of food and beverages. Information regarding BPA effects on colon cancer, one of the major causes of death in developed countries, is still scarce. Likewise, little is known about BPA drug interactions although its potential role in doxorubicin (DOX) chemoresistance has been suggested. This study aims to assess potential interactions between BPA and DOX on HT29 colon cancer cells. HT29 cell response was evaluated after exposure to BPA, DOX, or co-exposure to both chemicals. Transcriptional analysis of several cancer-associated genes (c-fos, AURKA, p21, bcl-xl and CLU) shows that BPA exposure induces slight up-regulation exclusively of bcl-xl without affecting cell viability. On the other hand, a sub-therapeutic DOX concentration (40nM) results in highly altered c-fos, bcl-xl, and CLU transcript levels, and this is not affected by co-exposure with BPA. Conversely, DOX at a therapeutic concentration (4μM) results in distinct and very severe transcriptional alterations of c-fos, AURKA, p21 and CLU that are counteracted by co-exposure with BPA resulting in transcript levels similar to those of control. Co-exposure with BPA slightly decreases apoptosis in relation to DOX 4μM alone without affecting DOX-induced loss of cell viability. These results suggest that BPA exposure can influence chemotherapy outcomes and therefore emphasize the necessity of a better understanding of BPA interactions with chemotherapeutic agents in the context of risk assessment.

18F-FDG measurement in primary lung cancer: SUV normalization to different distribution volumes

Introduction: Standard Uptake Value (SUV) is a measurement of the uptake in a tumour normalized on the basis of a distribution volume and is used to quantify 18F-Fluorodeoxiglucose (FDG) uptake in tumors, such as primary lung tumor. Several sources of error can affect its accuracy. Normalization can be based on body weight, body surface area (BSA) and lean body mass (LBM). The aim of this study is to compare the influence of 3 normalization volumes in the calculation of SUV: body weight (SUVW), BSA (SUVBSA) and LBM (SUVLBM), with and without glucose correction, in patients with known primary lung tumor. The correlation between SUV and weight, height, blood glucose level, injected activity and time between injection and image acquisition is evaluated. Methods: Sample included 30 subjects (8 female and 22 male) with primary lung tumor, with clinical indication for 18F-FDG Positron Emission Tomography (PET). Images were acquired on a Siemens Biography according to the department’s protocol. Maximum pixel SUVW was obtained for abnormal uptake focus through semiautomatic VOI with Quantification 3D isocontour (threshold 2.5). The concentration of radioactivity (kBq/ml) was obtained from SUVW, SUVBSA, SUVLBM and the glucose corrected SUV were mathematically obtained. Results: Statistically significant differences between SUVW, SUVBSA and SUVLBM and between SUVWgluc, SUVBSAgluc and SUVLBMgluc were observed (p=0.000<0.05). The blood glucose level showed significant positive correlations with SUVW (r=0.371; p=0.043) and SUVLBM (r=0.389; p=0.034). SUVBSA showed independence of variations with the blood glucose level. Conclusion: The measurement of a radiopharmaceutical tumor uptake normalized on the basis of different distribution volumes is still variable. Further investigation on this subject is recommended.