Efeitos tardios dos praguicidas organoclorados no homem

Available information on organochlorines and the chronic effects of exposure to them are set out. Organochlorinated compounds are the most persistent pesticides and can be found in all ecosystems. Although they are generally efficient in pest control, they are also a potent environment pollutant and can provoke health problems in man. The evidences of the carcinogenic potential of organochlorines are controversial and insufficient, but they have been related to an increase in the incidence of some kinds of tumors, such as leukemia and solid tumors. Reproductive effects, due to anti-androgenic and estrogenic action, on embryonic virilization, the incidence of abortion and the frequency of prematurity, have also been observed. The accumulation of the organochlorines in the adipous tissue is positively correlated to the increase in aging and could be implicated in the development of aging diseases, such as Parkinson's disease. The effects of pesticides on human health have not yet been completely elucidated. Genotoxicity is one of the most serious of the possible harmful effects caused by these compounds and calls for special attention in view of the irreversible nature of the process and to the long latency associated with its manifestation.Procurou-se relacionar as informações disponíveis sobre os organoclorados e os efeitos crônicos provocados pela exposição. Os compostos organoclorados são os praguicidas mais persistentes já fabricados. Embora sejam geralmente eficientes no controle das pragas, são importantes poluentes ambientais e potenciais causas de problemas de saúde para o homem, tendo sido proibidos ou controlados na maioria dos países. Com poucas exceções, os efeitos tardios desses compostos sobre a saúde humana são difíceis de detectar, em função de dificuldades metodológicas e da extrapolação dos resultados. A genotoxicidade está entre os mais sérios dos possíveis danos causados por esses compostos e merece atenção especial, devido à natureza irreversível do processo. Outro ponto a ser considerado é o aumento na incidência de alterações no desenvolvimento do trato reprodutivo e na fertilidade masculina observada nas últimas décadas provavelmente decorrente do aumento da exposição intra-uterina a compostos estrogênicos e anti-androgênicos, como os organoclorados

Cellular interactions in the tumor microenvironment: the role of secretome

Over the past years, it has become evident that cancer initiation and progression depends on several components of the tumor microenvironment, including inflammatory and immune cells, fibroblasts, endothelial cells, adipocytes, and extracellular matrix. These components of the tumor microenvironment and the neoplastic cells interact with each other providing pro and antitumor signals. The tumor-stroma communication occurs directly between cells or via a variety of molecules secreted, such as growth factors, cytokines, chemokines and microRNAs. This secretome, which derives not only from tumor cells but also from cancer-associated stromal cells, is an important source of key regulators of the tumorigenic process. Their screening and characterization could provide useful biomarkers to improve cancer diagnosis, prognosis, and monitoring of treatment responses.Agência financiadora Fundação de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) FAPESP 10/51168-0 12/06048-2 13/03839-1 National Council for Scientific and Technological Development (CNPq) CNPq 306216/2010-8 Fundacao para a Ciencia e a Tecnologia (FCT) UID/BIM/04773/2013 CBMR 1334info:eu-repo/semantics/publishedVersio

Inflammation and Cancer: Role of Annexin A1 and FPR2/ALX in Proliferation and Metastasis in Human Laryngeal Squamous Cell Carcinoma

The anti-inflammatory protein annexin A1 (ANXA1) has been associated with cancer progression and metastasis, suggesting its role in regulating tumor cell proliferation. We investigated the mechanism of ANXA1 interaction with formylated peptide receptor 2 (FPR2/ALX) in control, peritumoral and tumor larynx tissue samples from 20 patients, to quantitate the neutrophils and mast cells, and to evaluate the protein expression and co-localization of ANXA1/FPR2 in these inflammatory cells and laryngeal squamous cells by immunocytochemistry. in addition, we performed in vitro experiments to further investigate the functional role of ANXA1/FPR2 in the proliferation and metastasis of Hep-2 cells, a cell line from larynx epidermoid carcinoma, after treatment with ANXA1(2-26) (annexin A1 N-terminal-derived peptide), Boc2 (antagonist of FPR) and/or dexamethasone. Under these treatments, the level of Hep-2 cell proliferation, pro-inflammatory cytokines, ANXA1/FPR2 co-localization, and the prostaglandin signalling were analyzed using ELISA, immunocytochemistry and real-time PCR. An influx of neutrophils and degranulated mast cells was detected in tumor samples. in these inflammatory cells of peritumoral and tumor samples, ANXA1/FPR2 expression was markedly exacerbated, however, in laryngeal carcinoma cells, this expression was downregulated. ANXA1(2-26) treatment reduced the proliferation of the Hep-2 cells, an effect that was blocked by Boc2, and up-regulated ANXA1/FPR2 expression. ANXA1(2-26) treatment also reduced the levels of pro-inflammatory cytokines and affected the expression of metalloproteinases and EP receptors, which are involved in the prostaglandin signalling. Overall, this study identified potential roles for the molecular mechanism of the ANXA1/FPR2 interaction in laryngeal cancer, including its relationship with the prostaglandin pathway, providing promising starting points for future research. ANXA1 may contribute to the regulation of tumor growth and metastasis through paracrine mechanisms that are mediated by FPR2/ALX. These data may lead to new biological targets for therapeutic intervention in human laryngeal cancer.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fed Univ São Paulo UNIFESP, Paulista Sch Med EPM, São Paulo, BrazilFac Med FAMERP, Dept Mol Biol, Sao Jose Do Rio Preto, SP, BrazilFac Med FAMERP, Dept Otorhinolaringol, Sao Jose Do Rio Preto, SP, BrazilFac Med FAMERP, Dept Pathol, Sao Jose Do Rio Preto, SP, BrazilSão Paulo State Univ UNESP, Dept Biol & Zoot, Ilha Solteira, SP, BrazilUniv São Paulo, Inst Biosci, Dept Genet & Evolutionary Biol, São Paulo, BrazilSão Paulo State Univ UNESP, Dept Biol, Inst Biociencias Letras & Ciencias Exatas IBILCE, Saa Jose Do Rio Preto, SP, BrazilFed Univ São Paulo UNIFESP, Paulista Sch Med EPM, São Paulo, BrazilFAPESP: 2008/08187-4FAPESP: 2008/01655-2CNPq: 302768/2010-6Web of Scienc

Diabetes mellitus, metformin and head and neck cancer

Introduction: Diabetes mellitus (DM (Diabetes Mellitus)) is directly associated with some cancers. However, studies on the association between diabetes mellitus and head and neck cancer (HNC (Head and Neck Cancer)) have rendered controversial results. The objective of this study was to evaluate the association between DM and HNC, as well as the impact of metformin use on the risk of HNC. Material and methods: This case-control study was conducted within the framework of the Brazilian Head and Neck Genome Project in 2011-2014. The study included 1021 HNC cases with histologically confirmed squamous cell carcinoma of the head and neck admitted to five large hospitals in Sao Paulo state. A total of 1063 controls were selected in the same hospitals. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression. Results: Diabetic participants had a decreased risk of HNC (OR = 0.68; 95% CI: 0.49-0.95) than nondiabetic participants, and this risk was further decreased among diabetic metformin users (OR = 0.54; 95% CI: 0.29-0.99). Diabetic metformin users that were current smokers (OR = 0.13; 95% CI: 0.04-0.44) or had an alcohol consumption of >40 g/day (OR = 0.31; 95% CI: 0.11-0.88) had lower risk of HNC than equivalent non-diabetic participants. Conclusion: The risk of HNC was decreased among diabetic participants; metformin use may at least partially explain this inverse association. (C) 2016 Elsevier Ltd. All rights reserved.Peer reviewe

Evidence of a noncoding transcript of the RIPK2 gene overexpressed in head and neck tumor

Receptor-interacting proteins are a family of serine/threonine kinases, which integrate extra and intracellular stress signals caused by different factors, including infections, inflammation and DNA damage. Receptor-interacting serine/threonine-protein kinase 2 (RIP-2) is a member of this family and an important component of the nuclear factor NF-kappa-B signaling pathway. The corresponding human gene RIPK2 generates two transcripts by alternative splicing, the full-length and a short transcript. The short transcript has a truncated 5? sequence, which results in a predicted isoform with a partial kinase domain but able to transduce signals through its caspase recruitment domain. In this study, the expression of RIPK2 was investigated in human tissue samples and, in order to determine if both transcripts are similarly regulated at the transcriptional level, cancer cell lines were submitted to temperature and acid stresses. We observed that both transcripts are expressed in all tissues analyzed, with higher expression of the short one in tumor samples, and they are differentially regulated following temperature stress. Despite transcription, no corresponding protein for the short transcript was detected in tissues and cell lines analyzed. We propose that the shorter transcript is a noncoding RNA and that its presence in the cell may play regulatory roles and affect inflammation and other biological processes related to the kinase activity of RIP-2.Fil: Mancini Villagra, Ulises Maximiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: da Cunha, Bianca R.. Universidade de Sao Paulo; BrasilFil: Polachini, Giovana M.. No especifíca;Fil: Tiago, Tiago Henrique. No especifíca;Fil: Carlos H. T. P. da Silva. Universidade de Sao Paulo; BrasilFil: Feitosa, Olavo A.. Universidade de Sao Paulo; BrasilFil: Fukuyama, Erica E.. Arnaldo Vieira de Carvalho Cancer Institute; BrasilFil: López, Rossana V. M.. No especifíca;Fil: Dias Neto, Emmanuel. Universidade de Sao Paulo; BrasilFil: Nunes, Fabio D.. Universidade de Sao Paulo; BrasilFil: Severino, Patricia. Hospital Israelita Albert Einstein; BrasilFil: Tajara, Eloiza Helena Tajara. Universidade de Sao Paulo; Brasi

FGFR4 Profile as a Prognostic Marker in Squamous Cell Carcinoma of the Mouth and Oropharynx

Background: Fibroblast growth factor receptor 4 (FGFR4) is a member of a receptor tyrosine kinase family of enzymes involved in cell cycle control and proliferation. A common single nucleotide polymorphism (SNP) Gly388Arg variant has been associated with increased tumor cell motility and progression of breast cancer, head and neck cancer and soft tissue sarcomas. The present study evaluated the prognostic significance of FGFR4 in oral and oropharynx carcinomas, finding an association of FGFR4 expression and Gly388Arg genotype with tumor onset and prognosis. Patients and Methods: DNA from peripheral blood of 122 patients with oral and oropharyngeal squamous cell carcinomas was used to determine FGFR4 genotype by PCR-RFLP. Protein expression was assessed by immunohistochemistry (IHC) on paraffin-embedded tissue microarrays. Results: Presence of allele Arg388 was associated with lymphatic embolization and with disease related premature death. In addition, FGFR4 low expression was related with lymph node positivity and premature relapse of disease, as well as disease related death. Conclusion: Our results propose FGFR4 profile, measured by the Gly388Arg genotype and expression, as a novel marker of prognosis in squamous cell carcinoma of the mouth and oropharynx.FAPESPFAPESP [04/15022-0, 04/12054-9

Estimating genomic instability mediated by Alu retroelements in breast cancer

Alu-PCR is a relatively simple technique that can be used to investigate genomic instability in cancer. This technique allows identification of the loss, gain or amplification of gene sequences based on the analysis of segments between two Alu elements coupled with quantitative and qualitative analyses of the profiles obtained from tumor samples, surgical margins and blood. In this work, we used Alu-PCR to identify gene alterations in ten patients with invasive ductal breast cancer. Several deletions and insertions were identified, indicating genomic instability in the tumor and adjacent normal tissue. Although not associated with specific genes, the alterations, which involved chromosomal bands 1p36.23, 1q41, 11q14.3, 13q14.2, occurred in areas of well-known genomic instability in breast and other types of cancer. These results indicate the potential usefulness of Alu-PCR in identifying altered gene sequences in breast cancer. However, caution is required in its application since the Alu primer can produce non-specific amplification

Peripheral position of CCND1 and HER-2/neu oncogenes within chromosome territories in esophageal and gastric cancers non-related to amplification and overexpression

Interphase chromosomes have been shown to occupy discrete regions of the nucleus denominated chromosome territories (CTs), their active genes being preferentially positioned on the surfaces of these CTs, where they are accessible to transcriptional machinery. By means of FISH (Fluorescence in situ Hybridization), we analyzed the CCND1 and HER-2/neu gene positions within the CTs and their relationship with gene amplification and protein over-expression in esophageal and gastric cancers. The CCND1 and HER-2/Neu genes were more often positioned at the periphery (mean frequency of 60%-83%) of the CTs in tumor tissues of the esophagus and stomach. Moreover, this positioning revealed no association with either gene amplification or the protein over-expression status of these genes, although, in esophageal carcinoma, Kappa statistics showed a moderate agreement between amplification of the CCND1 gene (Kappa = 0.400) and its location within the CT, as well as with over-expression of the corresponding protein (Kappa = 0.444). Thus, our results suggest that gene positioning in interphase chromosomes does not follow a definitive pattern neither does it depend only on gene transcriptional activity. Apparently, this positioning could be both gene- and tissue-specific, and depends on other factors acting together, such as dense-gene, chromosome size, chromatin structure, and the level and stability of its expression.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP