Biomarkers for screening of lung cancer and pre-neoplastic lesions in a high risk Chilean population.

BACKGROUND: The mortality of lung cancer (LC), increases each year in the world, in spite of any advances, in development of new drugs to advance stages of LC. The high incidence of LC has been associated with smoking habit, genetic diversity and environmental pollution. Antofagasta region has been reported to have the highest LC mortality rate in Chile and its inhabitants were exposed to arsenic in their drinking water in concentrations as high as 870 µg/L. Non-invasive techniques such as biomarkers (Automatic Quantitative Cytometry: AQC and DR70) and Auto Fluorescence Bronchoscopy (AFB) might be potentially useful as a supplementary diagnostic approach and early detection. Early detection is one of the most important factors to intervene and prevent cancer progression in LC. This is a work of an ongoing prospective bimodality cancer surveillance study in high risk LC volunteers. Enrolment was done in subjects from Antofagasta and Metropolitan regions. In addition, we enrolled subjects who were suspected of having lung cancer. AQC, DR70 and AFB were used as tools in the detection of pre-neoplastic (PNL) and neoplastic lesions (NL). RESULTS: Half of the samples, classified as suspicious by AFB, were confirmed as metaplasia or dysplasia by histopathology. For LC, DR70 showed a higher sensitivity (95.8%) and specificity (91.9%) than AQC. However, for PNL AQC showed a higher sensitivity (91.9%) than DR70 (27.3%), although both with low PPV values. As a pre screener, both biomarkers might be employed as complementary tools to detect LC, especially as serially combined tests, with a sensitivity of 60% and a PPV of 65.2%. Additionally, the use of parallel combined tests might support the detection of PNL (sensitivity 91.2%; PPV 49.1%). CONCLUSION: This work adds information on cellular and molecular biomarkers to complement imaging techniques for early detection of LC in Latin America that might contribute to formulate policies concerning screening of LC. Supported by INNOVA-CORFO, Chile.

Bistable self-starting pulses with terahertz repetition rate in a semiconductor microring laser.

We report on the prediction of stable self-starting pulses in a GaAs bulk semiconductor microring laser with terahertz repetition rate. The pulses are obtained without active or passive mode locking. Especially interesting for practical applications is the bistability between pulses and continuous waves.

A biophysical model explains the spontaneous bursting behavior in the developing retina.

During early development, waves of activity propagate across the retina and play a key role in the proper wiring of the early visual system. During a particular phase of the retina development (stage II) these waves are triggered by a transient network of neurons, called Starburst Amacrine Cells (SACs), showing a bursting activity which disappears upon further maturation. The underlying mechanisms of the spontaneous bursting and the transient excitability of immature SACs are not completely clear yet. While several models have attempted to reproduce retinal waves, none of them is able to mimic the rhythmic autonomous bursting of individual SACs and reveal how these cells change their intrinsic properties during development. Here, we introduce a mathematical model, grounded on biophysics, which enables us to reproduce the bursting activity of SACs and to propose a plausible, generic and robust, mechanism that generates it. The core parameters controlling repetitive firing are fast depolarizing V-gated calcium channels and hyperpolarizing V-gated potassium channels. The quiescent phase of bursting is controlled by a slow after hyperpolarization (sAHP), mediated by calcium-dependent potassium channels. Based on a bifurcation analysis we show how biophysical parameters, regulating calcium and potassium activity, control the spontaneously occurring fast oscillatory activity followed by long refractory periods in individual SACs. We make a testable experimental prediction on the role of voltage-dependent potassium channels on the excitability properties of SACs and on the evolution of this excitability along development. We also propose an explanation on how SACs can exhibit a large variability in their bursting periods, as observed experimentally within a SACs network as well as across different species, yet based on a simple, unique, mechanism. As we discuss, these observations at the cellular level have a deep impact on the retinal waves description.

Chilean pilot study on the risk of lung cancer associated with codon 72 polymorphism in the gene of protein p53.

The p53 gene has a polymorphism at codon 72 that presents the arginine or proline genotype, although this polymorphism has been associated with genetically determined susceptibility to lung cancers, the literature has not been consistent with this association. In Chile lung cancer represents the second cause of mortality from cancer. p53 codon 72 polymorphism frequency was studied in a Chilean subpopulation of 133 healthy controls and 111 lung cancer patients. The allelic distribution of the three genotypes (ArgArg, ArgPro, ProPro) in healthy normal controls was 41, 44 and 15%, respectively, which differs slightly from that of lung cancer patients, which was 38, 40 and 22%. A relation between the presence of the Pro allele and lung cancer risk in male smokers was observed. Relative risks were O.R.=2.47 (95% CI: 1.34-4.54) for one single nucleotide polymorphic allele (Pro) and O.R.=3.88 (95% CI: 1.16-13.39) for ProPro genotype.

Occupational and environmental levels of mutagenic PAHs and respirable particulate matter associated with diesel exhaust in Santiago, Chile.

This work studied the mutagenic potential and polycyclic aromatic hydrocarbon (PAH) levels onto PM10 collected in diesel revision plants, in an urban area as well as in a rural area in Santiago, Chile. The PM10 average levels in diesel emission plants during working hours (there is no occupational PM10 Chilean standard) were significantly higher than the atmospheric Chilean PM10 standard and highly mutagenic and with high PAHs levels. Additionally, we evaluated the contribution of CYP1A1 and GSTM1 polymorphisms on 1-OH-pyrene urinary levels. The diesel-exposed workers carrying the CYP1A1*2A allele showed significantly higher 1-OH-P levels than the subjects from the rural area with the same genotype. The higher levels of 1-OH-P were found in individuals carrying the combined CYP1A1*2A and GSTM1 null genotype. This kind of information might be relevant to establish prevention, protection, and mitigation actions to protect public health.

Whole-genome sequencing analysis identifies a distinctive mutational spectrum in an arsenic-related lung tumor.

INTRODUCTION: Arsenic exposure is a significant cause of lung cancer in North America and worldwide. Arsenic-related tumors are structurally indistinguishable from those induced by other carcinogens. Because carcinogens, like tobacco, induce distinctive mutational signatures, we sought to characterize the mutational signature of an arsenic-related lung tumor from a never smoker with the use of whole-genome sequencing. METHODS: Tumor and lung tissues were obtained from a never smoker with lung squamous cell carcinoma (LUSC), without familiar history of lung cancer and chronically exposed to high levels of arsenic-contaminated drinking water. The Illumina HiSeq-2000 platform was used to sequence each genome at approximately 30-fold haploid coverage. The mutational signature was compared with those observed in previously characterized lung tumors. RESULTS: The arsenic-related tumor exhibited alterations common in LUSC, such as the increased number of copies at 3q26 (SOX2 locus). However, the arsenic-related genome not only harbored a lower number of point mutations, but also had a remarkably high fraction of T>G/A>C mutations and low fraction of C>A/G>T transversions, which is uncharacteristic of LUSCs. Furthermore, at the gene level, we identified a rare G>C mutation in TP53, which is uncommon in lung tumors in general (<0.2%) but has been observed in other arsenic-related malignancies. CONCLUSIONS: We generated the first whole-genome sequence of an LUSC from a never-smoker patient chronically exposed to arsenic, and identified a distinct mutational spectrum associated with arsenic exposure, providing novel evidence supporting the hypothesis that arsenic-induced lung tumors arise through molecular mechanisms that differ from those of the common lung cancer.

Arsenic biotransformation as a cancer promoting factor by inducing DNA damage and disruption of repair mechanisms.

Chronic exposure to arsenic in drinking water poses a major global health concern. Populations exposed to high concentrations of arsenic-contaminated drinking water suffer serious health consequences, including alarming cancer incidence and death rates. Arsenic is biotransformed through sequential addition of methyl groups, acquired from s-adenosylmethionine (SAM). Metabolism of arsenic generates a variety of genotoxic and cytotoxic species, damaging DNA directly and indirectly, through the generation of reactive oxidative species and induction of DNA adducts, strand breaks and cross links, and inhibition of the DNA repair process itself. Since SAM is the methyl group donor used by DNA methyltransferases to maintain normal epigenetic patterns in all human cells, arsenic is also postulated to affect maintenance of normal DNA methylation patterns, chromatin structure, and genomic stability. The biological processes underlying the cancer promoting factors of arsenic metabolism, related to DNA damage and repair, will be discussed here.

Arsenic exposure and the induction of human cancers.

Arsenic is a metalloid, that is, considered to be a human carcinogen. Millions of individuals worldwide are chronically exposed through drinking water, with consequences ranging from acute toxicities to development of malignancies, such as skin and lung cancer. Despite well-known arsenic-related health effects, the molecular mechanisms involved are not fully understood; however, the arsenic biotransformation process, which includes methylation changes, is thought to play a key role. This paper explores the relationship of arsenic exposure with cancer development and summarizes current knowledge of the potential mechanisms that may contribute to the neoplastic processes observed in arsenic exposed human populations.

Biomarkers for screening of lung cancer and pre-neoplastic lesions in a high risk Chilean population

BACKGROUND: The mortality of lung cancer (LC), increases each year in the world, in spite of any advances, in development of new drugs to advance stages of LC. The high incidence of LC has been associated with smoking habit, genetic diversity and environmental pollution. Antofagasta region has been reported to have the highest LC mortality rate in Chile and its inhabitants were exposed to arsenic in their drinking water in concentrations as high as 870 µg/L. Non-invasive techniques such as biomarkers (Automatic Quantitative Cytometry: AQC and DR70) and Auto Fluorescence Bronchoscopy (AFB) might be potentially useful as a supplementary diagnostic approach and early detection. Early detection is one of the most important factors to intervene and prevent cancer progression in LC. This is a work of an ongoing prospective bimodality cancer surveillance study in high risk LC volunteers. Enrolment was done in subjects from Antofagasta and Metropolitan regions. In addition, we enrolled subjects who were suspected of having lung cancer. AQC, DR70 and AFB were used as tools in the detection of pre-neoplastic (PNL) and neoplastic lesions (NL). RESULTS: Half of the samples, classified as suspicious by AFB, were confirmed as metaplasia or dysplasia by histopathology. For LC, DR70 showed a higher sensitivity (95.8%) and specificity (91.9%) than AQC. However, for PNL AQC showed a higher sensitivity (91.9%) than DR70 (27.3%), although both with low PPV values. As a pre screener, both biomarkers might be employed as complementary tools to detect LC, especially as serially combined tests, with a sensitivity of 60% and a PPV of 65.2%. Additionally, the use of parallel combined tests might support the detection of PNL (sensitivity 91.2%; PPV 49.1%). CONCLUSION: This work adds information on cellular and molecular biomarkers to complement imaging techniques for early detection of LC in Latin America that might contribute to formulate policies concerning screening of LC. Supported by INNOVA-CORFO, Chile.

Strategic approaches to informing the public about biotechnology in Latin America

The benefits of today's biotechnology products are not evident to consumers. The public will accept biotechnology only when individuals decide for themselves that biotec products will contribute to their personal well-being. To make such a decision, people will need greater awareness and understanding of how biotechnology will affect the environment, human health, local and national economies, and the well-being of society. A low level of awareness and understanding about biotechnology is characteristic of Latin America and the Caribbean countries, as elsewhere, efforts to remedy poor public perception often seem inadequate and do not reflect a well-designed strategy. In order to improve the understanding of the biotechnology and their human applications, a strategic plan for public communications is required. Specific objectives for this initiative may include: (1) to make evident to decision makers that modern biotechnology can be an effective tool for increasing agricultural productivity, and thereby economic growth, without imposing unacceptable risk to the environment or human and animal health; (2) to enable members of the public to make informed decisions about appropriate uses of biotechnology by providing accurate information about benefits, risks and impacts; or (3) to incorporate modern biotechnology into science curricula for secondary schools, university and college students, and agriculture extension officers. A variety of specialized expertise, including communication specialists, technical writers, graphic artists and illustrators to design information materials and conduct training is needed to implement this. Ideally, members bring expertise in biotechnology and biosafety, public communications and project management. The plan will need to identify scientists and technical experts who can provide expertise in science writing for general audiences...

The multinational biosafety project of the Organization of American States

The Organization of American States is supporting the project "Biosafety Regulations in Latin America and The Caribbean within the framework of the International Biosafety Protocol". The general objective is to strengthen national skills for the assessment and management of risks of biotechnology food products, and to build up public awareness about their benefits and risks in the participant countries, with the ultimate goal to promote their safe and sustainable use within a protective and trusting environment for the public. The first phase has been focused on the evaluation of the political and regulatory systems in Chile, Peru and Colombia, identification of needs, and development of a series of biosafety seminar-workshops in the three countries, with the participation of distinguished foreign experts. The second phase, which started in March 2003, has been extended to six countries of Central America and The Caribbean. The project is helping to identify the weaknesses and needs for the establishment of the biosafety protocol in each participating country. It has also establish the specific training needs and is given the bases for the design of general outlines of biosafety training plans, which will contribute to an efficient implementation of the International Biosafety Protocol. The project it is also allowing to coordinate actions between the countries for a better implementation of the protocol at a regional level. On the other hand, the project has allowed to assemble, around discussion tables, international experts with the main representatives of regulatory and academic institutions, business enterprises and NGOs, as well as with congressmen in scientific and technological matters and the protection of biodiversity. Thus, the project has permitted the establishment of cooperation linkages and has contributed to reinforce the notion of the importance of biosafety for national development and the preservation of local biodiversity.

Financiamiento de la investigación en Chile en biotecnología y en otras áreas relacionadas con el sector productivo / Financing research Chile in Biotechnology an other areas related with the productive sector

This study describes the financial support for resarch in chile in different areas related to the productive sector including biotechology. Four different sosurce swhich help research in the country through competitive resarch grants were analysed. These include: FUNDECYT (National Fund for Resarch and Technology), Fondo de Desarrollo Productivo de CORFO (Fund for Productive Development), Fondo de Investigaciones Agropecuarias (Fund for Research in Agriculture and Livestock) and the IV Program for Technical Cooperation Between the Chilean Government and UNDP. Biotechnology appears as one of the areas related to the productive sector having an important number of projects approved with a substantial financial support. Based in a survey, recomendations are made to improve the relationship between the productive and academic sector in biotecnology and other areas

Modulation of the hepatic antioxidant defense system by air polluants from urban areas

This study describes the changes induced by organic extracts from airborne particuiate matter in some enzymes related to the antioxidant defense system as well as in peroxisomal acyl CoA oxidase activity in rat liver. After 48 h of i.p. injection (40 mg/kg b.wt.) the hepatic GSH content decreased by about 30 per cent, which was accompanied by a parallel increase in glutathione-S-transferase activity. In contrast the activity of glutathione peroxidase was significantly decreased (p < 0.05).Peroxisomal acyl CoA-oxidase was enhanced by about 40 per cent with a parallel increase of liver catalase (27 per cent), the peroxisomal H2O2-destroying enzyme. With the only exception hepatic lipid peroxidation, that remains unchanged, all the effects showed a dose-dependent response with respect to the content of polycyclic aromatic hydrocarbons in the organic airborne extracts. However, the content of other chemical pollutants such as plasticizers, pestcides and other organic compounds must be taken into account. These results suggest that organic extracts from Santiago airborne particles might induce a prooxidant state. According to this view the increase in GSTs and catalase activity may be considered as a protective response against the damage induced by airborne pollutants.